Michaela Liedtke

All Publications

• Waldenstrom Macroglobulinemia/Lymphoplasmacytic Lymphoma, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology. Journal of the National Comprehensive Cancer Network : JNCCN Kumar, S. K., Callander, N. S., Adekola, K., Anderson, L. D., Baljevic, M., Baz, R., Campagnaro, E., Castillo, J. J., Costello, C., D'Angelo, C., Derman, B., Devarakonda, S., Elsedawy, N., Garfall, A., Godby, K., Hillengass, J., Holmberg, L., Htut, M., Huff, C. A., Hultcrantz, M., Kang, Y., Larson, S., Lee, H., Liedtke, M., Martin, T., Omel, J., Robinson, T., Rosenberg, A., Sborov, D., Schroeder, M. A., Sherbenou, D., Suvannasankha, A., Valent, J., Varshavsky-Yanovsky, A. N., Snedeker, J., Kumar, R. 2024; 22 (1D): e240001

  Abstract

  The treatment of Waldenstrom macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL) has evolved to include several new options. The NCCN Guidelines for WM/LPL provide a framework on which to base decisions regarding diagnosis, treatment, assessment of response to treatment, and follow-up of both newly diagnosed and previously treated WM/LPL.

  View details for DOI 10.6004/jnccn.2024.0001

  View details for PubMedID 38244272

• Implementation of a Pilot Clinic for Pediatric to Adult Cancer Survivorship Transitions. Journal of adolescent and young adult oncology Jin, A. H., Simon, P. J., Clayton, A., Benedict, C., Liedtke, M., Muffly, L., Schapira, L., Smith, S. M. 2023

  Abstract

  Childhood cancer survivors are recommended to have lifelong survivorship care, yet many become disengaged during pediatric to adult care transitions. We implemented a pilot clinic for adult survivors of pediatric or adolescent and young adult (AYA) leukemia transitioning to adult-focused survivorship care. The clinic featured AYA-specific care, bidirectional communication with primary care, and a quality improvement (QI) cycle. During the 1-year QI period, 27 patients were seen and 21 completed postvisit interviews. The clinic was positively received by patients and primary care providers, showed promise for improving self-management and care coordination, and highlighted the need for novel approaches to connect survivors with primary care.

  View details for DOI 10.1089/jayao.2023.0041

  View details for PubMedID 37615593

• Idecabtagene vicleucel for relapsed and refractory multiple myeloma: post hoc 18-month follow-up of a phase 1 trial. Nature medicine Lin, Y., Raje, N. S., Berdeja, J. G., Siegel, D. S., Jagannath, S., Madduri, D., Liedtke, M., Rosenblatt, J., Maus, M. V., Massaro, M., Petrocca, F., Yeri, A., Finney, O., Caia, A., Yang, Z., Martin, N., Campbell, T. B., Rytlewski, J., Fuller, J., Hege, K., Munshi, N. C., Kochenderfer, J. N. 2023

  Abstract

  Idecabtagene vicleucel (ide-cel) is a B-cell-maturation antigen (BCMA)-directed chimeric antigen receptor T cell therapy. We performed a post hoc analysis of a single-arm phase 1 multicenter study in relapsed/refractory multiple myeloma (CRB-401) (n = 62; median follow-up, 18.1 months). The primary endpoint was safety outcomes, and secondary endpoints included overall response rate (ORR), complete response (CR) and very good partial response (VGPR). The study met its primary endpoint with low rates of grade 3/grade 4 cytokine release syndrome (6.5%) and neurotoxicity (1.6%). ORR was 75.8%; 64.5% achieved VGPR or better and 38.7% achieved CR or stringent CR. Among exploratory endpoints, median duration of response, progression-free survival (PFS) and overall survival were 10.3, 8.8 and 34.2 months, respectively, and ide-cel expansion in blood and bone marrow correlated with clinical efficacy and postinfusion reduction of soluble BCMA. Patients with PFS ≥ 18 months had more naive and less exhausted T cells in apheresis material and improved functional T cell phenotype in the drug product compared with those with less durable responses. These results confirm ide-cel safety, tolerability and efficacy and describe T cell qualities that correlate with durable response. Clinicaltrials.gov identifier : NCT02658929 .

  View details for DOI 10.1038/s41591-023-02496-0

  View details for PubMedID 37592106

  View details for PubMedCentralID 8213772

• Birtamimab plus standard of care in light chain amyloidosis: the phase 3 randomized placebo-controlled VITAL trial. Blood Gertz, M. A., Cohen, A. D., Comenzo, R. L., Kastritis, E., Landau, H. J., Libby, E. N., Liedtke, M., Sanchorawala, V., Schonland, S., Wechalekar, A. D., Zonder, J. A., Palladini, G., Walling, J., Guthrie, S., Nie, C., Karp, C., Jin, Y., Kinney, G. G., Merlini, G. 2023

  Abstract

  Amyloid light chain (AL) amyloidosis is a rare, typically fatal disease characterized by accumulation of misfolded immunoglobulin light chains (LCs). Birtamimab is an investigational humanized monoclonal antibody designed to neutralize toxic LC aggregates and deplete insoluble organ-deposited amyloid via macrophage-induced phagocytosis. VITAL was a phase 3 randomized, double-blind, placebo-controlled clinical trial assessing the efficacy and safety of birtamimab + standard of care (SOC) in 260 newly diagnosed, treatment-naive patients with AL amyloidosis. Patients received 24 mg/kg intravenous birtamimab + SOC or placebo + SOC every 28 days. The primary composite endpoint was time to all-cause mortality (ACM) or centrally adjudicated cardiac hospitalization ≥91 days after first study drug infusion. The trial was terminated early after an interim futility analysis; there was no significant difference in the primary composite endpoint (hazard ratio [HR] = 0.826; 95% confidence interval [CI] 0.574-1.189; log-rank P = .303). A post hoc analysis in Mayo Stage IV patients, those at highest risk of early mortality, showed significant improvement in time to ACM with birtamimab at month 9 (HR = 0.413; 95% CI: 0.191-0.895; log-rank P = .021). At month 9, 74% of Mayo Stage IV patients treated with birtamimab and 49% of those given placebo survived. Overall, the rates of treatment-emergent adverse events (TEAEs) and serious TEAEs were generally similar between treatment arms. A confirmatory phase 3 randomized, double-blind, placebo-controlled clinical trial of birtamimab in patients with Mayo Stage IV AL amyloidosis (AFFIRM-AL; NCT04973137) is currently enrolling. The VITAL trial was registered at www.clinicaltrials.gov as #NCT02312206.

  View details for DOI 10.1182/blood.2022019406

  View details for PubMedID 37366170

• Enrolling patients in Cardiac Amyloid Reaching for Extended Survival (CARES) trials: Two placebo-controlled, double-blind, randomized, international phase 3 trials assessing CAEL-101 in patients with Mayo stage IIIa or stage IIIb AL amyloidosis. Liedtke, M., Palladini, G., Molina, M., Kastritis, E., Ianus, J., Catini, J., Quarta, C., Wechalekar, A. D., 301 & 302 Investigators LIPPINCOTT WILLIAMS & WILKINS. 2023

  View details for Web of Science ID 001053772005469

• Plasma cell leukemia: A multicenter retrospective study of 150 patients. Chineke, I., Wertheim, B. C., Roe, D., Larsen, A., Sborov, D. W., Vardell, V., Green, D., Degraff, D., Liedtke, M., Okoniewski, M., Wazir, M., Nadeem, O., Shubert, A., Silbermann, R., Schachter, L., Coffey, D., Schmidt, T., Brunner, M., Wong, S., Gowin, K. L. LIPPINCOTT WILLIAMS & WILKINS. 2023

  View details for Web of Science ID 001053772003532

• A phase II multi-arm study of magrolimab combinations in patients with relapsed/refractory multiple myeloma. Future oncology (London, England) Paul, B., Liedtke, M., Khouri, J., Rifkin, R., Gandhi, M. D., Kin, A., Levy, M. Y., Silbermann, R., Cottini, F., Sborov, D. W., Sandhu, I., Villarreal, L., Murphy, M., Gu, L., Chen, A., Rajakumaraswamy, N., Usmani, S. Z. 2023

  Abstract

  Magrolimab is a monoclonal antibody that blocks CD47, a 'do not eat me' signal overexpressed on tumor cells. CD47 is overexpressed in multiple myeloma (MM), which contributes to its pathogenesis. Preclinical studies have shown that CD47 blockade induces macrophage activation, resulting in elimination of myeloma cells, and that there is synergy between magrolimab and certain anticancer therapies. These findings suggest that magrolimab-based combinations may have a therapeutic benefit in MM. This phase II study investigates magrolimab in combination with commonly used myeloma therapies in patients with relapsed/refractory MM and includes a safety run-in phase followed by a dose-expansion phase. Primary end points include the incidence of dose-limiting toxicities and adverse events (safety run-in) and the objective response rate (dose expansion).

  View details for DOI 10.2217/fon-2022-0975

  View details for PubMedID 36779512

• Allogeneic BCMA-targeting CAR T cells in relapsed/refractory multiple myeloma: phase 1 UNIVERSAL trial interim results. Nature medicine Mailankody, S., Matous, J. V., Chhabra, S., Liedtke, M., Sidana, S., Oluwole, O. O., Malik, S., Nath, R., Anwer, F., Cruz, J. C., Htut, M., Karski, E. E., Lovelace, W., Dillon, M., Butz, E., Ying, W., Balakumaran, A., Kumar, S. K. 2023

  Abstract

  ALLO-715 is a first-in-class, allogeneic, anti-BCMA CAR T cell therapy engineered to abrogate graft-versus-host disease and minimize CAR T rejection. We evaluated escalating doses of ALLO-715 after lymphodepletion with an anti-CD52 antibody (ALLO-647)-containing regimen in 43 patients with relapsed/refractory multiple myeloma as part A of the ongoing first-in-human phase 1 UNIVERSAL trial. Primary objectives included determination of the safety and tolerability of ALLO-715 and the safety profile of the ALLO-647-containing lymphodepletion regimen. Key secondary endpoints were response rate and duration of response. Grade ≥3 adverse events were reported in 38 (88.0%) of patients. Cytokine release syndrome was observed in 24 patients (55.8%), with 1 grade ≥3 event (2.3%) and neurotoxicity in 6 patients (14%), with no grade ≥3 events. Infections occurred in 23 patients (53.5%), with 10 (23.3%) of grade ≥3. Overall, 24 patients (55.8%) had a response. Among patients treated with 320*106 CAR+ T cells and a fludarabine-, cyclophosphamide- and ALLO-647-based lymphodepletion regimen (n=24), 17 (70.8%) had a response including 11 (45.8%) with very good partial response or better and 6 (25%) with a complete response/stringent complete response. The median duration of response was 8.3months. These initial results support the feasibility and safety of allogeneic CAR T cell therapy for myeloma.

  View details for DOI 10.1038/s41591-022-02182-7

  View details for PubMedID 36690811

• Systemic Light Chain Amyloidosis, Version 2.2023, NCCN Clinical Practice Guidelines in Oncology. Journal of the National Comprehensive Cancer Network : JNCCN Kumar, S. K., Callander, N. S., Adekola, K., Anderson, L. D., Baljevic, M., Campagnaro, E., Castillo, J. J., Costello, C., D'Angelo, C., Devarakonda, S., Elsedawy, N., Garfall, A., Godby, K., Hillengass, J., Holmberg, L., Htut, M., Huff, C. A., Hultcrantz, M., Kang, Y., Larson, S., Lee, H. C., Liedtke, M., Martin, T., Omel, J., Rosenberg, A., Sborov, D., Valent, J., Berardi, R., Kumar, R. 2023; 21 (1): 67-81

  Abstract

  Primary systemic light chain amyloidosis (SLCA) is characterized by production of light chains that get converted to amyloid fibrils with an affinity for visceral organs and causing organ dysfunction. The therapy for SLCA is directed to recovering the function of the affected organs by targeting the abnormal plasma cell clone and slowing deposition of amyloid fibrils. The NCCN Guidelines for SLCA provide recommendations for workup, diagnosis, and treatment of primary as well as previously treated SLCA.

  View details for DOI 10.6004/jnccn.2023.0001

  View details for PubMedID 36652935

• Multiple Myeloma, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology. Journal of the National Comprehensive Cancer Network : JNCCN Kumar, S. K., Callander, N. S., Adekola, K., Anderson, L. D., Baljevic, M., Baz, R., Campagnaro, E., Castillo, J. J., Costello, C., D'Angelo, C., Devarakonda, S., Elsedawy, N., Garfall, A., Godby, K., Hillengass, J., Holmberg, L., Htut, M., Huff, C. A., Hultcrantz, M., Kang, Y., Larson, S., Lee, H. C., Liedtke, M., Martin, T., Omel, J., Robinson, T., Rosenberg, A., Sborov, D., Schroeder, M. A., Sherbenou, D., Suvannasankha, A., Valent, J., Varshavsky-Yanovsky, A. N., Kumar, R., Snedeker, J. 2023; 21 (12): 1281-1301

  Abstract

  The treatment of relapsed/refractory multiple myeloma (MM) has evolved to include several new options. These include new combinations with second generation proteasome inhibitors (PI); second generation immunomodulators, monoclonal antibodies, CAR T cells, bispecific antibodies, selinexor, venetoclax, and many others. Most patients with MM undergo several cycles of remissions and relapse, and therefore need multiple lines of combination therapies. Selecting treatment options for relapsed/refractory MM requires consideration of resistance status to specific classes, and patient-specific factors such as age and other comorbidities should be considered. The NCCN Guidelines for MM provide a framework on which to base decisions regarding workup, treatment, and follow-up of newly diagnosed and previously treated MM. This manuscript outlines the recommendations from NCCN Guidelines for MM specific to relapsed/refractory disease.

  View details for DOI 10.6004/jnccn.2023.0061

  View details for PubMedID 38081133

• Prevalence, mutational spectrum and clinical implications of clonal hematopoiesis of indeterminate potential in plasma cell dyscrasias. Seminars in oncology Testa, S., Kumar, J., Goodell, A. J., Zehnder, J. L., Alexander, K. M., Sidana, S., Arai, S., Witteles, R. M., Liedtke, M. 2022

  Abstract

  Clonal hematopoiesis of indeterminate potential (CHIP) is common both in healthy individuals and patients with hematological cancers. Recent studies have showed worse prognosis for patients with multiple myeloma (MM) and non-Hodgkin lymphoma undergoing stem cell transplant, that have concomitant presence of CHIP. Data regarding the clinical and biological role of CHIP in plasma cell dyscrasias (PCDs) is rapidly increasing. However, the prevalence and prognostic implication of CHIP in patients with MM outside of the transplant setting, and in those with other more indolent PCDs remains elusive. Here we explored the prevalence and clinical implications of CHIP detected through next-generation sequencing in 209 patients with PCDs including MM, light chain (AL) amyloidosis (ALA), monoclonal gammopathy of undetermined significance (MGUS), and smoldering multiple myeloma (SMM). To avoid attributing the mutations to the plasma cell clone, CHIP was defined as the presence of DNMT3A, TET2, or ASXL1 mutations in the peripheral blood or bone marrow (DTA-CH). The prevalence of DTA-CH was 19% in patients with PCDs, with no difference between each PCD. TET2 (23%) and DNMT3A (22%), were the most frequently mutated genes. DTA-CH correlated with older age in MM (P = .001) and MGUS/SMM (P = 0.0007), as well as with coronary artery disease or congestive heart failure in MM (P = .03). DTA-CH did not predict worse OS or PFS in either MM or ALA, nor it predict higher risk of progression to MM in patients with MGUS/SMM. Our results overall further elucidate the prevalence and mutational spectrum of CHIP in PCDs, providing more information regarding the clinical relevance of CHIP in this patient population.

  View details for DOI 10.1053/j.seminoncol.2022.11.001

  View details for PubMedID 36503855

• AL Amyloidosis for Cardiologists: Awareness, Diagnosis, and Future Prospects: JACC: CardioOncology State-of-the-Art Review. JACC. CardioOncology Wechalekar, A. D., Fontana, M., Quarta, C. C., Liedtke, M. 2022; 4 (4): 427-441

  Abstract

  Amyloid light chain (AL) amyloidosis is a rare, debilitating, often fatal disease. Symptoms of cardiomyopathy are common presenting features, and patients often are referred to cardiologists. Cardiac amyloid infiltration is the leading predictor of death. However, the variable presentation and perceived rarity of the disease frequently lead to delay in suspecting amyloidosis as a cause of heart failure, leading to misdiagnoses and a marked delay in diagnosis, with devastating consequences for the patient. A median time from symptom onset to correct diagnosis of about 2 years is often too long when median survival from diagnosis for patients with AL amyloidosis and cardiomyopathy is 4 months to 2 years. The authors highlight the challenges to diagnosis, identify gaps in the current knowledge, and summarize novel treatments on the horizon to raise awareness about the critical need for early recognition of symptoms and diagnosis of AL amyloidosis aimed at accelerating treatment and improving outcomes for patients.

  View details for DOI 10.1016/j.jaccao.2022.08.009

  View details for PubMedID 36444232

  View details for PubMedCentralID PMC9700258

• Real-world treatment patterns, costs, and outcomes in patients with AL amyloidosis: analysis of the Optum EHR and commercial claims databases. Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis Dispenzieri, A., Zonder, J., Hoffman, J., Wong, S. W., Liedtke, M., Abonour, R., D'Souza, A., Lee, C., Cote, S., Potluri, R., Ammann, E., Tran, N., Lam, A., Nair, S. 2022: 1-8

  Abstract

  BACKGROUND: This study characterised real-world treatment patterns, clinical outcomes, and cost-of-illness in patients with light-chain (AL) amyloidosis.METHODS: Data were extracted from the US-based Optum EHR and Clinformatics Data Mart (claims) databases (2008-2019) for patients newly diagnosed with AL amyloidosis and who initiated anti-plasma cell therapies. Healthcare resource utilisation (HCRU) and related costs were compared across lines of therapy (LOT). Incidences of cardiac and renal failure were evaluated using the Kaplan-Meier method.RESULTS: About 1347 patients (EHR, n=776; claims, n=571) were included. Median age was 68years; 56.8% were male. At initial diagnosis, 33.1% and 15.1% of patients had cardiac and renal failure, respectively. Most patients received bortezomib-containing treatment in LOT1 (69%); bortezomib-cyclophosphamide-dexamethasone was most common (26%). HCRU was similar across LOTs. Mean per-patient-per-month and per-patient-per-LOT costs were $19,343 and $105,944 for LOT1, $19,183 and $95,793 for LOT2, and $16,611 and $128,446 for LOT3, respectively. Costs were primarily driven by anti-plasma cell therapies, outpatient visits, and hospitalisations. The 5-year cardiac and renal failure rates following initial diagnosis were 64.5% and 39.0%, respectively.CONCLUSION: AL amyloidosis is associated with substantial costs and suboptimal outcomes, highlighting the need for new therapeutic approaches to prevent organ deterioration, and reduce disease burden.

  View details for DOI 10.1080/13506129.2022.2137400

  View details for PubMedID 36282014

• The impact of early PEG-asparaginase discontinuation in young adults with ALL: A post hoc analysis of the C10403 study. Blood advances Aldoss, I., Yin, J., Wall, A., Mrozek, K., Liedtke, M., Claxton, D., Foster, M. C., Appelbaum, F. R., Erba, H. P., Litzow, M. R., Tallman, M. S., Stone, R. M., Larson, R. A., Advani, A. S., Stock, W., Luger, S. M. 2022

  Abstract

  Asparaginase is a key component of pediatric-inspired regimens in young adults with acute lymphoblastic leukemia (ALL). Truncation of asparaginase therapy is linked to inferior outcomes in children with ALL. However, similar correlation in adults is lacking. Here, we studied the prevalence and risk factors associated with pegylated (PEG)-asparaginase discontinuation in young adults with ALL treated on the US intergroup CALGB 10403 study and examined the prognostic impact of early discontinuation (ED) (defined as <4 of 5 or 6 planned doses) on survival outcomes. The analysis included 176 patients who achieved complete remission and initiated the delayed intensification (DI) cycle. The median number of PEG-asparaginase doses administered before DI was 5 (range: 1-6), with 57 (32%) patients with early discontinuation. The ED patients were older (median=26 vs. 23 years; P=0.023). Survival was apparently lower for ED patients compared with those receiving =/> 4 doses, but this finding was not statistically significant (HR=1.82; 95%CI: 0.97-3.43, P=0.06), with corresponding 5-year OS rates of 66% and 80%, respectively. In patients with standard-risk ALL, the early discontinuation of PEG-asparaginase adversely influenced OS (HR=2.3; 95%CI: 1.02-5.22, P=0.04) with a trend toward inferior EFS (HR=1.84; 95%CI: 0.92-3.67, P=0.08). In contrast, there was no impact of early PEG-asparaginase discontinuation on OS (P=0.64) or EFS (P=0.32) in patients with high-risk disease based on the presence of high-risk cytogenetics, Ph-like genotype, and/or high WBC at presentation. In conclusion, early PEG-asparaginase discontinuation is common in young adults with ALL and may adversely impact survival of patients with standard-risk ALL.

  View details for DOI 10.1182/bloodadvances.2022007791

  View details for PubMedID 36269846

• Graded Cardiac Response Criteria for Patients With Systemic Light Chain Amyloidosis. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Muchtar, E., Dispenzieri, A., Wisniowski, B., Palladini, G., Milani, P., Merlini, G., Schonland, S., Veelken, K., Hegenbart, U., Geyer, S. M., Kumar, S. K., Kastritis, E., Dimopoulos, M. A., Liedtke, M., Witteles, R., Sanchorawala, V., Szalat, R., Landau, H., Petrlik, E., Lentzsch, S., Coltoff, A., Blade, J., Cibeira, M. T., Cohen, O., Foard, D., Wechalekar, A., Gertz, M. A. 2022: JCO2200643

  Abstract

  PURPOSE: Binary cardiac response assessment using cardiac biomarkers is prognostic in light chain amyloidosis. Previous studies suggested four-level cardiac responses using N-terminal prohormone of brain natiuretic peptide improves prognostic prediction. This study was designed to validate graded cardiac response criteria using N-terminal prohormone of brain natiuretic peptide/brain natiuretic peptide.PATIENTS AND METHODS: This retrospective, multicenter study included patients with light chain amyloidosis who achieved at least a hematologic partial response (PR) and were evaluable for cardiac response. Four response criteria were tested on the basis of natriuretic peptide response depth: cardiac complete response (CarCR), cardiac very good partial response (CarVGPR), cardiac PR (CarPR), and cardiac no response (CarNR). Response was classified as best response and at fixed time points (6, 12, and 24 months from therapy initiation). The study primary outcome was overall survival.RESULTS: 651 patients were included. Best CarCR, CarVGPR, CarPR, and CarNR were achieved in 16%, 26.4%, 22.9%, and 34.7% of patients, respectively. Patients in cardiac stage II were more likely to achieve CarCR than patients in cardiac stage IIIA and IIIB (22% v 13.5% v 3.2%; P < .001). A deeper cardiac response was associated with a longer survival (5-year overall survival 93%, 79%, 65%, and 33% for CarCR, CarVGPR, CarPR, and CarNR, respectively; P < .001). Fixed time-point analyses and time-varying covariates Cox regression analysis, to minimize survivorship bias, affirmed the independent survival advantage of deeper cardiac responses. Four-level response performed better than two-level response as early as 12 months from therapy initiation.CONCLUSION: Graded cardiac response criteria allow better assessment of cardiac improvement compared with the traditional binary response system. The study re-emphasizes the importance of early diagnosis, which increases the likelihood of deep cardiac responses.

  View details for DOI 10.1200/JCO.22.00643

  View details for PubMedID 36215675

• Developing high-affinity decoy receptors to treat multiple myeloma and diffuse large B cell lymphoma. The Journal of experimental medicine Miao, Y. R., Thakkar, K., Cenik, C., Jiang, D., Mizuno, K., Jia, C., Li, C. G., Zhao, H., Diep, A., Xu, Y., Zhang, X. E., Yang, T. T., Liedtke, M., Abidi, P., Leung, W., Koong, A. C., Giaccia, A. J. 2022; 219 (9)

  Abstract

  Disease relapse and treatment-induced immunotoxicity pose significant clinical challenges for patients with hematological cancers. Here, we reveal distinctive requirements for neutralizing TNF receptor ligands APRIL and BAFF and their receptor activity in MM and DLBCL, impacting protein translation and production in MM cells and modulating the translation efficiency of the ATM interactor (ATMIN/ACSIZ). Therapeutically, we investigated the use of BCMA decoy receptor (sBCMA-Fc) as an inhibitor of APRIL and BAFF. While wild-type sBCMA-Fc effectively blocked APRIL signaling in MM, it lacked activity in DLBCL due to its weak BAFF binding. To expand the therapeutic utility of sBCMA-Fc, we engineered an affinity-enhanced mutant sBCMA-Fc fusion molecule (sBCMA-Fc V3) 4- and 500-fold stronger in binding to APRIL and BAFF, respectively. The mutant sBCMA-Fc V3 clone significantly enhanced antitumor activity against both MM and DLBCL. Importantly, we also demonstrated an adequate toxicity profile and on-target mechanism of action in nonhuman primate studies.

  View details for DOI 10.1084/jem.20220214

  View details for PubMedID 35881112

• Triplet Therapy, Transplantation, and Maintenance until Progression in Myeloma. The New England journal of medicine Richardson, P. G., Jacobus, S. J., Weller, E. A., Hassoun, H., Lonial, S., Raje, N. S., Medvedova, E., McCarthy, P. L., Libby, E. N., Voorhees, P. M., Orlowski, R. Z., Anderson, L. D., Zonder, J. A., Milner, C. P., Gasparetto, C., Agha, M. E., Khan, A. M., Hurd, D. D., Gowin, K., Kamble, R. T., Jagannath, S., Nathwani, N., Alsina, M., Cornell, R. F., Hashmi, H., Campagnaro, E. L., Andreescu, A. C., Gentile, T., Liedtke, M., Godby, K. N., Cohen, A. D., Openshaw, T. H., Pasquini, M. C., Giralt, S. A., Kaufman, J. L., Yee, A. J., Scott, E., Torka, P., Foley, A., Fulciniti, M., Hebert, K., Samur, M. K., Masone, K., Maglio, M. E., Zeytoonjian, A. A., Nadeem, O., Schlossman, R. L., Laubach, J. P., Paba-Prada, C., Ghobrial, I. M., Perrot, A., Moreau, P., Avet-Loiseau, H., Attal, M., Anderson, K. C., Munshi, N. C., DETERMINATION Investigators 2022

  Abstract

  BACKGROUND: In patients with newly diagnosed multiple myeloma, the effect of adding autologous stem-cell transplantation (ASCT) to triplet therapy (lenalidomide, bortezomib, and dexamethasone [RVD]), followed by lenalidomide maintenance therapy until disease progression, is unknown.METHODS: In this phase 3 trial, adults (18 to 65 years of age) with symptomatic myeloma received one cycle of RVD. We randomly assigned these patients, in a 1:1 ratio, to receive two additional RVD cycles plus stem-cell mobilization, followed by either five additional RVD cycles (the RVD-alone group) or high-dose melphalan plus ASCT followed by two additional RVD cycles (the transplantation group). Both groups received lenalidomide until disease progression, unacceptable side effects, or both. The primary end point was progression-free survival.RESULTS: Among 357 patients in the RVD-alone group and 365 in the transplantation group, at a median follow-up of 76.0 months, 328 events of disease progression or death occurred; the risk was 53% higher in the RVD-alone group than in the transplantation group (hazard ratio, 1.53; 95% confidence interval [CI], 1.23 to 1.91; P<0.001); median progression-free survival was 46.2 months and 67.5 months. The percentage of patients with a partial response or better was 95.0% in the RVD-alone group and 97.5% in the transplantation group (P=0.55); 42.0% and 46.8%, respectively, had a complete response or better (P=0.99). Treatment-related adverse events of grade 3 or higher occurred in 78.2% and 94.2%, respectively; 5-year survival was 79.2% and 80.7% (hazard ratio for death, 1.10; 95% CI, 0.73 to 1.65).CONCLUSIONS: Among adults with multiple myeloma, RVD plus ASCT was associated with longer progression-free survival than RVD alone. No overall survival benefit was observed. (Funded by the National Heart, Lung, and Blood Institute and others; DETERMINATION ClinicalTrials.gov number, NCT01208662.).

  View details for DOI 10.1056/NEJMoa2204925

  View details for PubMedID 35660812

• Multiple Myeloma, Version 3.2022 Featured Updates to the NCCN Guidelines JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Callander, N. S., Baljevic, M., Adekola, K., Anderson, L. D., Campagnaro, E., Castillo, J. J., Costello, C., Devarakonda, S., Elsedawy, N., Faiman, M., Garfall, A., Godby, K., Hillengass, J., Holmberg, L., Htut, M., Huff, C., Hultcrantz, M., Kang, Y., Larson, S., Liedtke, M., Martin, T., Omel, J., Sborov, D., Shain, K., Stockerl-Goldstein, K., Weber, D., Berardi, R. A., Kumar, R., Kumar, S. K. 2022; 20 (1): 9-19

  Abstract

  The NCCN Guidelines for Multiple Myeloma provide recommendations for diagnosis, initial workup, treatment, follow-up, and supportive care for patients with various plasma cell neoplasms, including multiple myeloma. These NCCN Guidelines Insights highlight some of the important updates/changes specific to the treatment of patients with multiple myeloma in the 2022 version of the guidelines.

  View details for DOI 10.6004/jnccn.2022.0002

  View details for Web of Science ID 000807390300006

  View details for PubMedID 34991075

• Case Report: Mature Plasmacytoid Dendritic Cell Proliferation Associated With a Lymphoid Neoplasm. Frontiers in oncology Fei, F., Liedtke, M., Silva, O. 2022; 12: 903113

  Abstract

  Mature plasmacytoid dendritic cell proliferations (MPDCPs) are clonal, non-malignant pDC proliferations that have been reported to occur in association with myeloid neoplasms such as CMML, AML (pDC-AML), and, rarely, MDS or MPNs. Here we report the first case of a MPDCP associated with T-lymphoblastic leukemia (T-ALL), a lymphoid neoplasm. The MPDCP in this case involved ~50% of the bone marrow, was found in nodular aggregates, expressed CD123, CD4, and CD303, and lacked CD56 and TCL1 expression. In addition, the MPDCP lacked CD34 and TdT but showed aberrant expression of CD7, CD5, CD10, and CD13, markers expressed by the abnormal T-lymphoblastic cells. Mutational analysis demonstrated mutations in JAK3, NOTCH1, NRAS, KRAS, DNMT3A, and SH2B3 but no mutations in TET2, ASLX1 or ZRSR2. Analysis of the pDC frequency in a separate cohort of T-ALL and control patients demonstrated that bone marrow pDCs are often decreased in patients with T-ALL compared to controls. This is the first report of a MPDCP associated with a lymphoid neoplasm and provides further support that MPDCP can arise from a multipotent hematopoietic progenitor with lymphoid and dendritic cell potential.

  View details for DOI 10.3389/fonc.2022.903113

  View details for PubMedID 35875095

• Treatment outcomes of triple class refractory multiple myeloma: a benchmark for new therapies. Leukemia Bal, S., Malek, E., Kansagra, A., Usmani, S. Z., Vij, R., Godby, K. N., Cornell, R. F., Kang, Y., Umyarova, E., Giri, S., Chhabra, S., Liedtke, M., Callander, N. S., Hari, P., Kumar, S., Costa, L. J. 2021

  View details for DOI 10.1038/s41375-021-01471-3

  View details for PubMedID 34802043

• Comparison of Cilta-cel, an Anti-BCMA CAR-T Cell Therapy, Versus Conventional Treatment in Patients With Relapsed/Refractory Multiple Myeloma. Clinical lymphoma, myeloma & leukemia Costa, L. J., Lin, Y., Cornell, R. F., Martin, T., Chhabra, S., Usmani, S. Z., Jagannath, S., Callander, N. S., Berdeja, J. G., Kang, Y., Vij, R., Godby, K. N., Malek, E., Neppalli, A., Liedtke, M., Fiala, M., Tian, H., Valluri, S., Marino, J., Jackson, C. C., Banerjee, A., Kansagra, A., Schecter, J. M., Kumar, S., Hari, P. 2021

  Abstract

  BACKGROUND: In the single-arm, phase 1b/2 CARTITUDE-1 study, ciltacabtagene autoleucel (cilta-cel), an anti-B-cell maturation antigen chimeric antigen receptor T-cell (CAR-T) therapy, showed encouraging efficacy in US patients with multiple myeloma (MM) who previously received an immunomodulatory drug, proteasome inhibitor, and anti-CD38 monoclonal antibody (triple-class exposed).PATIENTS AND METHODS: A dataset of US patients refractory to an anti-CD38 monoclonal antibody (MAMMOTH) was used to identify patients who would meet eligibility for CARTITUDE-1 and received subsequent non-CAR-T therapy. The intent-to-treat (ITT) population in CARTITUDE-1 included patients who underwent apheresis (N=113); the modified ITT (mITT) population was the subset who received cilta-cel (n=97). Corresponding populations were identified from the MAMMOTH dataset: ITT population (n=190) and mITT population of patients without progression/death within 47 days (median apheresis-to-cilta-cel infusion time) from onset of therapy (n=122). Using 1:1 nearest neighbor propensity score matching to control for selected baseline covariates, 95 and 69 patients in CARTITUDE-1 ITT and mITT populations, respectively, were matched to MAMMOTH patients.RESULTS: In ITT cohorts of CARTITUDE-1 vs. MAMMOTH, improved overall response rate (ORR; 84% vs. 28% [P < .001]) and longer progression-free survival (PFS; hazard ratio [HR], 0.11 [95% confidence interval (CI), 0.05-0.22]) and overall survival (OS; HR, 0.20 [95% CI, 0.10-0.39]) were observed. Similar results were seen in mITT cohorts of CARTITUDE-1 vs. MAMMOTH (ORR: 96% vs. 30% [P < .001]; PFS: HR, 0.02 [95% CI, 0.01-0.14]; OS: HR, 0.05 [95% CI, 0.01-0.22]) and with alternative matching methods.CONCLUSION: Cilta-cel yielded significantly improved outcomes versus real-world therapies in triple-class exposed patients with relapsed/refractory MM.

  View details for DOI 10.1016/j.clml.2021.10.013

  View details for PubMedID 34840088

• Triple-class refractory disease as a modern therapeutic benchmark for clinical trials testing new agents for relapsed refractory Multiple Myeloma Malek, E., Kansagra, A., Costa, L., Usmani, S. Z., Vij, R., Kumar, S., Godby, K., Bal, S., Cornell, R., Kang, Y., Umyarova, E., Giri, S., Chhabra, S., Callander, N. S., Hari, P., Liedtke, M. CIG MEDIA GROUP, LP. 2021: S148-S149

  View details for Web of Science ID 000717640800255

• A Phase 2 Multi-Arm Study of Magrolimab Combinations in Patients with Relapsed/Refractory Multiple Myeloma Paul, B., Liedtke, M., Monge, J., Chaudhry, M., Rifkin, R., Gandhi, M., Khouri, J., Kin, A., Kovacsovics, T., Levy, M., Mohrbacher, A., Schmidt, W., Siegel, D. S., Silbermann, R., Byrne, A., Ncube, T., Murphy, M., Gu, L., Rajakumaraswamy, N., Chao, M., Usmani, S. WILEY. 2021: S11-S13

  View details for Web of Science ID 000707408900014

• Dasatinib and dexamethasone followed by hematopoietic cell transplantation for adults with Ph-positive ALL. Blood advances Wieduwilt, M. J., Yin, J., Wetzler, M., Uy, G. L., Powell, B. L., Kolitz, J. E., Liedtke, M., Stock, W., Beumer, J. H., Mattison, R. J., Storrick, E., Christner, S. M., Lewis, L. D., Devine, S. M., Stone, R. M., Larson, R. A. 2021

  Abstract

  Post-remission strategies after dasatinib-corticosteroid induction in adults with Ph-positive acute lymphoblastic leukemia (ALL) are not well studied. We evaluated the feasibility and efficacy of dasatinib and dexamethasone induction then protocol-defined post-remission therapies, including hematopoietic cell transplantation (HCT). Adults (N=65) with Ph-positive ALL received dasatinib and dexamethasone induction, methotrexate-based central nervous system (CNS) prophylaxis, reduced-intensity conditioning (RIC) allogeneic HCT, autologous HCT, or chemotherapy alone based on age and donor availability, and dasatinib-based maintenance. Key efficacy endpoints were disease-free survival (DFS) and overall survival (OS). The median age was 60 years (range, 22-87). The complete remission rate was 98.5%. With a median follow up of 59 months, 5-year DFS and OS were 37% (median, 30 months) and 48% (median, 56 months), respectively. For patients receiving RIC allogeneic HCT, autologous HCT, or chemotherapy, 5-year DFSs were 49%, 29%, and 34% and 5-year OSs were 62%, 57%, and 46%, respectively. Complete molecular response rate after CNS prophylaxis was 40%. Relative to the p190 isoform, p210 had shorter DFS (median 10 vs 34 months, P=0.002) and OS (median 16 months vs not reached, P=0.05). Relapse occurred in 25% of allogeneic HCT, 57% of autologous HCT, and 36% of chemotherapy patients. T315I mutation was detected in 6 of 8 marrow relapses. Dasatinib CNS concentrations were low. Dasatinib and dexamethasone followed by RIC allogeneic HCT, autologous HCT, or chemotherapy was feasible and efficacious, especially with RIC allogeneic HCT. Future studies should address the major causes of treatment failure: T315I mutation, the p210 BCR-ABL1 isoform, and CNS relapse.

  View details for DOI 10.1182/bloodadvances.2021004813

  View details for PubMedID 34492682

• A phase 1b dose-escalation/expansion study of BET inhibitor RO6870810 in patients with advanced multiple myeloma. Blood cancer journal Ramasamy, K., Nooka, A., Quach, H., Htut, M., Popat, R., Liedtke, M., Tuchman, S. A., Laubach, J., Gasparetto, C., Chanan-Khan, A., Hertzberg, M., deMario, M., Nueesch, E., Chesne, E., Franjkovic, I., Lechner, K., Kornacker, M., Cho, H. J. 2021; 11 (9): 149

  View details for DOI 10.1038/s41408-021-00545-w

  View details for PubMedID 34480019

• Structural changes of corneal epithelium in belantamab-associated superficial keratopathy using anterior segment optical coherence tomography. American journal of ophthalmology case reports Matsumiya, W., Karaca, I., Ghoraba, H., Akhavanrezayat, A., Mobasserian, A., Hassan, M., Regenold, J., Yasar, C., Liedtke, M., Kitazawa, K., Nguyen, Q. D. 2021; 23: 101133

  Abstract

  Purpose: To describe structural changes in corneal epithelium using anterior segment optical coherence tomography (AS-OCT) in two relapsed and refractory multiple myeloma (RRMM) patients with bilateral belantamab-associated superficial keratopathy (BASK).Observations case 1: A 56-year-old male who was diagnosed with RRMM and initiated on belantamab mafodotin, presented on day 42 (three weeks after the second infusion) with decreased pinhole visual acuity from 20/20 and 20/25 to 20/70 and 20/50 in the right eye and left eye, respectively. Slit-lamp examination revealed moderate superficial keratopathy with microcystic-like epithelial changes (MECs) in the paracentral cornea in both eyes. AS-OCT demonstrated increased bilateral heterogeneous signal intensity and hyperreflective lesions as well as increased thickness in the paracentral corneal epithelium with uninvolved central cornea. Given bilateral MECs, the third infusion was withheld, and then given on day 62 after five weeks of drug-free interval. Although MECs had improved on day 82, pinhole visual acuity remained at 20/50 and 20/40 in the right eye and the left eye. AS-OCT showed that hyperreflective lesions mostly resolved and corneal epithelial thickness returned to baseline, despite a slightly increased persisting heterogeneous signal intensity in the peripheral corneal epithelium in both eyes.Case 2: A 77-year-old male with RRMM was started on belantamab mafodotin infusions. His pinhole visual acuity decreased from 20/40 and 20/30 at baseline to 20/60 and 20/40 on day 41 (three weeks after the second infusion) in the right eye and left eye, respectively. Slit-lamp examination showed diffuse, moderate MECs in both eyes, which was more severe in the peripheral cornea. AS-OCT demonstrated increased bilateral heterogeneous signal intensity and hyperreflective lesions in the corneal epithelium, which are more severe in the right eye along with increased corneal epithelial thickness. Therefore, belantamab mafodotin was withheld.Conclusions and Impotance: AS-OCT objectively demonstrated structural changes such as signal intensity and thickness alterations with hyperreflective lesions in the corneal epithelium related to BASK. AS-OCT might be useful for clinicians to monitor ocular surface adverse events in RRMM patients receiving belantamab mafodotin and to adjust therapeutic plans for the patients.

  View details for DOI 10.1016/j.ajoc.2021.101133

  View details for PubMedID 34169181

• Concordance of peripheral blood and bone marrow measurable residual disease in adult acute lymphoblastic leukemia. Blood advances Muffly, L., Sundaram, V., Chen, C., Yurkiewicz, I., Kuo, E., Burnash, S., Spiegel, J. Y., Arai, S., Frank, M. J., Johnston, L. J., Lowsky, R., Meyer, E. H., Negrin, R. S., Rezvani, A. R., Sidana, S., Shiraz, P., Shizuru, J. A., Weng, W., Liedtke, M., Vempaty, H. T., Miklos, D. B. 2021; 5 (16): 3147-3151

  Abstract

  Monitoring of measurable residual disease (MRD) is essential to the management of acute lymphoblastic leukemia (ALL) and is typically performed through repeated bone marrow (BM) assessments. Using a next-generation sequencing (NGS) MRD platform, we performed a prospective observational study evaluating the correlation between peripheral blood (PB) and BM MRD in adults with ALL receiving cellular therapies (hematopoietic cell transplantation [HCT] and chimeric antigen receptor T-cell [CAR-T] therapies). Among the study cohort (N = 69 patients; 126 paired PB/BM samples), we found strong correlation between PB and BM MRD (r = 0.87; P < .001), with a sensitivity and specificity of MRD detection in the PB of 87% and 90%, respectively, relative to MRD in the BM. MRD became detectable in the PB in 100% of patients who subsequently relapsed following HCT, with median time from MRD+ to clinical relapse of 90 days, and in 85% of patients who relapsed following CAR T, with median time from MRD+ to clinical relapse of 60 days. In adult patients with ALL undergoing cellular therapies, we demonstrate strong concordance between NGS-based MRD detected in the PB and BM. Monitoring of ALL MRD in the PB appears to be an adequate alternative to frequent invasive BM evaluations in this clinical setting.

  View details for DOI 10.1182/bloodadvances.2021004234

  View details for PubMedID 34424318

• Outcomes after delayed and second autologous stem cell transplant in patients with relapsed multiple myeloma. Bone marrow transplantation Lemieux, C., Muffly, L. S., Iberri, D. J., Craig, J. K., Johnston, L. J., Lowsky, R., Shiraz, P., Rezvani, A. R., Frank, M. J., Weng, W., Meyer, E., Shizuru, J. A., Arai, S., Liedtke, M., Negrin, R. S., Miklos, D. B., Sidana, S. 2021

  Abstract

  We evaluated the outcomes of 168 patients undergoing delayed or second autologous stem cell transplant (ASCT) for relapsed multiple myeloma (MM) from 2010 to 2019. Overall, 21% (n=35) patients had received a prior transplant and 69% (n=116) underwent transplant at first relapse. Overall, 27% patients had high-risk cytogenetics and 15% had ISS stage III disease. Stem cell collection was performed after relapse in 72% and 35% of patients received maintenance therapy. Median PFS from salvage treatment and transplant were 28 and 19 months, respectively. Median OS from salvage treatment and transplant was 69 and 55 months. Multivariate analysis revealed that ASCT in first relapse was associated with superior PFS (HR 0.63, p=0.03) and OS (HR 0.59, p=0.04) compared to later lines of therapy. In addition, PFS of ≥36 months with prior therapy was associated with improved PFS (HR 0.62, p=0.04) and OS (HR 0.41, p=0.01). Ninety-five patients underwent delayed transplant at first relapse, median PFS and OS from start of therapy was 30 and 69 months, and median OS from diagnosis was 106 months. These data may serve as a guide when counseling patients undergoing ASCT for relapsed MM and provide a benchmark in designing clinical trials of transplantation/comparative treatments for relapsed MM.

  View details for DOI 10.1038/s41409-021-01371-1

  View details for PubMedID 34163014

• Event free survival in adults with relapsed ALL who underwent front-line therapy with CALGB 10403. Raychaudhuri, S., Yurkiewicz, I., Mannis, G. N., Medeiros, B. C., Coutre, S. E., Muffly, L. S., Liedtke, M. LIPPINCOTT WILLIAMS & WILKINS. 2021

  View details for DOI 10.1200/JCO.2021.39.15_suppl.e19005

  View details for Web of Science ID 000708120304096

• Multi-institutional study evaluating clinical outcome with allogeneic hematopoietic stem cell transplantation after blinatumomab in patients with B-cell acute lymphoblastic leukemia: real-world data. Bone marrow transplantation Badar, T., Szabo, A., Litzow, M., Burkart, M., Yurkiewicz, I., Dinner, S., Hefazi, M., Shallis, R. M., Podoltsev, N., Patel, A. A., Curran, E., Wadleigh, M., Balasubramanian, S., Yang, J., Arslan, S., Aldoss, I., Mattison, R., Cenin, D., Siebenaller, C., Advani, A., Liedtke, M., Atallah, E. 2021

  Abstract

  Safety and efficacy of allogeneic hematopoietic stem cell transplantation (alloHCT) consolidation after blinatumomab is largely undetermined. To address this issue, we assembled multi-center data of relapsed refractory (RR) acute lymphocytic leukemia (ALL) patients who received alloHCT after blinatumomab. From December 2014 to May 2019, 223 patients who received blinatumomab for RR ALL outside clinical trials were identified. Among them, 106 (47%) patients transplanted post blinatumomab were evaluated for response and toxicity. Ninety-two (87%) patients received alloHCT after achieving CR, while remaining received subsequent salvage prior to undergoing alloHCT. Progression free survival (PFS) and overall survival (OS) at 2 years post alloHCT was 48% (95% CI: 36-59%) and 58% (95% CI: 45-69%), respectively. The cumulative incidence of GIII-IV aGVHD at 3 months was 9.9% (95% CI: 5.0-16.6%). Similarly, cumulative incidence of moderate to severe cGVHD at 2 years was 34.4% (95% CI: 23.7-45.3%). The overall survival at 2 years was not significantly different in patient who achieved CR with MRD negative (68.4% [95% CI: 28.5-89.1%]) compared to CR with MRD positive (63.4% [95% CI: 47.8-75.4%]) prior to alloHCT (p=0.8). Our real-world analysis suggests that alloHCT is feasible and effective post blinatumomab in patients with RR ALL.

  View details for DOI 10.1038/s41409-021-01279-w

  View details for PubMedID 33824440

• Avoiding Catastrophe: Understanding Free Light Chain Testing in the Evaluation of ATTR Amyloidosis. Circulation. Heart failure Witteles, R. M., Liedtke, M. 2021: CIRCHEARTFAILURE120008225

  View details for DOI 10.1161/CIRCHEARTFAILURE.120.008225

  View details for PubMedID 33736459

• Comparison of CALGB 10403 (Alliance) and COG AALL0232 toxicity results in young adults with acute lymphoblastic leukemia. Blood advances Advani, A. S., Larsen, E., Laumann, K., Luger, S. M., Liedtke, M., Devidas, M., Chen, Z., Yin, J., Foster, M. C., Claxton, D., Coffan, K., Tallman, M. S., Appelbaum, F. R., Erba, H., Stone, R. M., Hunger, S. P., McNeer, J. L., Loh, M. L., Raetz, E., Winick, N., Carroll, W., Larson, R. A., Stock, W. 2021; 5 (2): 504–12

  Abstract

  Adolescents and young adults (AYAs) with acute lymphoblastic leukemia have improved outcomes when treated with pediatric-inspired regimens. CALGB 10403 was the largest prospective study to evaluate the feasibility of using a pediatric regimen in AYAs with acute lymphoblastic leukemia up to 40 years of age. This article presents the toxicity events observed in the CALGB 10403 study and compares these toxicities vs those observed among AYAs treated on the same arm of the companion Children's Oncology Group (COG) AALL0232 study. Toxicities in CALGB 10403 were similar to those observed in COG AALL0232. Some grade 3 to 4 adverse events were more often reported in CALGB 10403 compared with COG AALL0232 (hyperglycemia, hyperbilirubinemia, transaminase elevation, and febrile neutropenia). Adverse events correlated with body mass index ≥30 kg/m2 and some with increasing age. The mortality rate in CALGB 10403 was low (4%) and similar to that in the COG AALL0232 trial. A caveat to this analysis is that only 39% of CALGB 10403 patients completed all planned protocol treatment. In COG AALL0232, although 74% of patients aged <18 years completed treatment, only 57% of patients aged ≥18 years completed treatment. This scenario suggests that issues associated with age and treating physician may be a factor. Due to its improved survival rates compared with historical controls, the CALGB 10403 regimen is now a standard of care. The hope is that the rate of protocol completion will increase as more familiarity is gained with this regimen. These trials were registered at www.clinicaltrials.gov as #NCT00558519 (CALGB 10403) and #NCT00075725 (COG AALL0232).

  View details for DOI 10.1182/bloodadvances.2020002439

  View details for PubMedID 33496745

• Venetoclax induces deep hematologic remissions in t(11;14) relapsed/refractory AL amyloidosis. Blood cancer journal Premkumar, V. J., Lentzsch, S., Pan, S., Bhutani, D., Richter, J., Jagannath, S., Liedtke, M., Jaccard, A., Wechalekar, A. D., Comenzo, R., Sanchorawala, V., Royer, B., Rosenzweig, M., Valent, J., Schonland, S., Fonseca, R., Wong, S., Kapoor, P. 2021; 11 (1): 10

  Abstract

  Venetoclax is efficacious in relapsed/refractory t(11;14) multiple myeloma, thus warranting investigation in light-chain amyloidosis (AL). This retrospective cohort includes 43 patients with previously treated AL, from 14 centers in the US and Europe. Thirty-one patients harbored t(11;14), 11 did not, and one t(11;14) status was unknown. Patients received a venetoclax-containing regimen for at least one 21- or 28-day cycle; the median prior treatments was three. The hematologic response rate for all patients was 68%; 63% achieved VGPR/CR. t(11;14) patients had higher hematologic response (81% vs. 40%) and higher VGPR/CR rate (78% vs. 30%, odds ratio: 0.12, 95% CI 0.02-0.62) than non-t(11;14) patients. For the unsegregated cohort, median progression-free survival (PFS) was 31.0 months and median OS was not reached (NR). For t(11;14), median PFS was NR and for non-t(11;14) median PFS was 6.7 months (HR: 0.14, 95% CI 0.04-0.53). Multivariate analysis incorporating age, sex, prior lines of therapy, and disease stage suggested a risk reduction for progression or death in t(11;14) patients. Median OS was NR for either subgroup. The organ response rate was 38%; most responders harbored t(11;14). Grade 3 or higher adverse events occurred in 19% with 7% due to infections. These promising results require confirmation in a randomized clinical trial.

  View details for DOI 10.1038/s41408-020-00397-w

  View details for PubMedID 33431806

• Routine use of gemtuzumab ozogamicin in 7 + 3-based inductions for all 'non-adverse' risk AML. Leukemia & lymphoma Ladha, A. n., Hui, G. n., Cheung, E. n., Berube, C. n., Coutre, S. E., Gotlib, J. n., Liedtke, M. n., Zhang, T. Y., Muffly, L. n., Mannis, G. N. 2021: 1–6

  View details for DOI 10.1080/10428194.2021.1876869

  View details for PubMedID 33491527

• Acute Lymphoblastic Leukemia, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology. Journal of the National Comprehensive Cancer Network : JNCCN Brown, P. A., Shah, B., Advani, A., Aoun, P., Boyer, M. W., Burke, P. W., DeAngelo, D. J., Dinner, S., Fathi, A. T., Gauthier, J., Jain, N., Kirby, S., Liedtke, M., Litzow, M., Logan, A., Luger, S., Maness, L. J., Massaro, S., Mattison, R. J., May, W., Oluwole, O., Park, J., Przespolewski, A., Rangaraju, S., Rubnitz, J. E., Uy, G. L., Vusirikala, M., Wieduwilt, M., Lynn, B., Berardi, R. A., Freedman-Cass, D. A., Campbell, M. 2021; 19 (9): 1079-1109

  Abstract

  The NCCN Guidelines for Acute Lymphoblastic Leukemia (ALL) focus on the classification of ALL subtypes based on immunophenotype and cytogenetic/molecular markers; risk assessment and stratification for risk-adapted therapy; treatment strategies for Philadelphia chromosome (Ph)-positive and Ph-negative ALL for both adolescent and young adult and adult patients; and supportive care considerations. Given the complexity of ALL treatment regimens and the required supportive care measures, the NCCN ALL Panel recommends that patients be treated at a specialized cancer center with expertise in the management of ALL This portion of the Guidelines focuses on the management of Ph-positive and Ph-negative ALL in adolescents and young adults, and management in relapsed settings.

  View details for DOI 10.6004/jnccn.2021.0042

  View details for PubMedID 34551384

• Efficacy of inotuzumab ozogamicin in patients with Philadelphia chromosome-positive relapsed/refractory acute lymphoblastic leukemia. Cancer Stock, W., Martinelli, G., Stelljes, M., DeAngelo, D. J., Gokbuget, N., Advani, A. S., O'Brien, S., Liedtke, M., Merchant, A. A., Cassaday, R. D., Wang, T., Zhang, H., Vandendries, E., Jabbour, E., Marks, D. I., Kantarjian, H. M. 2020

  Abstract

  BACKGROUND: Patients with relapsed/refractory (R/R) Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) have a poor prognosis and limited treatment options.METHODS: The efficacy of inotuzumab ozogamicin (InO), a humanized anti-CD22 monoclonal antibody conjugated to the cytotoxic antibiotic calicheamicin, was evaluated in R/R ALL patients in the phase 1/2 study 1010 (NCT01363297) and open-label, randomized, phase 3 study 1022 (INO-VATE; NCT01564784). This analysis focused specifically on Ph+ R/R ALL patients. In study 1022, Ph+ patients were randomly assigned 1:1 to InO (n = 22) or standard intensive chemotherapy (SC) (n = 27) and 16 Ph+ patients in study 1010 received InO.RESULTS: In study 1022, rates of complete remission/complete remission with incomplete hematologic recovery (CR/CRi) and minimal residual disease (MRD) negativity (patients achieving CR/CRi) were higher with InO (CR/CRi = 73%; MRD = 81%) versus SC (CR/CRi = 56%; MRD = 33%). The corresponding rates in study 1010 were 56% (CR/CRi) and 100% (MRD). The hematopoietic stem cell transplantation (HSCT) rate in study 1022 was 41% versus 19% for InO versus SC; however, there was no benefit in overall survival (median OS: 8.7 vs 8.4 months; hazard ratio, 1.17 [95% CI, 0.64-2.14]). The probability of being event-free (progression-free survival) at 12 months was greater with InO versus SC (20.1% vs 4.8%).CONCLUSION: Given the substantial improvement in responses and rates of HSCT, InO is an important treatment option for patients with R/R Ph+ ALL. Future studies need to consider better characterization of disease characteristics, more sensitive MRD measurements, MRD-directed therapy before HSCT, and potentially combination therapies, including tyrosine kinase inhibitors.

  View details for DOI 10.1002/cncr.33321

  View details for PubMedID 33231879

• Inotuzumab ozogamicin for relapsed/refractory acute lymphoblastic leukemia: outcomes by disease burden. Blood cancer journal DeAngelo, D. J., Advani, A. S., Marks, D. I., Stelljes, M., Liedtke, M., Stock, W., Gokbuget, N., Jabbour, E., Merchant, A., Wang, T., Vandendries, E., Neuhof, A., Kantarjian, H., O'Brien, S. 2020; 10 (8): 81

  Abstract

  Adults with relapsed/refractory acute lymphoblastic leukemia (R/R ALL) have a poor prognosis, especially if disease burden is high. This post hoc analysis of the phase 3 INO-VATE trial examined the efficacy and safety of inotuzumab ozogamicin (InO) vs. standard of care chemotherapy (SC) among R/R ALL patients with low, moderate, or high disease burden, respectively, defined as bone marrow blasts (BMB)<50% (n=53 vs. 48), 50-90% (n=79 vs. 83), and >90% (n=30 vs. 30). Patients in the InO vs. SC arm with low, moderate, and high BMB%, respectively, had improved rates of complete remission/complete remission with incomplete hematologic recovery (74% vs. 46% [p=0.0022], 75 vs. 27% [p<0.0001], and 70 vs. 17% [p<0.0001]), and improved overall survival (hazard ratio: 0.64 [p=0.0260], 0.81 [p=0.1109], and 0.60 [p=0.0335]). Irrespective of BMB%, cytopenias were the most common treatment-emergent adverse events, and post-transplant veno-occlusive disease was more common with InO vs. SC. Patients with extramedullary disease or lymphoblastic lymphoma showed similar efficacy and safety outcomes. This favorable benefit-to-risk ratio of InO treatment irrespective of disease burden supports its use in challenging and high disease burden subpopulations. INO-VATE is registered at www.clinicaltrials.gov : #NCT01564784.

  View details for DOI 10.1038/s41408-020-00345-8

  View details for PubMedID 32769965

• Real-world outcomes of adult B-cell acute lymphocytic leukemia patients treated with blinatumomab. Blood advances Badar, T., Szabo, A., Advani, A., Wadleigh, M., Arslan, S., Khan, M. A., Aldoss, I., Siebenaller, C., Schultz, E., Hefazi, M., Shallis, R. M., Yurkiewicz, I., Podoltsev, N., Patel, A. A., Curran, E., Balasubramanian, S., Yang, J., Mattison, R. J., Burkart, M., Dinner, S., Liedtke, M., Litzow, M. R., Atallah, E. 2020; 4 (10): 2308–16

  Abstract

  The availability and use of blinatumomab symbolizes a paradigm shift in the management of B-cell acute lymphoblastic leukemia (ALL). We conducted a retrospective multicenter cohort analysis of 239 ALL patients (227 relapsed refractory [RR], n = 227; minimal residual disease [MRD], n = 12) who received blinatumomab outside of clinical trials to evaluate safety and efficacy in the "real-world" setting. The median age of patients at blinatumomab initiation was 48 years (range, 18-85). Sixty-one (26%) patients had ≥3 prior therapies and 46 (19%) had allogeneic hematopoietic cell transplantation before blinatumomab. The response rate (complete remission/complete remission with incomplete count recovery) in patients with RR disease was 65% (47% MRD-). Among 12 patients who received blinatumomab for MRD, 9 (75%) patients achieved MRD negativity. In patients with RR disease, median relapse-free survival and overall survival (OS) after blinatumomab was 32 months and 12.7 months, respectively. Among patients who received blinatumomab for MRD, median relapse-free survival was not reached (54% MRD- at 2 years) and OS was 34.7 months. Grade ≥3 cytokine release syndrome, neurotoxicity, and hepatotoxicity were observed in 3%, 7%, and 10% of patients, respectively. Among patients who achieved complete remission/complete remission with incomplete count recovery, consolidation therapy with allogeneic hematopoietic cell transplantation retained favorable prognostic significance for OS (hazard ratio, 0.54; 95% confidence interval, 0.30-0.97; P = .04). In this largest "real-world" experience published to date, blinatumomab demonstrated responses comparable to those reported in clinical trials. The optimal sequencing of newer therapies in ALL requires further study.

  View details for DOI 10.1182/bloodadvances.2019001381

  View details for PubMedID 32453836

• Autologous stem cell transplantation versus no transplant in patients above 70 with multiple myeloma. Lemieux, C., Muffly, L. S., Iberri, D., Rezvani, A., Lowsky, R., Frank, M., Craig, J. K., Liedtke, M., Negrin, R., Weng, W., Meyer, E., Johnston, L. J., Shizuru, J., Shiraz, P., Arai, S., Miklos, D., Sidana, S. LIPPINCOTT WILLIAMS & WILKINS. 2020

  View details for Web of Science ID 000560368307442

• Impact of proteasome inhibitor vs. IMiD maintenance therapy on outcomes of patients with high-risk multiple myeloma (HRMM). Tam, E., Iberri, D., Liedtke, M., Muffly, L. S., Shiraz, P., Frank, M., Lowsky, R., Rezvani, A., Negrin, R., Meyer, E., Arai, S., Johnston, L. J., Shizuru, J., Weng, W., Miklos, D., Sidana, S. LIPPINCOTT WILLIAMS & WILKINS. 2020

  View details for Web of Science ID 000560368307484

• Real-World Outcomes of Adult B-Cell Acute Lymphocytic Leukemia Patients Treated With Inotuzumab Ozogamicin. Clinical lymphoma, myeloma & leukemia Badar, T., Szabo, A., Wadleigh, M., Liedtke, M., Arslan, S., Siebenaller, C., Aldoss, I., Schultz, E., Hefazi, M., Litzow, M. R., Kuo, E., Wang, A., Curran, E., Shallis, R. M., Podoltsev, N., Balasubramanian, S., Yang, J., Mattison, R., Burkart, M., Dinner, S., Advani, A., Atallah, E. 2020

  Abstract

  BACKGROUND: Inotuzumab ozogamicin (InO) is an anti-CD22 monoclonal antibody-drug (calicheamicin) conjugate that has shown superior efficacy compared to conventional chemotherapy in relapsed/refractory (RR) B-cell acute lymphocytic leukemia (ALL) patients. We sought to find the safety and efficacy of InO in a real-world setting.PATIENTS AND METHODS: A multicenter cohort analysis on 84 RR ALL patients who received InO outside of clinical trials was conducted to evaluate response and toxicity.RESULTS: The median (range) age of patients at InO initiation was 50 (20-87) years. Forty patients (48%) had≥ 3 therapies and 23 patients (27%) underwent allogeneic hematopoietic stem-cell transplantation (allo-HCT) before InO. The median (range) number of cycles of InO provided was 2 (1-6), and cumulative dose was 3.3 (1.8-9.3) mg/m2. Overall response rate (complete remission/complete remission with incomplete count recovery) was 63%; 44% had complete remission with minimal residual disease negativity. Twenty-three patients (27%) with response received allo-HCT. The median duration of response was 11.5 months and when censored at allo-HCT was not reached (51% in remission at 2 years). The median overall survival after InO was 11.6 months and when censored at time of allo-HCT was 13.6 months. The most common grade 3 or higher adverse events observed were transaminitis (16%), hyperbilirubinemia (5%), bleeding (4%), veno-occlusive disease (2%), and hyperglycemia (2%). In multivariate analysis, allo-HCT after InO did not retain favorable significance for duration of response (hazard ratio= 1.27; 95% confidence interval, 0.89-1.61; P= .2) or overall survival (hazard ratio= 1.10; 95% confidence interval, 0.37-3.25; P= .85).CONCLUSION: InO was well tolerated and had significant efficacy in RR B-cell ALL patients.

  View details for DOI 10.1016/j.clml.2020.03.004

  View details for PubMedID 32291234

• Clinical Outcome with Allogeneic Hematopoietic Stem Cell Transplantation after Blinatumomab or Inotuzumab Ozogamicin in Patients with B-Cell Acute Lymphoblastic Leukemia: Real World Experience Badar, T., Advani, A. S., Liedtke, M., Arslan, S., Khan, M., Aldoss, I., Sienbenaller, C., Schultz, E., Hefazi, M., Shallis, R., Yurkiewicz, I., Podoltsev, N., Patel, A., Curran, E., Kuo, E., Wang, A., Balasubramanian, S., Yang, J., Mattison, R., Burkart, M., Dinner, S., Litzow, M. R., Wadleigh, M., Atallah, E. ELSEVIER SCIENCE INC. 2020: S101–S102

  View details for Web of Science ID 000516887900137

• Organ responses with daratumumab therapy in previously treated AL amyloidosis. Blood advances Chung, A. n., Kaufman, G. P., Sidana, S. n., Eckhert, E. n., Schrier, S. L., Lafayette, R. A., Arai, S. n., Witteles, R. M., Liedtke, M. n. 2020; 4 (3): 458–66

  Abstract

  Immunoglobulin light chain amyloidosis (AL amyloidosis) involves deposition of abnormally folded light chains into a wide range of tissues causing organ dysfunction, including in the heart and kidney. Daratumumab, a CD38-targeted antibody, has recently demonstrated efficacy in producing hematologic responses in previously treated disease. However, data on survival outcomes and organ responses to daratumumab are lacking. Seventy-two patients with previously treated AL amyloidosis who received daratumumab monotherapy with dexamethasone were retrospectively evaluated. With a median follow-up of 27 months, 2-year overall survival (OS) was 86.9% (median OS, not reached) and 2-year time-to-next treatment or death (TTNT)-free survival was 62% (median TTNT, not reached). Forty of 52 evaluable patients achieved a hematologic response (77%), with >60% of patients achieving a very good partial response or better; median time-to-hematologic response was 1 month. Fifty-seven patients (79%) had cardiac involvement, and 55% of evaluable patients achieved a cardiac response, with a median response time of 3.2 months among responders. Cardiac responses were associated with an improvement in OS, with landmark analysis for cardiac responses at 3 months trending toward statistical significance (100% vs 55% at 30 months, P = .051). Forty-seven patients (65%) had renal involvement, and 52% of evaluable patients achieved a renal response, with a median response time of 6 months among responders; there was no significant difference in OS between renal responders and nonresponders. This study demonstrates that daratumumab is highly effective in the treatment of previously treated AL amyloidosis, and a significant proportion of patients can achieve deep hematologic responses, as well as improvements in organ function.

  View details for DOI 10.1182/bloodadvances.2019000776

  View details for PubMedID 32027745

• Multiple Myeloma, Version 3.2021, NCCN Clinical Practice Guidelines in Oncology. Journal of the National Comprehensive Cancer Network : JNCCN Kumar, S. K., Callander, N. S., Adekola, K., Anderson, L., Baljevic, M., Campagnaro, E., Castillo, J. J., Chandler, J. C., Costello, C., Efebera, Y., Faiman, M., Garfall, A., Godby, K., Hillengass, J., Holmberg, L., Htut, M., Huff, C. A., Kang, Y., Hultcrantz, M., Larson, S., Liedtke, M., Martin, T., Omel, J., Shain, K., Sborov, D., Stockerl-Goldstein, K., Weber, D., Keller, J., Kumar, R. 2020; 18 (12): 1685–1717

  Abstract

  Multiple myeloma is a malignant neoplasm of plasma cells that accumulate in bone marrow, leading to bone destruction and marrow failure. This manuscript discusses the management of patients with solitary plasmacytoma, smoldering multiple myeloma, and newly diagnosed multiple myeloma.

  View details for DOI 10.6004/jnccn.2020.0057

  View details for PubMedID 33285522

• Sequencing of novel agents in relapsed/refractory B-cell acute lymphoblastic leukemia: Blinatumomab and inotuzumab ozogamicin may have comparable efficacy as first or second novel agent therapy in relapsed/refractory acute lymphoblastic leukemia. Cancer Badar, T. n., Szabo, A. n., Dinner, S. n., Liedtke, M. n., Burkart, M. n., Shallis, R. M., Yurkiewicz, I. R., Kuo, E. n., Khan, M. A., Balasubramanian, S. n., Yang, J. n., Hefazi, M. n., Podoltsev, N. n., Patel, A. n., Curran, E. n., Wang, A. n., Arslan, S. n., Aldoss, I. n., Siebenaller, C. n., Mattison, R. J., Litzow, M. R., Wadleigh, M. n., Advani, A. S., Atallah, E. n. 2020

  Abstract

  The availability of novel agents (NAs), including blinatumomab and inotuzumab ozogamicin (InO), has improved the outcomes of patients with relapsed/refractory (RR) B-cell acute lymphoblastic leukemia (ALL). Because of the relative effectiveness, it is often a challenge for clinicians to determine how to best sequence these NAs with respect to efficacy and toxicity.In this multicenter, retrospective study of patients with RR ALL treated with blinatumomab, InO, or both, their efficacy as a first or second NA was compared.Among 276 patients, 221 and 55 received blinatumomab and InO, respectively, as a first NA therapy. The complete remission (CR)/complete remission with incomplete count recovery (CRi) rate was 65% and 67% for the blinatumomab and InO groups, respectively (P = .73). The rate of treatment discontinuation due to adverse events was 4% and 7% in the blinatumomab and InO groups, respectively. Ninety-two patients (43%) in the blinatumomab group and 13 patients (29%) in the InO group proceeded with allogeneic hematopoietic stem cell transplantation. The median overall survival (OS) was 15 and 11.6 months in the blinatumomab and InO groups, respectively. A subset analysis was performed for 61 patients who received both NAs (blinatumomab and then InO [n = 40] or InO and then blinatumomab [n = 21]). The CR/CRi rate was 58% for patients who received InO as the second NA and 52% for patients who received blinatumomab as the second NA. The median OS was 10.5 for patients who received InO as the second NA and 5.9 months for patients who received blinatumomab as the second NA (P = .09).Although the limited power of this study to detect a significant difference between subgroups is acknowledged, the data suggest that blinatumomab and InO may have comparable efficacy as a first or second NA therapy in RR ALL.

  View details for DOI 10.1002/cncr.33340

  View details for PubMedID 33259056

• Overall survival of patients with triple-class refractory multiple myeloma treated with selinexor plus dexamethasone versus standard of care in MAMMOTH. American journal of hematology Cornell, R. n., Hari, P. n., Tang, S. n., Biran, N. n., Callander, N. n., Chari, A. n., Chhabra, S. n., Fiala, M. A., Gahvari, Z. n., Gandhi, U. n., Godby, K. n., Gupta, R. n., Jagannath, S. n., Jagosky, M. n., Kang, Y. n., Kansagra, A. n., Kauffman, M. n., Kodali, S. n., Kumar, S. K., Lakshman, A. n., Liedtke, M. n., Lonial, S. n., Ma, X. n., Malek, E. n., Mansour, J. n., McGehee, E. F., Neppalli, A. n., Paul, B. n., Richardson, P. n., Scott, E. C., Shacham, S. n., Shah, J. n., Siegel, D. S., Umyarova, E. n., Usmani, S. Z., Varnado, W. n., Vij, R. n., Costa, L. n. 2020

  View details for DOI 10.1002/ajh.26010

  View details for PubMedID 32974944

• Outcomes in Patients With Cardiac Amyloidosis Undergoing Heart Transplantation. JACC. Heart failure Barrett, C. D., Alexander, K. M., Zhao, H. n., Haddad, F. n., Cheng, P. n., Liao, R. n., Wheeler, M. T., Liedtke, M. n., Schrier, S. n., Arai, S. n., Weisshaar, D. n., Witteles, R. M. 2020

  Abstract

  The purpose of this study is to report outcomes after heart transplantation in patients with cardiac amyloidosis based on a large single-center experience.Cardiac amyloidosis causes significant morbidity and mortality, often leading to restrictive cardiomyopathy, progressive heart failure, and death. Historically, heart transplantation outcomes have been worse in patients with cardiac amyloidosis compared with other heart failure populations, in part due to the systemic nature of the disease. However, several case series have suggested that transplantation outcomes may be better in the contemporary era, likely in part due to the availability of more effective light chain suppressive therapies for light chain amyloidosis.This study examined all patients seen between 2004 and 2017, either at the Stanford University Medical Center or the Kaiser Permanente Santa Clara Medical Center, who were diagnosed with cardiac amyloidosis and ultimately underwent heart transplantation. This study examined pre-transplantation characteristics and post-transplantation outcomes in this group compared with the overall transplantation population at our center.During the study period, 31 patients (13 with light chain amyloidosis and 18 with transthyretin [ATTR] amyloidosis) underwent heart transplantation. Patients with ATTR amyloidosis were older, were more likely to be male, had worse baseline renal function, and had longer waitlist times compared with both patients with light chain amyloidosis and the overall transplantation population. Post-transplantation, there were no differences in post-operative bleeding, renal failure, infection, rejection, or malignancy. There was no significant difference in mortality between patients who underwent heart transplantation for amyloid cardiomyopathy and patients who underwent heart transplantation for all other indications.In carefully selected patients with cardiac amyloidosis, heart transplantation can be an effective therapeutic option with outcomes similar to those transplanted for other causes of heart failure.

  View details for DOI 10.1016/j.jchf.2019.12.013

  View details for PubMedID 32387068

• Single-cell mutational profiling enhances the clinical evaluation of AML MRD. Blood advances Ediriwickrema, A. n., Aleshin, A. n., Reiter, J. G., Corces, M. R., Köhnke, T. n., Stafford, M. n., Liedtke, M. n., Medeiros, B. C., Majeti, R. n. 2020; 4 (5): 943–52

  Abstract

  Although most patients with acute myeloid leukemia (AML) achieve clinical remission with induction chemotherapy, relapse rates remain high. Next-generation sequencing enables minimal/measurable residual disease (MRD) detection; however, clinical significance is limited due to difficulty differentiating between pre-leukemic clonal hematopoiesis and frankly malignant clones. Here, we investigated AML MRD using targeted single-cell sequencing (SCS) at diagnosis, remission, and relapse (n = 10 relapsed, n = 4 nonrelapsed), with a total of 310 737 single cells sequenced. Sequence variants were identified in 80% and 75% of remission samples for patients with and without relapse, respectively. Pre-leukemic clonal hematopoiesis clones were detected in both cohorts, and clones with multiple cooccurring mutations were observed in 50% and 0% of samples. Similar clonal richness was observed at diagnosis in both cohorts; however, decreasing clonal diversity at remission was significantly associated with longer relapse-free survival. These results show the power of SCS in investigating AML MRD and clonal evolution.

  View details for DOI 10.1182/bloodadvances.2019001181

  View details for PubMedID 32150611

• Outcomes with autologous stem cell transplant vs. non-transplant therapy in patients 70 years and older with multiple myeloma. Bone marrow transplantation Lemieux, C. n., Muffly, L. S., Rezvani, A. n., Lowsky, R. n., Iberri, D. J., Craig, J. K., Frank, M. J., Johnston, L. J., Liedtke, M. n., Negrin, R. n., Weng, W. K., Meyer, E. n., Shizuru, J. n., Shiraz, P. n., Arai, S. n., Miklos, D. B., Sidana, S. n. 2020

  Abstract

  We evaluated 79 patients with multiple myeloma (MM) ≥70 years referred to our blood and marrow transplant clinic, within 1 year of diagnosis from 2010 to 2019, for consideration of autologous stem cell transplant (ASCT). Thirty-eight (48%) of 79 patients underwent ASCT. ASCT was not pursued in 41 (52%) patients due to: patient or physician preference in 80% (n = 33) or ineligibility in 20% (n = 8). Baseline characteristics of patients in the two groups were similar. Median PFS from treatment start amongst patients undergoing ASCT (n = 38) vs. not (n = 41) was 41 months vs. 33 months, p = 0.03. There was no difference in OS, with estimated 5-year OS of 73% vs. 83%, respectively (p = 0.86). Day +100 transplant-related mortality (TRM) was 0%. ASCT was an independent favorable prognostic factor for PFS in multivariate analysis, after accounting for HCT-CI score, performance status, hematologic response, and maintenance. Finally, patients ≥70 years undergoing ASCT had similar PFS compared to a contemporaneous institutional cohort of patients <70 years (n = 631) (median PFS from transplant: 36 vs. 47 months, p = 0.25). In this retrospective analysis, ASCT was associated with low TRM and better PFS in fit older adults with MM compared to non-transplant therapy, with comparable benefits as seen in younger patients.

  View details for DOI 10.1038/s41409-020-01026-7

  View details for PubMedID 32782351

• Single-cell multiomic analysis identifies regulatory programs in mixed-phenotype acute leukemia. Nature biotechnology Granja, J. M., Klemm, S., McGinnis, L. M., Kathiria, A. S., Mezger, A., Corces, M. R., Parks, B., Gars, E., Liedtke, M., Zheng, G. X., Chang, H. Y., Majeti, R., Greenleaf, W. J. 2019

  Abstract

  Identifying the causes of human diseases requires deconvolution of abnormal molecular phenotypes spanning DNA accessibility, gene expression and protein abundance1-3. We present a single-cell framework that integrates highly multiplexed protein quantification, transcriptome profiling and analysis of chromatin accessibility. Using this approach, we establish a normal epigenetic baseline for healthy blood development, which we then use to deconvolve aberrant molecular features within blood from patients with mixed-phenotype acute leukemia4,5. Despite widespread epigenetic heterogeneity within the patient cohort, we observe common malignant signatures across patients as well as patient-specific regulatory features that are shared across phenotypic compartments of individual patients. Integrative analysis of transcriptomic and chromatin-accessibility maps identified 91,601 putative peak-to-gene linkages and transcription factors that regulate leukemia-specific genes, such as RUNX1-linked regulatory elements proximal to the marker gene CD69. These results demonstrate how integrative, multiomic analysis of single cells within the framework of normal development can reveal both distinct and shared molecular mechanisms of disease from patient samples.

  View details for DOI 10.1038/s41587-019-0332-7

  View details for PubMedID 31792411

• Impact of minimal residual disease status in patients with relapsed/refractory acute lymphoblastic leukemia treated with inotuzumab ozogamicin in the phase III INO-VATE trial. Leukemia research Jabbour, E., Gokbuget, N., Advani, A., Stelljes, M., Stock, W., Liedtke, M., Martinelli, G., O'Brien, S., Wang, T., Laird, A. D., Vandendries, E., Neuhof, A., Nguyen, K., Dakappagari, N., DeAngelo, D. J., Kantarjian, H. 2019; 88: 106283

  Abstract

  Minimal residual disease (MRD) negativity is a key prognostic indicator of outcome in acute lymphocytic leukemia. In the INO-VATE trial (clinicaltrials.gov identifier: NCT01564784), patients with relapsed/refractory acute lymphocytic leukemia who received inotuzumab versus standard chemotherapy achieved greater remission and MRD-negativity rates as well as improved overall survival: hazard ratio 0.75, one-sided P = 0.0105. The current analysis assessed the prognostic value of MRD negativity at the end of inotuzumab treatment. All patients who received inotuzumab (n = 164) were included. Among patients with complete remission/complete remission with incomplete hematologic response (CR/CRi; n = 121), MRD-negative status (by multiparametric flow cytometry) was defined as <1 * 10-4 blasts/nucleated cells. MRD negativity was achieved in 76 patients at the end of treatment. Compared with MRD-positive, MRD-negative status with CR/CRi was associated with significantly improved overall survival and progression-free survival, respectively: hazard ratio (97.5% confidence interval; one-sided P-value) 0.512 (97.5% CI [0.313-0.835]; P = 0.0009) and 0.423 (97.5% CI [0.256-0.699]; P < 0.0001). Median overall survival was 14.1 versus 7.2 months, in the MRD-negative versus MRD-positive groups. Patients in first salvage who achieved MRD negativity at the end of treatment experienced significantly improved survival versus that seen in MRD-positive patients, particularly for those patients who proceeded to stem cell transplant. Among patients with relapsed/refractory acute lymphocytic leukemia who received inotuzumab, those with MRD-negative CR/CRi had the best survival outcomes.

  View details for DOI 10.1016/j.leukres.2019.106283

  View details for PubMedID 31790983

• Multiple Myeloma, Version 1.2020 Featured Updates to the NCCN Guidelines JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Kumar, S. K., Callender, N. S., Hillengass, J., Liedtke, M., Baljevic, M., Campagnaro, E., Castillo, J. J., Chandler, J. C., Cornell, R. F., Costello, C., Efebera, Y., Faiman, M., Garfall, A., Godby, K., Holmberg, L., Htut, M., Huff, C., Kang, Y., Landgren, O., Malek, E., Martin, T., Omel, J., Raje, N., Sborov, D., Singhal, S., Stockerl-Goldstein, K., Tan, C., Weber, D., Johnson-Chilla, A., Keller, J., Kumar, R. 2019; 17 (10): 1155–65

  Abstract

  The NCCN Guidelines for Multiple Myeloma provide recommendations for diagnosis, workup, treatment, follow-up, and supportive care for patients with monoclonal gammopathy of renal significance, solitary plasmacytoma, smoldering myeloma, and multiple myeloma. These NCCN Guidelines Insights highlight some of the important updates and changes in the 1.2020 version of the NCCN Guidelines for Multiple Myeloma.

  View details for DOI 10.6004/jnccn.2019.0049

  View details for Web of Science ID 000489225300002

  View details for PubMedID 31590151

• Real world vs. clinical trial outcomes of triple class refractory penta-exposed multiple myeloma (MM) Cornell, R., Parameswaran, H., Tang, S., Barnstead, A., Biran, N., Callander, N., Chari, A., Chhabra, S., Fiala, M., Gahvari, Z., Gandhi, U., Godby, K., Gupta, R., Jagannath, S., Jagosky, M., Kang, Y., Kansagra, A., Kauffman, M., Kodali, S., Kumar, S., Lakshman, A., Liedtke, M., Lonial, S., Ma, X., Malek, E., Mansour, J., McGehee, E., Narayana, S., Neppalli, A., Paul, B., Richardson, P. G., Scott, E., Shacham, S., Shah, J., Siegel, D. S., Umyarova, E., Usmani, S., Varnado, W., Vij, R., Costa, L. CIG MEDIA GROUP, LP. 2019: E115–E116

  View details for DOI 10.1016/j.clml.2019.09.191

  View details for Web of Science ID 000491229800194

• Outcomes of patients with multiple myeloma refractory to CD38-targeted monoclonal antibody therapy LEUKEMIA Gandhi, U. H., Cornell, R. F., Lakshman, A., Gahvari, Z. J., McGehee, E., Jagosky, M. H., Gupta, R., Varnado, W., Fiala, M. A., Chhabra, S., Malek, E., Mansour, J., Paul, B., Barnstead, A., Kodali, S., Neppalli, A., Liedtke, M., Narayana, S., Godby, K. N., Kang, Y., Kansagra, A., Umyarova, E., Scott, E. C., Hari, P., Vij, R., Usmani, S. Z., Callander, N. S., Kumar, S. K., Costa, L. J. 2019; 33 (9): 2266–75

  View details for DOI 10.1038/s41375-019-0435-7

  View details for Web of Science ID 000484399300011

• AL Amyloidosis for the Cardiologist and Oncologist Epidemiology, Diagnosis, and Management JACC: CARDIOONCOLOGY Witteles, R. M., Liedtke, M. 2019; 1 (1): 117–30

  View details for DOI 10.1016/j.jaccao.2019.08.002

  View details for Web of Science ID 000613113100016

• Gene Signatures to Distinguish Amyloid Cardiomyopathy Risk in Multiple Myeloma Patients Jha, A., Morgado, I., Lee, D. J., Alexander, K., Tsai, C., Schimmel, K., Ward, J., Witteles, R., Liedtke, M., Liao, R., Dangwal, S. LIPPINCOTT WILLIAMS & WILKINS. 2019

  View details for Web of Science ID 000511467800441

• Inotuzumab ozogamicin versus standard of care in relapsed or refractory acute lymphoblastic leukemia: Final report and long-term survival follow-up from the randomized, phase 3 INO-VATE study CANCER Kantarjian, H. M., DeAngelo, D. J., Stelljes, M., Liedtke, M., Stock, W., Goekbuget, N., O'Brien, S. M., Jabbour, E., Wang, T., White, J., Sleight, B., Vandendries, E., Advani, A. S. 2019; 125 (14): 2474–87

  View details for DOI 10.1002/cncr.32116

  View details for Web of Science ID 000476763700018

• Single-cell mutational profiling of paired AML samples at diagnosis, remission and relapse: Implications for therapeutic resistance and MRD detection Aleshin, A., Durruthy-Durruthy, R., Corces, R., Liedtke, M., Eastburn, D., Majeti, R. AMER ASSOC CANCER RESEARCH. 2019

  View details for DOI 10.1158/1538-7445.AM2019-5130

  View details for Web of Science ID 000488279405472

• Outcome of relapsed or refractory acute lymphoblastic leukemia patients with extramedullary disease or lymphoblastic lymphoma receiving inotuzumab ozogamicin or standard care in the INO-VATE trial Marks, D. I., DeAngelo, D. J., Stelljes, M., Liedtke, M., Stock, W., Gokbuget, N., O'Brien, S., Jabbour, E., Merchant, A., Wang, T., Vandendries, E., Neuhof, A., Advani, A., Kantarjian, H. NATURE PUBLISHING GROUP. 2019: 149–51

  View details for Web of Science ID 000487707800154

• Grading cardiac response in AL amyloidosis: implications for relapse and survival BRITISH JOURNAL OF HAEMATOLOGY Eckhert, E., Witteles, R., Kaufman, G., Lafayette, R., Arai, S., Schrier, S., O'Shaughnessy, M., Liedtke, M. 2019; 186 (1): 144–46

  View details for DOI 10.1111/bjh.15717

  View details for Web of Science ID 000472576700020

• B-cell maturation antigen directed monoclonal antibody therapies for multiple myeloma IMMUNOTHERAPY Eckhert, E., Hewitt, R., Liedtke, M. 2019; 11 (9): 801–11

  View details for DOI 10.2217/imt-2018-0199

  View details for Web of Science ID 000469496800006

• Anti-BCMA CAR T-Cell Therapy bb2121 in Relapsed or Refractory Multiple Myeloma NEW ENGLAND JOURNAL OF MEDICINE Raje, N., Berdeja, J., Lin, Y., Siegel, D., Jagannath, S., Madduri, D., Liedtke, M., Rosenblatt, J., Maus, M. V., Turka, A., Lam, L., Morgan, R. A., Friedman, K., Massaro, M., Wang, J., Russotti, G., Yang, Z., Campbell, T., Hege, K., Petrocca, F., Quigley, M., Munshi, N., Kochenderfer, J. N. 2019; 380 (18): 1726–37

  View details for DOI 10.1056/NEJMoa1817226

  View details for Web of Science ID 000467767800008

• A pediatric regimen for older adolescents and young adults with acute lymphoblastic leukemia: results of CALGB 10403 BLOOD Stock, W., Luger, S. M., Advani, A. S., Yin, J., Harvey, R. C., Mullighan, C. G., Willman, C. L., Fulton, N., Laumann, K. M., Malnassy, G., Paietta, E., Parker, E., Geyer, S., Mrozek, K., Bloomfield, C. D., Sanford, B., Marcucci, G., Liedtke, M., Claxton, D. F., Foster, M. C., Bogart, J. A., Grecula, J. C., Appelbaum, F. R., Erba, H., Litzow, M. R., Tallman, M. S., Stone, R. M., Larson, R. A. 2019; 133 (14): 1548–59

  View details for DOI 10.1182/blood-2018-10-881961

  View details for Web of Science ID 000464144400006

• Contemporary Outcomes in Patients with Cardiac Amyloidosis Undergoing Heart Transplantation Alexander, K., Barrett, C., Dobos, K., Cheng, P., Liao, R., Wheeler, M., Liedtke, M., Weisshaar, D., Witteles, R. ELSEVIER SCIENCE INC. 2019: S215

  View details for DOI 10.1016/j.healun.2019.01.524

  View details for Web of Science ID 000461365101209

• Inotuzumab ozogamicin versus standard of care in relapsed or refractory acute lymphoblastic leukemia: Final report and long-term survival follow-up from the randomized, phase 3 INO-VATE study. Cancer Kantarjian, H. M., DeAngelo, D. J., Stelljes, M., Liedtke, M., Stock, W., Gokbuget, N., O'Brien, S. M., Jabbour, E., Wang, T., Liang White, J., Sleight, B., Vandendries, E., Advani, A. S. 2019

  Abstract

  BACKGROUND: Inotuzumab ozogamicin (InO) is an antibody-drug conjugate used for adults with relapsed/refractory B-cell precursor (BCP) acute lymphoblastic leukemia (ALL). The INotuzumab Ozogamicin trial to inVestigAte Tolerability and Efficacy (INO-VATE) previously reported improved outcomes with InO versus standard-of-care (SoC) chemotherapy. This article reports the final INO-VATE results (≥2years of follow-up) and additional analyses of patient characteristics associated with improved outcomes.METHODS: Between August 27, 2012, and January 4, 2015, this multicenter, parallel, open-label, phase 3 trial randomized 326 adults with relapsed/refractory ALL to InO (n=164) or SoC (n=162); 307 received 1 or more doses of the study drug (164 in the InO arm and 143 in the SoC arm).RESULTS: The complete remission (CR)/complete remission with incomplete hematologic recovery (CRi) rate was higher with InO versus SoC (73.8% vs 30.9%; 1-sided P<.0001), with consistent CR/CRi rates across patient subgroups. The median overall survival (OS) was 7.7months with InO and 6.2months with SoC, with 2-year OS rates of 22.8% and 10.0%, respectively (overall hazard ratio, 0.75; 97.5% confidence interval [CI], 0.57-0.99; 1-sided P=.0105). The predictors of OS with InO were the best minimal residual disease status, baseline platelet count, duration of first remission, achievement of CR/CRi, and follow-up hematopoietic stem cell transplantation (HSCT; all 2-sided P values <.05). More InO arm patients proceeded directly to HSCT after achieving CR/CRi before any follow-up induction therapy (39.6% [95% CI, 32.1%-47.6%] vs 10.5% [6.2%-16.3%]; 1-sided P<.0001). The most frequent all-grade and grade 3 or higher adverse events in both arms were hematologic. Veno-occlusive disease (VOD)/sinusoidal obstruction syndrome (SOS) was more frequent with InO (23 of 164 [14.0%] vs 3 of 143 [2.1%]).CONCLUSIONS: In patients with relapsed/refractory BCP ALL in INO-VATE, InO was associated with a greater likelihood of CR/CRi across key patient subgroups, and it served as a bridge to HSCT. Potential VOD/SOS risk factors must be considered when InO treatment decisions are being made.

  View details for PubMedID 30920645

• Outcomes of patients with multiple myeloma refractory to CD38-targeted monoclonal antibody therapy. Leukemia Gandhi, U. H., Cornell, R. F., Lakshman, A., Gahvari, Z. J., McGehee, E., Jagosky, M. H., Gupta, R., Varnado, W., Fiala, M. A., Chhabra, S., Malek, E., Mansour, J., Paul, B., Barnstead, A., Kodali, S., Neppalli, A., Liedtke, M., Narayana, S., Godby, K. N., Kang, Y., Kansagra, A., Umyarova, E., Scott, E. C., Hari, P., Vij, R., Usmani, S. Z., Callander, N. S., Kumar, S. K., Costa, L. J. 2019

  Abstract

  The introduction of CD38-targeting monoclonal antibodies (CD38 MoABs), daratumumab and isatuximab, has significantly impacted the management of patients with multiple myeloma (MM). Outcomes of patients with MM refractory to CD38 MoABs have not been described. We analyzed outcomes of 275MM patients at 14 academic centers with disease refractory to CD38 MoABs. Median interval between MM diagnosis and refractoriness to CD38 MoAB (T0) was 50.1 months. The median overall survival (OS) from T0 for the entire cohort was 8.6 [95% C.I. 7.5-9.9] months, ranging from 11.2 months for patients not simultaneously refractory to an immunomodulatory (IMiD) agent and a proteasome inhibitor (PI) to 5.6 months for "penta-refractory" patients (refractory to CD38 MoAB, 2 PIs and 2 IMiDs). At least one subsequent treatment regimen was employed after T0 in 249 (90%) patients. Overall response rate to first regimen after T0 was 31% with median progression-free survival (PFS) and OS of 3.4 and 9.3 months, respectively. PFS was best achieved with combinations of carfilzomib and alkylator (median 5.7 months), and daratumumab and IMiD (median 4.5 months). Patients with MM refractory to CD38 MoAB have poor prognosis and this study provides benchmark for new therapies to be tested in this population.

  View details for PubMedID 30858549

• Therapy-related myeloid neoplasms after treatment for plasma-cell disorders. Best practice & research. Clinical haematology Chung, A., Liedtke, M. 2019; 32 (1): 54–64

  Abstract

  Therapy-related myeloid neoplasms (t-MN), including therapy-related acute myeloid leukaemia and myelodysplastic syndrome, are second primary malignancies (SPM) that are of growing importance as patients with plasma cell disorders (PCD) such as multiple myeloma (MM) are living longer with more effective therapies. Both patient-specific and treatment-specific factors likely impact the risk of t-MN development after diagnosis and treatment of PCD. Alkylating chemotherapy, especially melphalan, has been strongly tied to the risk of t-MN. More recently, there has been a shift away from long-term alkylating therapies to immunomodulatory agents and high-dose therapy with autologous stem cell transplant (HD-ASCT). This shift has led to improved survival and long-term outcomes for most MM patients. However, the risks of t-MN remain despite the improved efficacy of these treatments, and patients who develop t-MN have a poor prognosis. Understanding the risk factors predisposing MM patients to t-MN can thus help to tailor individualized therapy to maximize anti-myeloma efficacy and minimize the risks of t-MN.

  View details for PubMedID 30927976

• Therapy-related myeloid neoplasms after treatment for plasma-cell disorders BEST PRACTICE & RESEARCH CLINICAL HAEMATOLOGY Chung, A., Liedtke, M. 2019; 32 (1): 54–64

  View details for DOI 10.1016/j.beha.2019.02.003

  View details for Web of Science ID 000464091800008

• Prognostic implications of cytogenetics in adults with acute lymphoblastic leukemia treated with inotuzumab ozogamicin. American journal of hematology Jabbour, E., Advani, A. S., Stelljes, M., Stock, W., Liedtke, M., Gokbuget, N., Martinelli, G., O'Brien, S., White, J. L., Wang, T., Paccagnella, M. L., Sleight, B., Vandendries, E., DeAngelo, D. J., Kantarjian, H. M. 2019

  Abstract

  Karyotype is frequently used to predict response and outcome in leukemia. This post hoc exploratory analysis evaluated the relationship between baseline cytogenetics and outcome in patients with relapsed/refractory acute lymphoblastic leukemia (R/R ALL) treated with inotuzumab ozogamicin (InO), a humanized CD22 antibody conjugated to calicheamicin, in the phase 3, open-label, randomized INO-VATE trial. Data as of March 8, 2016, are presented in this analysis. Of the 326 patients randomized, 284 had screening karyotyping data (144 in the InO arm and 140 in the standard care [SC] arm). With InO, complete remission or complete remission with incomplete hematologic recovery (CR/CRi), minimal residual disease negativity rates, and overall survival (OS) were not significantly different between cytogenetic subgroups. CR/CRi rates favored InO over SC in the diploid with ≥20 metaphases, complex, and "other" cytogenetic subgroups. The OS hazard ratio favored InO over SC in the diploid with ≥20 metaphases, complex, and other cytogenetic subgroups. Generally, InO is effective and provides substantial clinical benefit in patients with R/R ALL who have specific baseline karyotypes. This article is protected by copyright. All rights reserved.

  View details for PubMedID 30623490

• Therapy-related acute lymphoblastic leukemia is a distinct entity with adverse genetic features and clinical outcomes. Blood advances Saygin, C. n., Kishtagari, A. n., Cassaday, R. D., Reizine, N. n., Yurkiewicz, I. n., Liedtke, M. n., Stock, W. n., Larson, R. A., Levine, R. L., Tallman, M. S., Park, J. H., Kerr, C. n., Przychodzen, B. n., Sekeres, M. A., Kalaycio, M. E., Carraway, H. E., Hamilton, B. K., Sobecks, R. n., Gerds, A. n., Mukherjee, S. n., Nazha, A. n., Maciejewski, J. P., Advani, A. S. 2019; 3 (24): 4228–37

  Abstract

  Patients with therapy-related acute lymphoblastic leukemia (t-ALL) represent a small subset of acute lymphoblastic leukemia (ALL) patients who received genotoxic therapy (ie, chemotherapy or radiation) for a prior malignancy. These patients should be distinguished from patients with de novo ALL (dn-ALL) and ALL patients who have a history of prior malignancy but have not received cytotoxic therapies in the past (acute lymphoblastic leukemia with prior malignancy [pm-ALL]). We report a retrospective multi-institutional study of patients with t-ALL (n = 116), dn-ALL (n = 100), and pm-ALL (n = 20) to investigate the impact of prior cytotoxic therapies on clinical outcomes. Compared with patients with pm-ALL, t-ALL patients had a significantly shorter interval between the first malignancy and ALL diagnosis and a higher frequency of poor-risk cytogenetic features, including KMT2A rearrangements and myelodysplastic syndrome-like abnormalities (eg, monosomal karyotype). We observed a variety of mutations among t-ALL patients, with the majority of patients exhibiting mutations that were more common with myeloid malignancies (eg, DNMT3A, RUNX1, ASXL1), whereas others had ALL-type mutations (eg, CDKN2A, IKZF1). Median overall survival was significantly shorter in the t-ALL cohort compared with patients with dn-ALL or pm-ALL. Patients who were eligible for hematopoietic cell transplantation had improved long-term survival. Collectively, our results support t-ALL as a distinct entity based on its biologic and clinical features.

  View details for DOI 10.1182/bloodadvances.2019000925

  View details for PubMedID 31869410

• Cutaneous plasmablastic plasmacytoma. Blood Chung, A. n., Liedtke, M. n. 2019; 134 (23): 2116

  View details for DOI 10.1182/blood.2019002821

  View details for PubMedID 31805196

• A Changing Landscape of Mortality for Systemic Light Chain Amyloidosis. JACC. Heart failure Barrett, C. D., Dobos, K. n., Liedtke, M. n., Tuzovic, M. n., Haddad, F. n., Kobayashi, Y. n., Lafayette, R. n., Fowler, M. B., Arai, S. n., Schrier, S. n., Witteles, R. M. 2019

  Abstract

  The purpose of this study was to address the overall trends in mortality since the adoption of modern therapies for treatment of systemic amyloidosis, and to reconsider the prognostic significance of individual components of the current staging system.Systemic light chain (AL) amyloidosis involves deposition of immunoglobulin light chains in organs throughout the body and is known to have the highest mortality when significant cardiac involvement is present. Survival has historically been poor but may be improving as systemic therapies continue to advance. This study assesses whether recent advancements in light chain directed therapy have led to improved survival in patients with systemic AL amyloidosis.We reviewed all cases of patients who were evaluated for a new diagnosis of AL amyloidosis at the Stanford Amyloid Center between 2009 and 2016. Patients' stage at diagnosis was determined according to the most commonly used staging system. Clinical data, overall survival from diagnosis, and the independent influence of each component of the staging system were analyzed.At total of 194 patients were identified with a new diagnosis of systemic AL amyloidosis. Median overall survival was 59 months and 6 months for stage 3 and 4 patients, respectively. Median overall survival was not reached in stage 1 and 2 groups, as survival was >50% by the end of the study. Mean overall survival was 118 months, 76 months, 64 months, and 27 months in Stages 1, 2, 3, and 4 patients, respectively. Although N-terminal pro-B-type natriuretic peptide and troponin I concentrations had large effects on prognosis, differences in serum free light chains (dFLC) on initial staging laboratory results ≥18 mg/dl, part of the current staging system, did not contribute significantly to prognosis for values ≥5 mg/dl.Survival for patients with systemic AL amyloidosis has improved for patients at all stages of disease in the present era of rapid advancements in light chain-reducing therapies. Cardiac biomarkers at diagnosis, but not baseline dFLC ≥18 mg/dl, continue to provide important prognostic information.

  View details for DOI 10.1016/j.jchf.2019.07.007

  View details for PubMedID 31606365

• Grading cardiac response in AL amyloidosis: implications for relapse and survival. British journal of haematology Eckhert, E., Witteles, R., Kaufman, G., Lafayette, R., Arai, S., Schrier, S., O'Shaughnessy, M., Liedtke, M. 2018

  View details for PubMedID 30569572

• Daratumumab vs. pomalidomide for the treatment of relapsed/refractory multiple myeloma: a cost-effectiveness analysis. American journal of hematology Gong, C. L., Studdert, A. L., Liedtke, M. 2018

  View details for PubMedID 30536952

• Antibody-based therapies in patients with acute lymphoblastic leukemia. Hematology. American Society of Hematology. Education Program Dinner, S., Liedtke, M. 2018; 2018 (1): 9–15

  Abstract

  The use of multiagent combination chemotherapy regimens results in cure rates of >90% for children and 40% for adults with acute lymphoblastic leukemia (ALL) but is associated with extensive toxicity and disappointingly low efficacy in relapsed patients. ALL blast cells express several surface antigens, including CD20, CD22, and CD19, which represent valuable targets for immunotherapy. Monoclonal antibodies, antibody-drug conjugates, and bispecific T-cell-engaging antibodies targeting these antigens offer novel mechanisms of action. Within the last several years, the anti-CD20 antibody rituximab has been added to chemotherapy for newly diagnosed patients <60 years with CD20+ pre-B ALL and significantly improved the 2-year event-free survival from 52% to 65%. In adults with relapsed or refractory CD22+ ALL, the antibody-drug conjugate inotuzumab ozogamicin resulted in a complete response rate of 81% and median overall survival of 7.7 months with reduced toxicity compared with standard chemotherapy. Similarly, the bispecific T-cell-engaging antibody blinatumomab yielded a complete response rate of 44% and a median overall survival of 7.7 months in an extensively treated ALL population. Moreover, 80% of ALL patients in complete remission with evidence of minimal residual disease (MRD) achieved a complete MRD response following treatment with blinatumomab. These results highlight the tremendous promise of antibody-based treatment approaches for ALL. Ongoing and future research is critical to further define the role of the various immunotherapies in the frontline treatment of ALL. Additional challenges include the optimal sequencing of the available antibodies in the relapsed setting as well as their integration with stem cell transplant and chimeric antigen receptor T-cell therapy.

  View details for PubMedID 30504286

• Single-Cell Mutational Profiling of Clonal Evolution in De Novo AML during Therapy and Relapse Aleshin, A., Durruthy-Durruthy, R., Corces, M., Stafford, M., Liedtke, M., Medeiros, B. C., Eastburn, D. J., Majeti, R. AMER SOC HEMATOLOGY. 2018

  View details for DOI 10.1182/blood-2018-99-118089

  View details for Web of Science ID 000454837604140

• A Phase II Study of Dasatinib and Dexamethasone As Primary Therapy Followed By Transplantation for Adults with Newly Diagnosed Ph/BCR-ABL1-Positive Acute Lymphoblastic Leukemia (Ph plus ALL): Final Results of Alliance/CALGB Study 10701 Wieduwilt, M. J., Yin, J., Wetzler, M., Uy, G. L., Powell, B. L., Kolitz, J. E., Liedtke, M., Stock, W., Beumer, J. H., Mattison, R. J., Storrick, E., Devine, S., Smith, S. E., Stone, R. M., Larson, R. A. AMER SOC HEMATOLOGY. 2018

  View details for DOI 10.1182/blood-201/1-99-120029

  View details for Web of Science ID 000454837601018

• Antibody-based therapies in patients with acute lymphoblastic leukemia HEMATOLOGY-AMERICAN SOCIETY OF HEMATOLOGY EDUCATION PROGRAM Dinner, S., Liedtke, M. 2018: 9-15

  View details for DOI 10.1182/asheducation-2018.1.9

  View details for Web of Science ID 000451862100002

• Twice-weekly ixazomib in combination with lenalidomide-dexamethasone in patients with newly diagnosed multiple myeloma BRITISH JOURNAL OF HAEMATOLOGY Richardson, P. G., Hofmeister, C. C., Rosenbaum, C. A., Htut, M., Vesole, D. H., Berdeja, J. G., Liedtke, M., Chari, A., Smith, S. D., Lebovic, D., Raje, N., Byrne, C., Liao, E., Gupta, N., Di Bacco, A., Estevam, J., Berg, D., Baz, R. 2018; 182 (2): 231–44

  Abstract

  Weekly ixazomib with lenalidomide-dexamethasone (Rd) is feasible and has shown activity in newly diagnosed multiple myeloma (NDMM) patients. This phase 1/2 study (NCT01383928) evaluated the recommended phase 2 dose (RP2D), pharmacokinetics, safety and efficacy of twice-weekly ixazomib plus Rd in NDMM; 64 patients were enrolled across both phases. Patients received twice-weekly oral ixazomib 3·0 or 3·7 mg plus lenalidomide 25 mg and dexamethasone 20 mg (10 mg in cycles 9-16) for up to sixteen 21-day cycles, followed by maintenance with twice-weekly ixazomib alone. No dose-limiting toxicities were reported in cycle 1; the RP2D was 3·0 mg based on overall tolerability across multiple cycles. In 62 evaluable patients, the confirmed overall response rate was 94% (68% ≥very good partial response; 24% complete response). Median progression-free survival was 24·9 months. Responses (median duration 36·9 months for patients receiving the RP2D) deepened during treatment. Grade 3 drug-related adverse events (AEs) occurred in 64% of patients, including: rash, 13%; peripheral neuropathy, 8%; hyperglycaemia, 8%. There were no grade 4 drug-related AEs. Thirteen patients discontinued due to AEs. Twice-weekly ixazomib-Rd offers substantial activity with promising long-term outcomes in NDMM patients but may be associated with greater toxicity compared with weekly ixazomib-Rd in this setting.

  View details for DOI 10.1111/bjh.15394

  View details for Web of Science ID 000437830100010

  View details for PubMedID 29938772

  View details for PubMedCentralID PMC6055619

• Effect of Fitbit and iPad Wearable Technology in Health-Related Quality of Life in Adolescent and Young Adult Cancer Patients JOURNAL OF ADOLESCENT AND YOUNG ADULT ONCOLOGY Yurkiewicz, I. R., Simon, P., Liedtke, M., Dahl, G., Dunn, T. 2018; 7 (5): 579–83

  View details for DOI 10.1089/jayao.2018.0022

  View details for Web of Science ID 000436028600001

• Effect of Fitbit and iPad Wearable Technology in Health-Related Quality of Life in Adolescent and Young Adult Cancer Patients. Journal of adolescent and young adult oncology Yurkiewicz, I. R., Simon, P., Liedtke, M., Dahl, G., Dunn, T. 2018

  Abstract

  PURPOSE: Adolescent and young adult (AYA) patients with cancer face significant challenges with regard to fatigue, reduced physical activity, and social isolation, which may negatively impact quality of life. This study investigated whether the use of digital wearable technology (Fitbits, along with synced iPads) can affect health-related quality of life (HRQOL) in AYA aged patients with cancer.MATERIALS AND METHODS: This was a prospective cohort study that offered Fitbits and iPads to all AYA patients aged 15 to 29 at an academic medical center at the time of cancer diagnosis. Patients completed the Short Form Health Survey developed by RAND (RAND-36) assessing eight dimensions of HRQOL on entering the study and at the time of their 6-month follow-up or the end of treatment, whichever occurred first. At the time of follow-up, patients also completed a questionnaire that assessed user experience, including frequency of wearable device use, enjoyment, challenges, and participation, in online communities.RESULTS: Thirty-three patients participated in the study. Most patients reported enjoying the digital technology and using the devices to track multiple aspects of their health (85%). Most also reported a subjective increase in physical activity (79%). After the intervention, participants demonstrated significant improvements across all eight dimensions of HRQOL measured by the RAND-36 (p<0.00 to 0.01).CONCLUSION: Distributing wearable technology at the time of diagnosis may provide an avenue for improving HRQOL in adolescents and young adults with cancer.

  View details for PubMedID 29924668

• Efficacy and Safety Analysis by Age Cohort of Inotuzumab Ozogamicin in Patients With Relapsed or Refractory Acute Lymphoblastic Leukemia Enrolled in INO-VATE CANCER Jabbour, E. J., DeAngelo, D. J., Stelljes, M., Stock, W., Liedtke, M., Gokbuget, N., O'Brien, S., Wang, T., Paccagnella, M., Sleight, B., Vandendries, E., Advani, A. S., Kantarjian, H. M. 2018; 124 (8): 1722–32

  Abstract

  Inotuzumab ozogamicin (InO) has demonstrated efficacy and tolerability in patients aged 18 to 78 years with relapsed/refractory acute lymphoblastic leukemia (ALL) in the INO-VATE trial. This subset analysis compared the efficacy and safety of InO in younger and older patients.Intent-to-treat analyses of morphologic responses and overall survival (OS) included 326 randomized patients, and safety assessments included 307 patients receiving 1 or more doses of the study treatment. Of the 326 patients, 164 received InO at a starting dose of 1.8 mg/m2 /cycle (0.8 mg/m2 on day 1 and 0.5 mg/m2 on days 8 and 15 of a 21- to 28-day cycle [≤6 cycles]); 60 patients were aged ≥55 years, and 104 were aged <55 years.For older and younger patients, the median duration of InO therapy and the types and frequencies of adverse events of any grade were generally similar. Although the remission rates, median duration of remission (DOR), and progression-free survival were similar with InO for those aged <55 years and those aged ≥55 years, OS was longer for younger patients (median, 8.6 vs 5.6 months; hazard ratio, 0.610). Among patients proceeding to hematopoietic stem cell transplantation after InO treatment (28% of older patients and 58% of younger patients), the incidence of veno-occlusive disease was greater in older patients (41% vs 17%). The study database was not locked at the time of this analysis.InO was tolerable in older patients with relapsed/refractory ALL. Although OS was longer for younger patients versus older patients, InO demonstrated high response rates with similar DOR in the 2 age groups. Cancer 2018;124:1722-32. © 2018 American Cancer Society.

  View details for PubMedID 29381191

• Clinical implications of gastrointestinal symptoms in systemic amyloidosis NEUROGASTROENTEROLOGY AND MOTILITY Yen, T., Chen, F. W., Witteles, R. M., Liedtke, M., Nguyen, L. A. 2018; 30 (4): e13229

  Abstract

  Gastrointestinal (GI) symptoms in systemic amyloidosis patients are poorly characterized. This purpose of this study is to define the epidemiology and clinical implications of such symptoms.This was a retrospective cohort study of 583 amyloid patients seen at a tertiary referral center. Of 96 symptomatic patients, 82 received endoscopic biopsies, subsequently grouped into those with histologic evidence of GI amyloid (biopsy proven) vs without (biopsy absent).16.8% of patients had GI symptoms, and had more abnormal NT-proBNP, cardiac ejection fraction, serum albumin, and alkaline phosphatase (P < .01). Of those who received endoscopy, the sites of highest diagnostic yield were stomach, duodenum and colon. The most common symptom was abdominal pain, nausea, or vomiting (50.0%). Of the symptomatic patients, only 37 (45%) had biopsy proven GI amyloid. Biopsy proven patients more often had cardiac involvement (P < .005), and more often received hematologic therapy or transplant (P = .01). Biopsy absent patients had more frequent neurologic involvement (P = .17). Biopsy status had no significant correlation with other indicators of amyloid burden, GI symptoms or management.Nearly one in six amyloid patients have GI symptoms, and half do not have GI amyloid. The type of symptom does not predict endoscopic findings. Most biopsy absent patients are not managed as a functional disorder despite no alternative etiology. Gastroenterologists may have an increased role to play in the care of systemic amyloidosis beyond performing endoscopies, such as evaluating cardiac amyloid patients for concurrent GI amyloid.

  View details for PubMedID 29024324

• Report of the relapsed/refractory cohort of SWOG S0919: A phase 2 study of idarubicin and cytarabine in combination with pravastatin for acute myelogenous leukemia (AML). Leukemia research Advani, A. S., Li, H. n., Michaelis, L. C., Medeiros, B. C., Liedtke, M. n., List, A. F., O'Dwyer, K. n., Othus, M. n., Erba, H. P., Appelbaum, F. R. 2018; 67: 17–20

  Abstract

  Inhibition of cholesterol synthesis and uptake sensitizes acute myeloid leukemia (AML) blasts to chemotherapy. A Phase 2 study of high dose pravastatin given in combination with idarubicin and cytarabine demonstrated an impressive response rate [75% complete remission (CR), CR with incomplete count recovery (CRi)]. However, this population was a favorable risk group as eligible patients had to have a CR/CRi lasting ≥3 months following their most recent chemotherapy. Therefore, the study was amended to treat patients with poor risk disease including those with CR/CRi <6 months following their last induction regimen or with refractory disease. Here, we present results in this poor risk group. This trial included a significant number of patients with poor risk cytogenetics (43%) and poor risk molecular mutations. The response rate was 30% and approximately one-fourth of patients were able to proceed to allogeneic hematopoietic stem cell transplant (HSCT). The median overall survival for patients proceeding to allogeneic HSCT is 27.1 months. Although this trial did not meet criteria for a positive study based on the response rate (p = .062), these results are encouraging given the poor risk population and suggest that targeting the cholesterol pathway may have therapeutic benefit in AML.

  View details for PubMedID 29407182

• Inotuzumab ozogamicin: a CD22 mAb-drug conjugate for adult relapsed or refractory B-cell precursor acute lymphoblastic leukemia DRUG DESIGN DEVELOPMENT AND THERAPY Yurkiewicz, I. R., Muffly, L., Liedtke, M. 2018; 12: 2293–2300

  Abstract

  Despite improved rates of remission and cure in newly diagnosed adult acute lymphoblastic leukemia (ALL), the prognosis for patients with relapsed or refractory disease remains poor and the 5-year overall survival rate after relapse is under 10%. A recent paradigm shift has focused on the promise of targeted immunotherapy rather than standard chemotherapy, as ALL blast cells express a variety of antigens, and monoclonal antibodies may be developed to identify and destroy the leukemic cells. Inotuzumab ozogamicin is a CD22 monoclonal antibody conjugated to the cytotoxic antibiotic calicheamicin. CD22 expression is detected on leukemic blasts in over 90% of patients with ALL. Based on promising results from preclinical studies, inotuzumab ozogamicin was tested in Phase 1/2 and Phase 3 clinical trials and it demonstrated improved complete remission rates, progression-free survival and overall survival in relapsed or refractory adult ALL compared to standard therapy. Ongoing studies are evaluating the value of inotuzumab ozogamicin when given in combination with chemotherapy as part of upfront treatment. This review discusses the drug's biochemical properties and mechanism of action, preclinical research outcomes, clinical trial results, adverse events and toxicities, drug approval and ongoing investigations.

  View details for PubMedID 30087554

• A phase I, open-label, dose-escalation study of amrubicin in combination with lenalidomide and weekly dexamethasone in previously treated adults with relapsed or refractory multiple myeloma. International journal of hematology Dinner, S. n., Dunn, T. J., Price, E. n., Coutré, S. E., Gotlib, J. n., Berube, C. n., Kaufman, G. P., Medeiros, B. C., Liedtke, M. n. 2018

  Abstract

  This phase 1 study investigated the safety of the anthracycline amrubicin combined with lenalidomide and dexamethasone in adults with relapsed or refractory multiple myeloma. A standard 3 + 3 design was used. Patients received intravenous amrubicin 40-80 mg/m2 on day one, lenalidomide 15 mg orally on days 1-14, and dexamethasone 40 mg orally weekly on 21 day cycles. 14 patients were enrolled, and completed a median of three cycles. The maximum tolerated dose was not reached. One patient experienced dose limiting toxicity of dizziness and diarrhea. The most frequent non-hematologic toxicity was infection (79%). Serious adverse events included cord compression and sepsis. Three patients (21%) had a partial response or better, and seven (50%) had stable disease. The median duration of response was 4.4 months, and the median progression-free survival was 3 months. Amrubicin combined with lenalidomide and dexamethasone, was safe and demonstrated clinical activity in relapsed or refractory multiple myeloma.Clinicaltrials.gov identifier: NCT01355705.

  View details for PubMedID 29802551

• Prognostic impact of incomplete hematologic count recovery and minimal residual disease on outcome in adult acute lymphoblastic leukemia at the time of second complete response LEUKEMIA & LYMPHOMA Saygin, C., Papadantonakis, N., Cassaday, R. D., Liedtke, M., Fischer, K., Dunn, T., Patel, B. J., Sobecks, R., Kalaycio, M., Sekeres, M. A., Mukherjee, S., Gerds, A. T., Hamilton, B. K., Carraway, H. E., Advani, A. S. 2018; 59 (2): 363–71

  Abstract

  Outcomes of relapsed adult acute lymphoblastic leukemia (ALL) have improved over time with the introduction of new therapies as well as better supportive care. However, there is still a need for easy-to-use and accurate prognostic tools for patients in first relapse. Whether complete response (CR) with incomplete count recovery (CRh) can be grouped with CR in relapsed ALL trials has not been formally studied. We analyzed 106 ALL patients at first relapse who were treated at three academic centers and achieved CR/CRh. White blood cell count at initial diagnosis and receiving hematopoietic cell transplant (HCT) were independent predictors of overall survival after relapse, while minimal residual disease (MRD) positivity and performance of HCT were predictors of relapse free survival (RFS). Patients who achieved MRD negativity and underwent HCT had the best outcomes. Our results suggest that MRD is a more powerful predictor of outcome than CRh.

  View details for PubMedID 28693363

• NCCN Guidelines (R) Insights Multiple Myeloma, Version 3.2018 Featured Updates to the NCCN Guidelines JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Kumar, S. K., Callander, N. S., Alsina, M., Atanackovic, D., Biermann, J., Castillo, J., Chandler, J. C., Costello, C., Faiman, M., Fung, H. C., Godby, K., Hofmeister, C., Holmberg, L., Holstein, S., Huff, C., Kang, Y., Kassim, A., Liedtke, M., Malek, E., Martin, T., Neppalli, V. T., Omel, J., Raje, N., Singhal, S., Somlo, G., Stockerl-Goldstein, K., Weber, D., Yahalom, J., Kumar, R., Shead, D. A. 2018; 16 (1): 11–20

  Abstract

  The NCCN Guidelines for Multiple Myeloma provide recommendations for diagnosis, evaluation, treatment, including supportive-care, and follow-up for patients with myeloma. These NCCN Guidelines Insights highlight the important updates/changes specific to the myeloma therapy options in the 2018 version of the NCCN Guidelines.

  View details for DOI 10.6004/jnccn.2018.0002

  View details for Web of Science ID 000419099800003

  View details for PubMedID 29295877

• Epidemiology and Clinical Implications of Gastrointestinal Symptoms in Systemic Amyloidosis Yen, T., Chen, F., Witteles, R., Liedtke, M., Nguyen, L. NATURE PUBLISHING GROUP. 2017: S240

  View details for Web of Science ID 000439259001037

• Clonal Expansion and Interrelatedness of Distinct B-Lineage Compartments in Multiple Myeloma Bone Marrow CANCER IMMUNOLOGY RESEARCH Hansmann, L., Han, A., Penter, L., Liedtke, M., Davis, M. M. 2017; 5 (9): 744–54

  Abstract

  Multiple myeloma is characterized by the clonal expansion of malignant plasma cells in the bone marrow. But the phenotypic diversity and the contribution of less predominant B-lineage clones to the biology of this disease have been controversial. Here, we asked whether cells bearing the dominant multiple myeloma immunoglobulin rearrangement occupy phenotypic compartments other than that of plasma cells. To accomplish this, we combined 13-parameter FACS index sorting and t-Stochastic Neighbor Embedding (t-SNE) visualization with high-throughput single-cell immunoglobulin sequencing to track selected B-lineage clones across different stages of human B-cell development. As expected, the predominant clones preferentially mapped to aberrant plasma cell compartments, albeit phenotypically altered from wild type. Interestingly, up to 1.2% of cells of the predominant clones colocalized with B-lineage cells of a normal phenotype. In addition, minor clones with distinct immunoglobulin sequences were detected in up to 9% of sequenced cells, but only 2 out of 12 of these clones showed aberrant immune phenotypes. The majority of these minor clones showed intraclonal silent nucleotide differences within the CDR3s and varying frequencies of somatic mutations in the immunoglobulin genes. Therefore, the phenotypic range of multiple myeloma cells in the bone marrow is not confined to aberrant-phenotype plasma cells but extends to low frequencies of normal-phenotype B cells, in line with the recently reported success of B cell-targeting cellular therapies in some patients. The majority of minor clones result from parallel nonmalignant expansion. Cancer Immunol Res; 5(9); 744-54. ©2017 AACR.

  View details for PubMedID 28768640

  View details for PubMedCentralID PMC5590392

• Novel therapeutic approaches for AL amyloid Liedtke, M. KARGER. 2017: 194

  View details for Web of Science ID 000411428400469

• NEOD001 DEMONSTRATES DURABLE PERIPHERAL NEUROPATHY RESPONSES IN PATIENTS WITH LIGHT CHAIN AMYLOIDOSIS AND PERSISTENT ORGAN DYSFUNCTION: RESULTS FROM A PHASE 1/2 STUDY Gertz, M., Comenzo, R. L., Landau, H., Sanchorawala, Weiss, B. M., Zonder, J. A., Walling, J., Kinney, G. G., Koller, M., Schenk, D. B., Guthrie, S. D., Liu, E., Alvarez-Baron, E., Liedtke, M. WILEY. 2017: 289–90

  View details for Web of Science ID 000409243500161

• NEOD001 demonstrates organ biomarker responses in patients with light chain amyloidosis and persistent organ dysfunction independently of previous hematologic response Liedtke, M., Comenzo, R. L., Landau, H., Sanchorawala, V., Weiss, B. M., Zonder, J. A., Schoenland, S. O., Walling, J., Kinney, G. G., Koller, M., Schenk, D. B., Guthrie, S. D., Liu, E., Gertz, M. A. KARGER. 2017: 34–35

  View details for Web of Science ID 000411428400085

• Daratumumab yields rapid and deep hematologic responses in patients with heavily pretreated AL amyloidosis BLOOD Kaufman, G. P., Schrier, S. L., Lafayette, R. A., Arai, S., Witteles, R. M., Liedtke, M. 2017; 130 (7): 900–902

  Abstract

  The majority of patients with immunoglobulin light chain amyloidosis (AL) fail to achieve a complete response (CR) to standard light chain suppressive chemotherapy, and almost all patients eventually experience hematologic relapse and progression of organ involvement. Additional well-tolerated treatment options are needed. We present our retrospective experience of 25 consecutive previously treated AL patients who received daratumumab, a CD38-directed monoclonal antibody approved for the treatment of multiple myeloma. Daratumumab was administered at 16 mg/kg weekly for 8 weeks, then every 2 weeks for 8 doses, and then every 4 weeks. Patients had received a median of 3 prior lines of therapy, with a previous hematologic CR in only 5 patients. The overall hematologic response rate to daratumumab was 76%, including CR in 36% and very good partial response in 24%. Median time to response was 1 month. Therapy was well tolerated, even among the 72% of patients with cardiac AL involvement. Grade 1-2 infusion reactions occurred in 15 patients, but no grade 3 or 4 reactions were observed. Daratumumab is a highly effective agent that produced rapid and deep hematologic responses without unexpected toxicity in our cohort of heavily pretreated AL patients.

  View details for PubMedID 28615223

• Inotuzumab ozogamicin in adults with relapsed or refractory CD22-positive acute lymphoblastic leukemia: a phase 1/2 study BLOOD ADVANCES DeAngelo, D. J., Stock, W., Stein, A. S., Shustov, A., Liedtke, M., Schiffer, C. A., Vandendries, E., Liau, K., Ananthakrishnan, R., Boni, J., Laird, A., Fostvedt, L., Kantarjian, H. M., Advani, A. S. 2017; 1 (15): 1167–80

  Abstract

  This study evaluated the safety, antitumor activity, pharmacokinetics, and pharmacodynamics of inotuzumab ozogamicin (InO) for CD22-positive relapsed/refractory acute lymphoblastic leukemia. In phase 1, patients received InO 1.2 (n = 3), 1.6 (n = 12), or 1.8 (n = 9) mg/m2 per cycle on days 1, 8, and 15 over a 28-day cycle (≤6 cycles). The recommended phase 2 dose (RP2D) was confirmed (expansion cohort; n = 13); safety and activity of InO were assessed in patients receiving the RP2D in phase 2 (n = 35) and in all treated patients (n = 72). The RP2D was 1.8 mg/m2 per cycle (0.8 mg/m2 on day 1; 0.5 mg/m2 on days 8 and 15), with reduction to 1.6 mg/m2 per cycle after complete remission (CR) or CR with incomplete marrow recovery (CRi). Treatment-related toxicities were primarily cytopenias. Four patients experienced treatment-related venoocclusive disease/sinusoidal obstruction syndrome (VOD/SOS; 1 fatal). Two VOD/SOS events occurred during treatment without intervening transplant; of 24 patients proceeding to poststudy transplant, 2 experienced VOD/SOS after transplant. Forty-nine (68%) patients had CR/CRi, with 41 (84%) achieving minimal residual disease (MRD) negativity. Median progression-free survival was 3.9 (95% confidence interval, 2.9-5.4) months; median overall survival was 7.4 (5.7-9.2) months for all treated patients, with median 23.7 (range, 6.8-29.8) months of follow-up for all treated patients alive at data cutoff. Achievement of MRD negativity was associated with higher InO exposure. InO was well tolerated and demonstrated high single-agent activity and MRD-negativity rates. This trial was registered at www.clinicaltrials.gov as #NCT01363297.

  View details for DOI 10.1182/bloodadvances.2016001925

  View details for Web of Science ID 000404535700019

  View details for PubMedID 29296758

  View details for PubMedCentralID PMC5728308

• NEOD001 demonstrates organ biomarker responses in patients with light chain amyloidosis and persistent organ dysfunction independently of previous haematological response Liedtke, M., Comenzo, R. L., Landau, H., Sanchorawala, V., Weiss, B. M., Zonder, J. A., Walling, J., Kinney, G. G., Koller, M., Schenk, D. B., Guthrie, S. D., Liu, E., Gertz, M. A. WILEY. 2017: 441

  View details for Web of Science ID 000401005301403

• NEOD001 DEMONSTRATES CARDIAC BIOMARKER RESPONSES IN PATIENTS WITH LIGHT CHAIN AMYLOIDOSIS: RESULTS FROM THE PHASE 1/2 STUDY Liedtke, M., Comenzo, R., Landau, H., Sanchorawala, V., Weiss, B., Zonder, J., Walling, J., Kinney, G., Koller, M., Schenk, D. B., Guthrie, S., Liu, E., Gertz, M. ELSEVIER SCIENCE INC. 2017: 825

  View details for Web of Science ID 000397342301347

• Recommendations from the Amyloidosis Research Consortium Educational Roundtable at the American College of Cardiology Annual Meeting, 1 April 2016 Maurer, M., Lousada, I., Hanna, M., Ruberg, F., Mohty, D., Dispenzieri, A., Liedtke, M., Paulson, I., Vest, J., Grogan, M. TAYLOR & FRANCIS LTD. 2017: 165–66

  View details for PubMedID 28434366

• Multiple Myeloma, Version 3.2017 Clinical Practice Guidelines in Oncology JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Kumar, S. K., Callander, N. S., Alsina, M., Atanackovic, D., Biermann, J. S., Chandler, J. C., Costello, C., Faiman, M., Fung, H. C., Gasparetto, C., Godby, K., Hofmeister, C., Holmberg, L., Holstein, S., Huff, C. A., Kassim, A., Liedtke, M., Martin, T., Omel, J., Raje, N., Reu, F. J., Singhal, S., Somlo, G., Stockerl-Goldstein, K., Treon, S. P., Weber, D., Yahalom, J., Shead, D. A., Kumar, R. 2017; 15 (2): 230-?

  Abstract

  Multiple myeloma (MM) is caused by the neoplastic proliferation of plasma cells. These neoplastic plasma cells proliferate and produce monoclonal immunoglobulin in the bone marrow causing skeletal damage, a hallmark of multiple myeloma. Other MM-related complications include hypercalcemia, renal insufficiency, anemia, and infections. The NCCN Multiple Myeloma Panel members have developed guidelines for the management of patients with various plasma cell dyscrasias, including solitary plasmacytoma, smoldering myeloma, multiple myeloma, systemic light chain amyloidosis, and Waldenström's macroglobulinemia. The recommendations specific to the diagnosis and treatment of patients with newly diagnosed MM are discussed in this article.

  View details for Web of Science ID 000394927100008

  View details for PubMedID 28188192

• Functional Cardiac Recovery and Hematologic Response to Chemotherapy in Patients With Light-Chain Amyloidosis (from the Stanford University Amyloidosis Registry). The American journal of cardiology Tuzovic, M. n., Kobayashi, Y. n., Wheeler, M. n., Barrett, C. n., Liedtke, M. n., Lafayette, R. n., Schrier, S. n., Haddad, F. n., Witteles, R. n. 2017; 120 (8): 1381–86

  Abstract

  Cardiac involvement is common in patients with light-chain (AL) amyloidosis and portends a poor prognosis, although little is known about the changes in cardiac mechanics after chemotherapy. We sought to explore the relation between amyloidosis staging and baseline cardiac mechanics and to investigate short-term changes in cardiac mechanics after chemotherapy. We identified 41 consecutive patients from the Stanford Amyloid Center who had echocardiograms and free light-chain values before and after chemotherapy, along with 40 age- and gender-matched controls. Echocardiographic assessment included left ventricular global longitudinal strain, E/e' ratio, and left atrial (LA) stiffness. Hematologic response to chemotherapy was defined as ≥50% reduction in the difference between the involved and the uninvolved free light chain (dFLC). The mean age was 66.9 ± 8.4 years and 66% were men. Before chemotherapy, global longitudinal strain, E/e' ratio, and LA stiffness were impaired in patients with amyloidosis compared with controls, and the severity of impairment worsened with advanced staging. After chemotherapy, hematologic response was observed in 30 (73%) patients. There was a significant association between the change in dFLC and cardiac function (E/e' ratio: r = -0.43, p = 0.01; LA stiffness: r = -0.35, p = 0.05). There was no significant improvement in cardiac mechanics in patients without a hematologic response to chemotherapy. In conclusion, amyloidosis stage correlated with noninvasive measurements of cardiac mechanics, and improvement in dFLC correlated with cardiac improvement on short-term follow-up echocardiography.

  View details for PubMedID 28844519

• Efficacy and safety of midostaurin in patients with advanced systemic mastocytosis: 10-year median follow-up of a phase II trial. Leukemia DeAngelo, D. J., George, T. I., Linder, A. n., Langford, C. n., Perkins, C. n., Ma, J. n., Westervelt, P. n., Merker, J. D., Berube, C. n., Coutre, S. n., Liedtke, M. n., Medeiros, B. n., Sternberg, D. n., Dutreix, C. n., Ruffie, P. A., Corless, C. n., Graubert, T. J., Gotlib, J. n. 2017

  Abstract

  Patients with advanced systemic mastocytosis (SM) (e.g. aggressive SM (ASM), SM with an associated hematologic neoplasm (SM-AHN) and mast cell leukemia (MCL)) have limited treatment options and exhibit reduced survival. Midostaurin is an oral multikinase inhibitor that inhibits D816V-mutated KIT, a primary driver of SM pathogenesis. We conducted a phase II trial of midostaurin 100 mg twice daily, administered as 28-day cycles, in 26 patients (ASM, n=3; SM-AHN, n= 17; MCL, n=6) with at least one sign of organ damage. During the first 12 cycles, the overall response rate was 69% (major/partial response: 50/19%) with clinical benefit in all advanced SM variants. With ongoing therapy, 2 patients achieved a complete remission of their SM. Midostaurin produced a ⩾50% reduction in bone marrow mast cell burden and serum tryptase level in 68% and 46% of patients, respectively. Median overall survival for the entire cohort was 40 months, and 18.5 months for MCL patients. Low-grade gastrointestinal side effects were common and manageable with antiemetics. The most frequent grade 3/4 nonhematologic and hematologic toxicities were asymptomatic hyperlipasemia (15%) and anemia (12%). With median follow-up of 10 years, no unexpected toxicities emerged. These data establish the durable activity and tolerability of midostaurin in advanced SM.Leukemia advance online publication, 25 August 2017; doi:10.1038/leu.2017.234.

  View details for PubMedID 28744009

• Inotuzumab Ozogamicin versus Standard Therapy for Acute Lymphoblastic Leukemia. New England journal of medicine Kantarjian, H. M., DeAngelo, D. J., Stelljes, M., Martinelli, G., Liedtke, M., Stock, W., Gökbuget, N., O'Brien, S., Wang, K., Wang, T., Paccagnella, M. L., Sleight, B., Vandendries, E., Advani, A. S. 2016; 375 (8): 740-753

  Abstract

  The prognosis for adults with relapsed acute lymphoblastic leukemia is poor. We sought to determine whether inotuzumab ozogamicin, an anti-CD22 antibody conjugated to calicheamicin, results in better outcomes in patients with relapsed or refractory acute lymphoblastic leukemia than does standard therapy.In this phase 3 trial, we randomly assigned adults with relapsed or refractory acute lymphoblastic leukemia to receive either inotuzumab ozogamicin (inotuzumab ozogamicin group) or standard intensive chemotherapy (standard-therapy group). The primary end points were complete remission (including complete remission with incomplete hematologic recovery) and overall survival.Of the 326 patients who underwent randomization, the first 218 (109 in each group) were included in the primary intention-to-treat analysis of complete remission. The rate of complete remission was significantly higher in the inotuzumab ozogamicin group than in the standard-therapy group (80.7% [95% confidence interval {CI}, 72.1 to 87.7] vs. 29.4% [95% CI, 21.0 to 38.8], P<0.001). Among the patients who had complete remission, a higher percentage in the inotuzumab ozogamicin group had results below the threshold for minimal residual disease (0.01% marrow blasts) (78.4% vs. 28.1%, P<0.001); the duration of remission was longer in the inotuzumab ozogamicin group (median, 4.6 months [95% CI, 3.9 to 5.4] vs. 3.1 months [95% CI, 1.4 to 4.9]; hazard ratio, 0.55 [95% CI, 0.31 to 0.96]; P=0.03). In the survival analysis, which included all 326 patients, progression-free survival was significantly longer in the inotuzumab ozogamicin group (median, 5.0 months [95% CI, 3.7 to 5.6] vs. 1.8 months [95% CI, 1.5 to 2.2]; hazard ratio, 0.45 [97.5% CI, 0.34 to 0.61]; P<0.001); the median overall survival was 7.7 months (95% CI, 6.0 to 9.2) versus 6.7 months (95% CI, 4.9 to 8.3), and the hazard ratio was 0.77 (97.5% CI, 0.58 to 1.03) (P=0.04). In the safety population, the most frequent grade 3 or higher nonhematologic adverse events with inotuzumab ozogamicin were liver-related. Veno-occlusive liver disease of any grade occurred in 15 patients (11%) who received inotuzumab ozogamicin and in 1 patient (1%) who received standard therapy.The rate of complete remission was higher with inotuzumab ozogamicin than with standard therapy, and a higher percentage of patients in the inotuzumab ozogamicin group had results below the threshold for minimal residual disease. Both progression-free and overall survival were longer with inotuzumab ozogamicin. Veno-occlusive liver disease was a major adverse event associated with inotuzumab ozogamicin. (Funded by Pfizer; INO-VATE ALL ClinicalTrials.gov number, NCT01564784.).

  View details for DOI 10.1056/NEJMoa1509277

  View details for PubMedID 27292104

• NEOD001 demonstrates cardiac biomarker responses in patients with light chain amyloidosis and persistent organ dysfunction: results from the expansion phase of a phase 1/2 study Liedtke, M., Comenzo, R. L., Landau, H., Sanchorawala, V., Weiss, B. M., Zonder, J. A., Walling, J., Kinney, G. G., Koller, M., Gertz, M. A. OXFORD UNIV PRESS. 2016: 220

  View details for Web of Science ID 000383869501085

• First-in-Human Phase I/II Study of NEOD001 in Patients With Light Chain Amyloidosis and Persistent Organ Dysfunction. Journal of clinical oncology Gertz, M. A., Landau, H., Comenzo, R. L., Seldin, D., Weiss, B., Zonder, J., Merlini, G., Schönland, S., Walling, J., Kinney, G. G., Koller, M., Schenk, D. B., Guthrie, S. D., Liedtke, M. 2016; 34 (10): 1097-1103

  Abstract

  Light chain (AL) amyloidosis is caused by the accumulation of misfolded proteins, which induces the dysfunction of vital organs. NEOD001 is a monoclonal antibody targeting these misfolded proteins. We report interim data from a phase I/II dose-escalation/expansion study of NEOD001 in patients with AL amyloidosis and persistent organ dysfunction (NCT01707264).Patients who had completed at least one previous anti-plasma cell-directed therapy, had partial hematologic response or better, and had persistent organ dysfunction received NEOD001 intravenously every 28 days. Dose levels of 0.5, 1, 2, 4, 8, 16, and 24 mg/kg were evaluated (3 + 3 study design). Primary objectives were to determine the maximum tolerated dose and the recommended dose for future studies and to evaluate safety/tolerability. Secondary and exploratory objectives included pharmacokinetics, immunogenicity, and organ responses on the basis of published consensus criteria.Twenty-seven patients were enrolled in seven cohorts (dose-escalation component). No drug-related serious adverse events (AEs), discontinuations because of drug-related AEs, dose-limiting toxicities, or antidrug antibodies were reported. The most frequent AEs were fatigue, upper respiratory tract infection, cough, and dyspnea. Recommended dosing was 24 mg/kg. Pharmacokinetics support intravenous dosing every 28 days. Of 14 cardiac-evaluable patients, eight (57%) met the criteria for cardiac response and six (43%) had stable disease. Of 15 renal-evaluable patients, nine (60%) met the criteria for renal response and six (40%) had stable disease.Monthly infusions of NEOD001 were safe and well tolerated. Recommended future dosing was 24 mg/kg. Organ response rates compared favorably with those reported previously for chemotherapy. A phase II expansion is ongoing. A global phase III study (NCT02312206) has been initiated. Antibody therapy targeting misfolded proteins is a potential new therapy for the management of AL amyloidosis.

  View details for DOI 10.1200/JCO.2015.63.6530

  View details for PubMedID 26858336

• Multiple Myeloma, Version 3.2016 Featured Updates to the NCCN Guidelines JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Anderson, K. C., Alsina, M., Atanackovic, D., Biermann, J. S., Chandler, J. C., Costello, C., Djulbegovic, B., Fung, H. C., Gasparetto, C., Godby, K., Hofmeister, C., Holmberg, L., Holstein, S., Huff, C. A., Kassim, A., Krishnan, A. Y., Kumar, S. K., Liedtke, M., Lunning, M., Raje, N., Reu, F. J., Singhal, S., Somlo, G., Stockerl-Goldstein, K., Treon, S. P., Weber, D., Yahalom, J., Shead, D. A., Kumar, R. 2016; 14 (4): 389-400

  Abstract

  These NCCN Guidelines Insights highlight the important updates/changes specific to the 2016 version of the NCCN Clinical Practice Guidelines in Oncology for Multiple Myeloma. These changes include updated recommendations to the overall management of multiple myeloma from diagnosis and staging to new treatment options.

  View details for Web of Science ID 000374082300004

• A phase 1, open-label, dose-escalation study of pralatrexate in combination with bortezomib in patients with relapsed/refractory multiple myeloma. British journal of haematology Dunn, T. J., Dinner, S., Price, E., Coutré, S. E., Gotlib, J., Hao, Y., Berube, C., Medeiros, B. C., Liedtke, M. 2016; 173 (2): 253-259

  Abstract

  Pralatrexate inhibits folic acid metabolism, and preclinical studies have shown that it is cytotoxic to multiple myeloma cells. This phase 1 study investigated the safety and efficacy of pralatrexate in combination with bortezomib in adults with relapsed or refractory multiple myeloma. A standard 3 + 3 design was used. Patients received intravenous pralatrexate at doses ranging from 10 to 30 mg/m(2) and intravenous bortezomib at a dose of 1·3 mg/m(2) on days 1, 8 and 15 of each 4-week cycle. Eleven patients were enrolled and completed a median of two cycles. The maximum tolerated dose was 20 mg/m(2) . Two patients experienced dose-limiting toxicity of mucositis. The most frequent non-haematological toxicities were fatigue (55%) and mucositis (45%). There were three serious adverse events in three patients: rash, sepsis and hypotension. One patient (9%) had a very good partial response, 1 (9%) had a partial response, 1 (9%) had minimal response and two (18%) had progressive disease. The median duration of response was 4 months, the median time to next treatment was 3·4 months and the median time to progression was 4 months. Pralatrexate, in combination with bortezomib, was generally safe and demonstrated modest activity in relapsed or refractory multiple myeloma. Clinicaltrials.gov identifier: NCT01114282.

  View details for DOI 10.1111/bjh.13946

  View details for PubMedID 27040320

• Sequential azacitidine plus lenalidomide in previously treated elderly patients with acute myeloid leukemia and higher risk myelodysplastic syndrome. Leukemia & lymphoma Narayan, R., Garcia, J. S., Percival, M. M., Berube, C., Coutre, S., Gotlib, J., Greenberg, P., Liedtke, M., Hewitt, R., Regan, K., Williamson, C., Doykan, C., Cardone, M. H., McMillan, A., Medeiros, B. C. 2016; 57 (3): 609-615

  Abstract

  The outcome of sequential azacitidine with lenalidomide has not been reported in previously treated patients with acute myeloid leukemia (AML) and higher risk myelodysplastic syndrome (MDS). We describe a phase 2 study evaluating the safety and efficacy of this combination in elderly patients with AML and MDS with prior hypomethylating agent (HMA) and/or immunomodulatory agent exposure. Patients were treated on a 42-day cycle with azacitidine at 75 mg/m2 SQ/IV daily on days 1-7, followed by lenalidomide 50 mg orally daily on days 8-28. Median number of treatment cycles on study was two (range, 1-11). Of 32 evaluable patients, the overall response rate was 25%. Neutropenic fever was the most common serious adverse event, but overall the combination was well-tolerated. The median overall survival (OS) for responders versus non-responders was 9.8 versus 4.0 months, respectively (HR 0.36, p=0.016). In conclusion, this combination demonstrated modest clinical activity in this poor risk population.

  View details for DOI 10.3109/10428194.2015.1091930

  View details for PubMedID 26374199

• Recurrent Subepidermal Blistering Dermatosis Heralding Disease Relapse in IgA Kappa Multiple Myeloma: Report of a Case and a Review of the Literature. Clinical lymphoma, myeloma & leukemia Leatham, H. W., Novoa, R., Liedtke, M., Kwong, B. Y. 2016; 16 (1): e1-5

  View details for DOI 10.1016/j.clml.2015.11.007

  View details for PubMedID 26708980

• Identification of Doxorubicin as an Inhibitor of the IRE1a-XBP1 Axis of the Unfolded Protein Response. Scientific reports Jiang, D., Lynch, C., Medeiros, B. C., Liedtke, M., Bam, R., Tam, A. B., Yang, Z., Alagappan, M., Abidi, P., Le, Q., Giaccia, A. J., Denko, N. C., Niwa, M., Koong, A. C. 2016; 6: 33353-?

  Abstract

  Activation of the IRE1α-XBP1 branch of the unfolded protein response (UPR) has been implicated in multiple types of human cancers, including multiple myeloma (MM). Through an in silico drug discovery approach based on protein-compound virtual docking, we identified the anthracycline antibiotic doxorubicin as an in vitro and in vivo inhibitor of XBP1 activation, a previously unknown activity for this widely utilized cancer chemotherapeutic drug. Through a series of mechanistic and phenotypic studies, we showed that this novel activity of doxorubicin was not due to inhibition of topoisomerase II (Topo II). Consistent with its inhibitory activity on the IRE1α-XBP1 branch of the UPR, doxorubicin displayed more potent cytotoxicity against MM cell lines than other cancer cell lines that have lower basal IRE1α-XBP1 activity. In addition, doxorubicin significantly inhibited XBP1 activation in CD138(+) tumor cells isolated from MM patients. Our findings suggest that the UPR-modulating activity of doxorubicin may be utilized clinically to target IRE1α-XBP1-dependent tumors such as MM.

  View details for DOI 10.1038/srep33353

  View details for PubMedID 27634301

  View details for PubMedCentralID PMC5025885

• Report of the Relapsed/Refractory Cohort of SWOG S0919: A Phase 2 Study of Idarubicin and Cytarabine in Combination with Pravastatin for Acute Myelogenous Leukemia Advani, A. S., Li, H., Michaelis, L. C., Medeiros, B. C., Liedtke, M., List, A. F., O'Dwyer, K., Othus, M., Erba, H. P., Appelbaum, F. R. AMER SOC HEMATOLOGY. 2015

  View details for Web of Science ID 000368021800060

• Multiple Myeloma, Version 2.2016 JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Anderson, K. C., Alsina, M., Atanackovic, D., Biermann, J. S., Chandler, J. C., Costello, C., Djulbegovic, B., Fung, H. C., Gasparetto, C., Godby, K., Hofmeister, C., Holmberg, L., Holstein, S., Huff, C. A., Kassim, A., Krishnan, A. Y., Kumar, S. K., Liedtke, M., Lunning, M., Raje, N., Singhal, S., Smith, C., Somlo, G., Stockerl-Goldstein, K., Treon, S. P., Weber, D., Yahalom, J., Shead, D. A., Kumar, R. 2015; 13 (11): 1398-1435

  Abstract

  Multiple myeloma (MM) is a malignant neoplasm of plasma cells that accumulate in bone marrow, leading to bone destruction and marrow failure. Recent statistics from the American Cancer Society indicate that the incidence of MM is increasing. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) included in this issue address management of patients with solitary plasmacytoma and newly diagnosed MM.

  View details for Web of Science ID 000364277500010

  View details for PubMedID 26553768

  View details for PubMedCentralID PMC4891187

• CD93 Marks a Non-Quiescent Human Leukemia Stem Cell Population and Is Required for Development of MLL-Rearranged Acute Myeloid Leukemia. Cell stem cell Iwasaki, M., Liedtke, M., Gentles, A. J., Cleary, M. L. 2015; 17 (4): 412-421

  Abstract

  Leukemia stem cells (LSCs) are thought to share several properties with hematopoietic stem cells (HSCs), including cell-cycle quiescence and a capacity for self-renewal. These features are hypothesized to underlie leukemic initiation, progression, and relapse, and they also complicate efforts to eradicate leukemia through therapeutic targeting of LSCs without adverse effects on HSCs. Here, we show that acute myeloid leukemias (AMLs) with genomic rearrangements of the MLL gene contain a non-quiescent LSC population. Although human CD34(+)CD38(-) LSCs are generally highly quiescent, the C-type lectin CD93 is expressed on a subset of actively cycling, non-quiescent AML cells enriched for LSC activity. CD93 expression is functionally required for engraftment of primary human AML LSCs and leukemogenesis, and it regulates LSC self-renewal predominantly by silencing CDKN2B, a major tumor suppressor in AML. Thus, CD93 expression identifies a predominantly cycling, non-quiescent leukemia-initiating cell population in MLL-rearranged AML, providing opportunities for selective targeting and eradication of LSCs.

  View details for DOI 10.1016/j.stem.2015.08.008

  View details for PubMedID 26387756

  View details for PubMedCentralID PMC4592469

• Mass Cytometry Analysis Shows That a Novel Memory Phenotype B Cell Is Expanded in Multiple Myeloma CANCER IMMUNOLOGY RESEARCH Hansmann, L., Blum, L., Ju, C., Liedtke, M., Robinson, W. H., Davis, M. M. 2015; 3 (6): 650-660

  Abstract

  It would be very beneficial if the status of cancers could be determined from a blood specimen. However, peripheral blood leukocytes are very heterogeneous between individuals, and thus high-resolution technologies are likely required. We used cytometry by time-of-flight and next-generation sequencing to ask whether a plasma cell cancer (multiple myeloma) and related precancerous states had any consistent effect on the peripheral blood mononuclear cell phenotypes of patients. Analysis of peripheral blood samples from 13 cancer patients, 9 precancer patients, and 9 healthy individuals revealed significant differences in the frequencies of the T-cell, B-cell, and natural killer-cell compartments. Most strikingly, we identified a novel B-cell population that normally accounts for 4.0% ± 0.7% (mean ± SD) of total B cells and is up to 13-fold expanded in multiple myeloma patients with active disease. This population expressed markers previously associated with both memory (CD27(+)) and naïve (CD24(lo)CD38(+)) phenotypes. Single-cell immunoglobulin gene sequencing showed polyclonality, indicating that these cells are not precursors to the myeloma, and somatic mutations, a characteristic of memory cells. SYK, ERK, and p38 phosphorylation responses, and the fact that most of these cells expressed isotypes other than IgM or IgD, confirmed the memory character of this population, defining it as a novel type of memory B cells.

  View details for DOI 10.1158/2326-6066.CIR-14-0236-T

  View details for Web of Science ID 000357430000010

  View details for PubMedID 25711758

  View details for PubMedCentralID PMC4457663

• The VITAL study: A randomized, double-blind, placebo-controlled, global, phase III study of NEOD001 in patients with AL amyloidosis and cardiac dysfunction. Liedtke, M., Merlini, G., Landau, H., Comenzo, R., Seldin, D. C., Weiss, B. M., Zonder, J. A., Walling, J., Kinney, G., Koller, M., Gertz, M. A. AMER SOC CLINICAL ONCOLOGY. 2015

  View details for Web of Science ID 000358036904876

• Outcomes after heart transplantation for amyloid cardiomyopathy in the modern era. American journal of transplantation Davis, M. K., Kale, P., Liedtke, M., Schrier, S., Arai, S., Wheeler, M., Lafayette, R., Coakley, T., Witteles, R. M. 2015; 15 (3): 650-658

  Abstract

  We conducted a review of patients undergoing heart transplantation (HT) at our institution for amyloid cardiomyopathy (ACM) between 2008 and 2013. Complete follow-up was available for all patients. Nineteen patients with ACM underwent HT during the study period, accounting for 9.4% of all HT performed at our institution during this period. Amyloid subtype was light chain (AL) in 9 patients and transthyretin (ATTR) in 10 (2 wild-type, 7 familial, 1 unknown). Eight of nine patients with AL amyloidosis began chemotherapy prior to HT, six have resumed chemotherapy since HT, and five have undergone autologous stem cell transplantation. Most recent free light chain levels in AL patients decreased by a median of 85% from peak values. Only one patient developed recurrent graft amyloidosis, occurring at 3.5 years post-HT and asymptomatic. After a median follow-up of 380 days, 17 (89.5%) patients are alive. To our knowledge, this is the largest single-center series reported of ACM patients undergoing HT in the modern era. Our results suggest that acceptable outcomes following HT can be achieved in the short-to-intermediate term and that this is a feasible option for end-stage ACM with careful patient selection and aggressive control of amyloidogenic light chains in AL patients.

  View details for DOI 10.1111/ajt.13025

  View details for PubMedID 25648766

• A Phase I Dose-Escalation Study of Carfilzomib in Patients with Previously-Treated Systemic Light-Chain (AL) Amyloidosis Cohen, A. D., Scott, E. C., Liedtke, M., Kaufman, J. L., Landau, H., Vesole, D. H., Gomes, C. L., Gasparetto, C., Lentzsch, S., Rosenzweig, M., Sanchorawala, V., Smith, D. D., Comenzo, R. L., Durie, B. M. AMER SOC HEMATOLOGY. 2014

  View details for Web of Science ID 000349233808070

• Salvage therapy with mitoxantrone, etoposide and cytarabine in relapsed or refractory acute lymphoblastic leukemia LEUKEMIA RESEARCH Liedtke, M., Dunn, T., Dinner, S., Coutre, S. E., Berubea, C., Gotlib, J., Patel, S., Medeiros, B. 2014; 38 (12): 1441-1445

  Abstract

  The survival of patients with relapsed or refractory acute lymphoblastic leukemia (ALL) is poor. We performed a retrospective analysis of 40 patients treated with five days of mitoxantrone 8mg/m(2)/day, etoposide 100mg/m(2)/day, and cytarabine 1000mg/m(2)/day (MEC). The complete remission rate was 30% and median remission duration was 11.2 months. Median overall survival was 6.5 months. In univariate analysis, patients in first relapse had improved overall survival compared to ≥second relapse (p=0.02). Thirty-day mortality rate was 7.5%. In relapsed or refractory ALL, MEC demonstrated moderate activity, but did not improve survival compared to published salvage chemotherapy regimens.

  View details for DOI 10.1016/j.leukres.2014.09.018

  View details for Web of Science ID 000345614400011

• Indolent T-lymphoblastic Proliferation With Disseminated Multinodal Involvement and Partial CD33 Expression. American journal of surgical pathology Ohgami, R. S., Sendamarai, A. K., Atwater, S. K., Liedtke, M., Fleming, M. D., Natkunam, Y., Warnke, R. A. 2014; 38 (9): 1298-1304

  Abstract

  Although indolent T-lymphoblastic proliferations (iT-LBP) are rare, this diagnosis should be excluded in any patient with an extrathymic proliferation of immature TdT+T cells. Unlike T-lymphoblastic leukemia/lymphoma, patients with iT-LBP do not require chemotherapy. We report a case of iT-LBP with disseminated multinodal involvement in an otherwise healthy 49-year-old woman. Multiple lymph node biopsies were performed over the course of several months demonstrating persistent and anatomically diffuse involvement. Over 18 months, and without therapy, she has remained healthy, and her lymphadenopathy significantly improved. No bone marrow or peripheral blood involvement was ever identified. Atypical T cells showed an immunophenotypic spectrum of T-cell antigen expression with partial CD33 on a subset of T cells detected by both flow cytometry and immunohistochemistry. Both T-cell clonality and Human Androgen Receptor Assay (HUMARA) studies, performed on lymph node biopsy specimens, were negative. This case represents the first detailed clinical, morphologic, molecular, and immunophenotypic description of disseminated multinodal involvement by nonclonal iT-LBP with partial CD33 expression on T cells.

  View details for DOI 10.1097/PAS.0000000000000197

  View details for PubMedID 24618611

• Current therapy and novel agents for relapsed or refractory acute lymphoblastic leukemia LEUKEMIA & LYMPHOMA Dinner, S., Lee, D., Liedtke, M. 2014; 55 (8): 1715-1724

  Abstract

  Despite high rates of complete remission in newly diagnosed adult acute lymphoblastic leukemia (ALL), rates of long-term leukemia-free survival are disappointingly low. Treatment of relapsed disease with chemotherapy, even in patients able to pursue consolidation with allogeneic stem cell transplant, has demonstrated limited success. There are no established standards of care in this setting and few standard treatment options. Novel agents targeting antigens on the lymphoblast cell surface offer unique side effect and anti-leukemic profiles which suggest that their use alone or in combination with chemotherapy may achieve improved outcomes for relapsed or refractory ALL.

  View details for DOI 10.3109/10428194.2013.856428

  View details for Web of Science ID 000340224100006

  View details for PubMedID 24251864

• Effects of serum and plasma matrices on multiplex immunoassays. Immunologic research Rosenberg-Hasson, Y., Hansmann, L., Liedtke, M., Herschmann, I., Maecker, H. T. 2014; 58 (2-3): 224-233

  Abstract

  Multiplexed fluorescence or electrochemiluminescence immunoassays of soluble cytokines are commonly performed in the context of human serum or plasma, to look for disease biomarkers and to monitor the immune system in a simple and minimally invasive way. These assays provide challenges due to the complexities of the matrix (serum or plasma) and the presence of many cytokines near the limit of detection of the assay. Here, we compare the readout of matched serum and plasma samples, which are generally correlated. However, a subset of cytokines usually have higher levels in serum, and the non-specific background is significantly increased in serum versus plasma. Presumably as a result of this non-specific background, disease-related decreases in low-abundance cytokines can sometimes be detected in plasma but not in serum. We further show, through spike recovery experiments, that both serum and plasma inhibit the readout of many cytokines, with some variability between donors, but with serum causing greater inhibition than plasma in many cases. Standard diluents from different vendors can partially reverse this inhibition to varying degrees. Dilution of samples can also partly overcome the inhibitory effect of the matrix. We also show that dilution is nonlinear and differentially affects various cytokines. Together, these data argue that (1) plasma is a more sensitive matrix for detecting changes in certain low-abundance cytokines; (2) calculation of concentrations in serum or plasma matrices is inherently inaccurate; and (3) dilution of samples should not be assumed to be linear, i.e., all comparisons need to be made among similarly diluted samples.

  View details for DOI 10.1007/s12026-014-8491-6

  View details for PubMedID 24522699

• Implantable cardioverter-defibrillator placement in patients with cardiac amyloidosis HEART RHYTHM Varr, B. C., Zarafshar, S., Coakley, T., Liedtke, M., Lafayette, R. A., Arai, S., Schrier, S. L., Witteles, R. M. 2014; 11 (1): 158-162

  View details for DOI 10.1016/j.hrthm.2013.10.026

  View details for PubMedID 24121001

• A single-center experience of the nationwide daunorubicin shortage: substitution with doxorubicin in adult acute lymphoblastic leukemia. Leukemia & lymphoma Patel, S., Liedtke, M., Ngo, D., Medeiros, B. C. 2013; 54 (10): 2231-2235

  Abstract

  Due to a national shortage of daunorubicin we evaluated the effects of substituting doxorubicin 1:1 in the induction phase for adult patients with newly diagnosed acute lymphoblastic leukemia (ALL). We identified 10 patients receiving doxorubicin instead of daunorubicin as part of their induction on Cancer and Leukemia Group B (CALGB) 9511 or CALGB10403 and retrospectively compared them to 83 patients who received treatment on the same protocols with daunorubicin. Response rates were similar, independent of anthracycline received, with either CALGB9511 or CALGB10403. In either regimen, doxorubicin resulted in longer absolute neutrophil count (ANC) recovery time and hospitalization. Doxorubicin as part of CALGB9511 resulted in greater than three-fold higher mucositis. Sepsis and death during induction were significantly more frequent in patients who received doxorubicin on CALGB10403. While remission rates were similar, the use of doxorubicin was associated with prolonged neutropenia, higher risk of mucositis, infection and sepsis, and prolonged hospitalization. Higher induction mortality observed with doxorubicin substitution in this analysis needs further study.

  View details for DOI 10.3109/10428194.2013.772606

  View details for PubMedID 23383599

• Lenalidomide, melphalan and dexamethasone in a population of patients with immunoglobulin light chain amyloidosis with high rates of advanced cardiac involvement. Haematologica Dinner, S., Witteles, W., Afghahi, A., Witteles, R., Arai, S., Lafayette, R., Schrier, S. L., Liedtke, M. 2013; 98 (10): 1593-1599

  Abstract

  Immunoglobulin light chain amyloidosis remains incurable despite recent therapeutic advances, and is particularly difficult to treat in patients with amyloid cardiomyopathy. Based on evidence of activity in multiple myeloma, we designed a pilot study of an oral regimen of lenalidomide in combination with dexamethasone and low dose melphalan in order to evaluate its safety and efficacy in patients with amyloidosis, including those with advanced cardiac involvement. Twenty-five patients were enrolled. Ninety-two percent of patients had cardiac involvement by amyloidosis, and 36% of patients met criteria for Mayo Clinic cardiac stage III disease. Patients received up to 9 cycles of treatment, consisting of lenalidomide 10 mg/day orally on days 1 - 21 (28 day cycle); melphalan 0.18mg/kg orally on days 1-4; and dexamethasone 40 mg orally on days 1, 8, 15, 22. High rates (33%) of cardiac arrhythmias and low rates of treatment completion (12.5%) were observed. Ten patients died during the study, all within the first several months of treatment due to acute cardiac events. The overall hematologic response rate was 58%, however organ responses were seen in only 8% of patients. Overall survival at one year was 58%. While we confirmed the hematologic response rates observed with similar regimens, front line treatment with melphalan, lenalidomide and dexamethasone was toxic, ineffective, and did not alter survival outcomes for patients with high risk cardiac disease. Our data highlight the importance of developing novel treatment approaches for amyloid cardiomyopathy. The trial was registered at www.clinicaltrials.gov (NCT00890552).

  View details for DOI 10.3324/haematol.2013.084574

  View details for PubMedID 23716538

• AG10 inhibits amyloidogenesis and cellular toxicity of the familial amyloid cardiomyopathy-associated V122I transthyretin PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Penchala, S. C., Connelly, S., Wang, Y., Park, M. S., Zhao, L., Baranczak, A., Rappley, I., Vogel, H., Liedtke, M., Witteles, R. M., Powers, E. T., Reixach, N., Chan, W. K., Wilson, I. A., Kelly, J. W., Graef, I. A., Alhamadsheh, M. M. 2013; 110 (24): 9992-9997

  Abstract

  The misassembly of soluble proteins into toxic aggregates, including amyloid fibrils, underlies a large number of human degenerative diseases. Cardiac amyloidoses, which are most commonly caused by aggregation of Ig light chains or transthyretin (TTR) in the cardiac interstitium and conducting system, represent an important and often underdiagnosed cause of heart failure. Two types of TTR-associated amyloid cardiomyopathies are clinically important. The Val122Ile (V122I) mutation, which alters the kinetic stability of TTR and affects 3% to 4% of African American subjects, can lead to development of familial amyloid cardiomyopathy. In addition, aggregation of WT TTR in individuals older than age 65 y causes senile systemic amyloidosis. TTR-mediated amyloid cardiomyopathies are chronic and progressive conditions that lead to arrhythmias, biventricular heart failure, and death. As no Food and Drug Administration-approved drugs are currently available for treatment of these diseases, the development of therapeutic agents that prevent TTR-mediated cardiotoxicity is desired. Here, we report the development of AG10, a potent and selective kinetic stabilizer of TTR. AG10 prevents dissociation of V122I-TTR in serum samples obtained from patients with familial amyloid cardiomyopathy. In contrast to other TTR stabilizers currently in clinical trials, AG10 stabilizes V122I- and WT-TTR equally well and also exceeds their efficacy to stabilize WT and mutant TTR in whole serum. Crystallographic studies of AG10 bound to V122I-TTR give valuable insights into how AG10 achieves such effective kinetic stabilization of TTR, which will also aid in designing better TTR stabilizers. The oral bioavailability of AG10, combined with additional desirable drug-like features, makes it a very promising candidate to treat TTR amyloid cardiomyopathy.

  View details for DOI 10.1073/pnas.1300761110

  View details for Web of Science ID 000320930100085

  View details for PubMedID 23716704

• The prognostic value of diagnosing concurrent multiple myeloma in immunoglobulin light chain amyloidosis BRITISH JOURNAL OF HAEMATOLOGY Dinner, S., Witteles, W., Witteles, R., Lam, A., Arai, S., Lafayette, R., George, T. I., Schrier, S. L., Liedtke, M. 2013; 161 (3): 367-372

  Abstract

  The prevalence and prognostic value of a concomitant diagnosis of symptomatic or asymptomatic multiple myeloma (MM), as defined by the current International Myeloma Working Group (IMWG) criteria, in patients with immunoglobulin light chain amyloidosis (AL), are unknown. We studied 46 consecutive patients with AL who underwent quantification of serum M-protein and clonal bone marrow plasma cells, as well as a comprehensive evaluation for end organ damage by MM. Using standard morphology and CD138 immunohistochemical staining, 57% and 80% of patients were found to have concomitant MM, respectively. Nine patients exhibited end organ damage consistent with a diagnosis of symptomatic MM. While overall survival was similar between AL patients with or without concurrent myeloma (1-year overall survival 68% vs. 87%; P = 0.27), a diagnosis of symptomatic myeloma was associated with inferior outcome (1-year overall survival 39% vs. 81%; P = 0.005). Quantification of bone marrow plasma cells by both standard morphology and CD138 immunohistochemistry identified a much higher prevalence of concurrent MM in patients with AL than previously reported. Evaluation of bone marrow plasma cell infiltration and presence of myeloma associated end organ damage could be clinically useful for prognostication of patients with AL.

  View details for DOI 10.1111/bjh.12269

  View details for PubMedID 23432783

• Sequential azacitidine plus lenalidomide combination for elderly patients with untreated acute myeloid leukemia. Haematologica Pollyea, D. A., Zehnder, J., Coutre, S., Gotlib, J. R., Gallegos, L., Abdel-Wahab, O., Greenberg, P., Zhang, B., Liedtke, M., Berube, C., Levine, R., Mitchell, B. S., Medeiros, B. C. 2013; 98 (4): 591-596

  Abstract

  There are limited treatment options for older patients with acute myeloid leukemia and prognosis of these patients remains poor, thereby warranting development of novel therapies. We evaluated the efficacy and safety of azacitidine in combination with lenalidomide as front-line therapy for older patients with acute myeloid leukemia. Patients ≥ 60 years of age with untreated acute myeloid leukemia received azacitidine 75 mg/m2 for 7 days followed by escalating doses of lenalidomide daily for 21 days starting on day 8 of each cycle every 6 weeks. Patients received continued therapy until disease progression, unacceptable toxicity, or completion of 12 cycles. Forty-two patients (median age, 74 years) were enrolled with equal distribution according to European LeukemiaNet risk. The overall response rate was 40% (rate of complete remission with or without complete recovery of blood counts = 28%). The median time to complete remission with or without complete recovery of blood counts was 12 weeks, and duration of this status was 28 weeks (range, 4 - >104 weeks). Therapy-related acute myeloid leukemia and a high score on the Hematopoietic Cell Transplantation Comorbidity Index were negative predictors of response. Early death was noted in 17% of patients. Grades ≥ 3 toxicities were uncommon and most adverse events were gastrointestinal, fatigue and myelosuppression. In conclusion, a sequential combination of azacitidine plus lenalidomide has clinical activity in older patients with acute myeloid leukemia, and further studies of this combination are underway.

  View details for DOI 10.3324/haematol.2012.076414

  View details for PubMedID 23242596

• Multiple Myeloma, Version 1.2013 Featured Updates to the NCCN Guidelines JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Anderson, K. C., Alsina, M., Bensinger, W., Biermann, J. S., Cohen, A. D., Devine, S., Djulbegovic, B., Faber, E. A., Gasparetto, C., Hernandez-Illizaliturri, F., Huff, C. A., Kassim, A., Krishnan, A. Y., Liedtke, M., Meredith, R., Raje, N., Schriber, J., Singhal, S., Somlo, G., Stockerl-Goldstein, K., Treon, S. P., Weber, D., Yahalom, J., Yunus, F., Shead, D. A., Kumar, R. 2013; 11 (1): 11-17

  Abstract

  These NCCN Guidelines Insights highlight the important updates/changes specific to the management of relapsed or progressive disease in the 2013 version of the NCCN Clinical Practice Guidelines in Oncology for Multiple Myeloma. These changes include the addition of new regimens as options for salvage therapy and strategies to mitigate the adverse effects and risks associated with newer regimens for the treatment of multiple myeloma.

  View details for Web of Science ID 000313575200004

• Amrubicin, a Novel Investigational Anthracycline, in Combination with Lenalidomide and Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma: Results of a Phase 1 Dose-Escalation Study 54th Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Dinner, S. N., Dunn, T. J., Medeiros, B. C., Coutre, S. E., Berube, C., Gotlib, J., Liedtke, M. AMER SOC HEMATOLOGY. 2012

  View details for Web of Science ID 000313838903369

• Absolute lymphocyte count at day 28 independently predicts event-free and overall survival in adults with newly diagnosed acute lymphoblastic leukemia AMERICAN JOURNAL OF HEMATOLOGY Sun, D., Elson, P., Liedtke, M., Medeiros, B. C., Earl, M., Alizadeh, A., Bates, J., Sekeres, M. A., Coutre, S., Kalaycio, M., Sobecks, R., Copelan, E., Advani, A. S. 2012; 87 (10): 957-960

  Abstract

  We investigated the prognostic impact of absolute lymphocyte count (ALC) following induction chemotherapy in newly diagnosed adult acute lymphoblastic leukemia (ALL). Patients with ALC ≥350 cells/μL at day 28 had a median overall survival (OS) of 47.4 months when compared with 17.6 months for those with an ALC <350 cells/μL (HR = 1.98, P = 0.007). Among patients who achieved a complete remission, median event-free survival (EFS) for those with ALC ≥350 cells/μL on day 28 was 42.1 months when compared with 13.9 months in those with ALC <350 cells/μL (HR = 2.08, P = 0.006). In multivariable analysis, the ALC on day 28 (<350 cells/μL vs. ≥350 cells/μL, P ≤ .0004 for OS and EFS) along with WBC at diagnosis (≤6.0 or >30.0 K/μL vs. >6.0-30.0 K/μL, P ≤ 0.002 for OS and EFS) and cytogenetics (abnormal vs. normal, P = 0.002 for OS and P = 0.02 for EFS) were independent prognostic factors of both OS and EFS. Combining these three factors segregates patients in three well-defined risk groups. These data suggest that ALC can be used in combination with other prognostic features to better predict outcome and that targeting the immune system to improve ALC may be a worthwhile strategy in ALL.

  View details for DOI 10.1002/ajh.23279

  View details for Web of Science ID 000309065700081

  View details for PubMedID 22729847

• Hemophagocytic lymphohistiocytosis in pregnancy: A case report and review of treatment options. Hematology (Amsterdam, Netherlands) Dunn, T., Cho, M., Medeiros, B., Logan, A., Ungewickell, A., Liedtke, M. 2012

  Abstract

  Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening inflammatory disorder characterized by uncontrolled proliferation and activation of histiocytes with phagocytosis of normal hematopoietic cells. A 41-year-old woman, 19 weeks pregnant with twins, and a history of Still's disease, presented with rash, fever, and headache. Laboratory studies revealed transaminitis, hyperbilirubinemia, and eventually severe neutropenia as well as elevations in ferritin, lactate dehydrogenase, and C-reactive protein. A bone marrow biopsy confirmed HLH. She declined standard HLH-treatment but responded well to high-dose corticosteroids. Her blood counts remained stable following corticosteroid taper, and she delivered healthy twin girls at 30-week gestation. Few cases of HLH during pregnancy have been reported. In some cases, the condition has proved fatal. Therefore recognizing signs and symptoms of HLH is essential to avoid treatment delay. In our case, high-dose corticosteroids alone were a safe and effective therapy for the mother and fetuses resulting in long-term disease control.

  View details for DOI 10.1179/1607845412Y.000000007

  View details for PubMedID 22980356

• Safety, efficacy and biological predictors of response to sequential azacitidine and lenalidomide for elderly patients with acute myeloid leukemia LEUKEMIA Pollyea, D. A., Kohrt, H. E., Gallegos, L., Figueroa, M. E., Abdel-Wahab, O., Zhang, B., Bhattacharya, S., Zehnder, J., Liedtke, M., Gotlib, J. R., Coutre, S., Berube, C., Melnick, A., Levine, R., Mitchell, B. S., Medeiros, B. C. 2012; 26 (5): 893-901

  Abstract

  Acute myeloid leukemia (AML) is a disease of the elderly. Poor outcomes with standard therapies necessitate novel approaches. Outpatient regimens sufficiently potent and well tolerated to induce remissions and enable continuation therapy may be beneficial. In this phase-1 study, we determined the maximum tolerated dose (MTD) and the efficacy for sequential azacitidine and lenalidomide as remission induction and continuation therapy in elderly, previously untreated patients. We investigated the impact on global DNA methylation and bone marrow cytokines, and sought biological predictors of response. Eighteen patients were enrolled. The MTD was not reached. Median follow-up was 8.2 months (10.3 months for survivors). Common adverse events included fatigue, injection site reactions, constipation, nausea, pruritus and febrile neutropenia. Ten patients responded (56%), and the rate of complete remissions (CRs) or CRs with incomplete recovery of blood counts for evaluable patients was 44% (7/16). The median response duration was 6.2 months. DNA demethylation and changes in bone marrow cytokines were observed; responders had a unique cytokine profile and a trend towards lower methylation levels. Sequential azacitidine and lenalidomide was well tolerated with encouraging clinical and biological activity in previously untreated elderly AML patients. This trial is registered at ClinicalTrials.gov (NCT00890929).

  View details for DOI 10.1038/leu.2011.294

  View details for Web of Science ID 000303883500005

  View details for PubMedID 22033493

• More Than a Frog in the Throat A Case Series and Review of Localized Laryngeal Amyloidosis ARCHIVES OF OTOLARYNGOLOGY-HEAD & NECK SURGERY Stevenson, R., Witteles, R., Damrose, E., Arai, S., Lafayette, R. A., Schrier, S., Afghahi, A., Liedtke, M. 2012; 138 (5): 509-511

  View details for PubMedID 22652951

• Heart transplantation and cardiac amyloidosis: Approach to screening and novel management strategies JOURNAL OF HEART AND LUNG TRANSPLANTATION Varr, B. C., Liedtke, M., Arai, S., Lafayette, R. A., Schrier, S. L., Witteles, R. M. 2012; 31 (3): 325-331

  Abstract

  Limited data exist regarding screening methods and outcomes for orthotopic heart transplantation (OHT) in cardiac amyloidosis. As a result, uncertainty exists over the best approach to OHT for cardiac amyloidosis and for the timing of critical post-transplant therapies. This article reviews 6 patients who underwent OHT for cardiac amyloidosis at the Stanford University Amyloid Center from 2008 to present. All patients with light-chain amyloidosis received chemotherapy in the interval between OHT and autologous hematopoietic stem cell transplant. Five patients remain alive up to 25 months after OHT, without evidence of recurrent cardiac amyloid deposition. A novel strategy of OHT, followed by light-chain suppressive chemotherapy before autologous hematopoietic stem cell transplant, is feasible for patients with light-chain amyloidosis.

  View details for DOI 10.1016/j.healun.2011.09.010

  View details for PubMedID 22051505

• The Transcription Factor Encyclopedia GENOME BIOLOGY Yusuf, D., Butland, S. L., Swanson, M. I., Bolotin, E., Ticoll, A., Cheung, W. A., Zhang, X. Y., Dickman, C. T., Fulton, D. L., Lim, J. S., Schnabl, J. M., Ramos, O. H., Vasseur-Cognet, M., de Leeuw, C. N., Simpson, E. M., Ryffel, G. U., Lam, E. W., Kist, R., Wilson, M. S., Marco-Ferreres, R., Brosens, J. J., Beccari, L. L., Bovolenta, P., Benayoun, B. A., Monteiro, L. J., Schwenen, H. D., Grontved, L., Wederell, E., Mandrup, S., Veitia, R. A., Chakravarthy, H., Hoodless, P. A., Mancarelli, M. M., Torbett, B. E., Banham, A. H., Reddy, S. P., Cullum, R. L., Liedtke, M., Tschan, M. P., Vaz, M., Rizzino, A., Zannini, M., Frietze, S., Farnham, P. J., Eijkelenboom, A., Brown, P. J., Laperriere, D., Leprince, D., de Cristofaro, T., Prince, K. L., Putker, M., del Peso, L., Camenisch, G., Wenger, R. H., Mikula, M., Rozendaal, M., Mader, S., Ostrowski, J., Rhodes, S. J., Van Rechem, C., Boulay, G., Olechnowicz, S. W., Breslin, M. B., Lan, M. S., Nanan, K. K., Wegner, M., Hou, J., Mullen, R. D., Colvin, S. C., Noy, P. J., Webb, C. F., Witek, M. E., Ferrell, S., Daniel, J. M., Park, J., Waldman, S. A., Peet, D. J., Taggart, M., Jayaraman, P., Karrich, J. J., Blom, B., Vesuna, F., O'Geen, H., Sun, Y., Gronostajski, R. M., Woodcroft, M. W., Hough, M. R., Chen, E., Europe-Finner, G. N., Karolczak-Bayatti, M., Bailey, J., Hankinson, O., Raman, V., LeBrun, D. P., Biswal, S., Harvey, C. J., DeBruyne, J. P., Hogenesch, J. B., Hevner, R. F., Heligon, C., Luo, X. M., Blank, M. C., Millen, K. J., Sharlin, D. S., Forrest, D., Dahlman-Wright, K., Zhao, C., Mishima, Y., Sinha, S., Chakrabarti, R., Portales-Casamar, E., Sladek, F. M., Bradley, P. H., Wasserman, W. W. 2012; 13 (3)

  Abstract

  Here we present the Transcription Factor Encyclopedia (TFe), a new web-based compendium of mini review articles on transcription factors (TFs) that is founded on the principles of open access and collaboration. Our consortium of over 100 researchers has collectively contributed over 130 mini review articles on pertinent human, mouse and rat TFs. Notable features of the TFe website include a high-quality PDF generator and web API for programmatic data retrieval. TFe aims to rapidly educate scientists about the TFs they encounter through the delivery of succinct summaries written and vetted by experts in the field. TFe is available at http://www.cisreg.ca/tfe.

  View details for DOI 10.1186/gb-2012-13-3-r24

  View details for Web of Science ID 000308544200009

  View details for PubMedID 22458515

  View details for PubMedCentralID PMC3439975

• Phase I trial of a novel human monoclonal antibody mAb216 in patients with relapsed or refractory B-cell acute lymphoblastic leukemia HAEMATOLOGICA-THE HEMATOLOGY JOURNAL Liedtke, M., Twist, C. J., Medeiros, B. C., Gotlib, J. R., Berube, C., Bieber, M. M., Bhat, N. M., Teng, N. N., Coutre, S. E. 2012; 97 (1): 30-37

  Abstract

  This phase I trial was conducted to determine the safety and pharmacokinetics of monoclonal antibody 216, a human monoclonal Immunoglobulin M antibody targeting a linear B-cell lactosamine antigen, administered alone and in combination with vincristine in patients with relapsed or refractory B-cell acute lymphoblastic leukemia, and to preliminarily assess tumor targeting and efficacy.Three cohorts of patients received escalating doses of monoclonal antibody 216 administered as an intravenous infusion. In the case of poor response to the first dose of monoclonal antibody 216 alone, defined as less than 75% reduction in peripheral blood blast count, a second dose of the antibody with vincristine was given between days 4 and 7. Responses were assessed weekly until day 35. Serum concentration of monoclonal antibody 216 was measured before and after infusion. Monoclonal antibody 216 targeting was determined with an anti-idiotypic antibody to monoclonal antibody 216 and preliminary efficacy was analyzed by changes in peripheral blood blasts.Thirteen patients were enrolled. One episode of grade 3 epistaxis was the only dose-limiting toxicity observed. All patients showed a poor response to the first monoclonal antibody 216 infusion with a decrease in peripheral blasts from 6-65% in 9 patients. In 8 patients, addition of vincristine to monoclonal antibody 216 resulted in an average reduction of the peripheral blasts of 81%. One patient without peripheral blasts achieved a hypoplastic marrow without evidence of leukemia after one infusion of monoclonal antibody 216 and monoclonal antibody 216/vincristine each. Monoclonal antibody 216 was detected on peripheral blasts in all patients.Treatment with monoclonal antibody 216 in combination with vincristine is feasible and well tolerated in patients with relapsed or refractory B-cell acute lymphoblastic leukemia. Binding of monoclonal antibody 216 to leukemic blasts was efficient, and favorable early responses were observed.

  View details for DOI 10.3324/haematol.2011.045997

  View details for Web of Science ID 000299870500009

  View details for PubMedID 21993685

  View details for PubMedCentralID PMC3248928

• Cardiac Amyloidosis: Screening Criteria for Heart Transplantation and New Strategies for Post-Transplant Therapy 15th Annual Scientific Meeting of the Heart-Failure-Society-of-America Varr, B. C., Liedtke, M., Arai, S., Lafayette, R. A., Schrier, S. L., Witteles, R. M. CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS. 2011: S45–S46

  View details for Web of Science ID 000293938700145

• Second-line mitoxantrone, etoposide, and cytarabine for acute myeloid leukemia: A single-center experience AMERICAN JOURNAL OF HEMATOLOGY Kohrt, H. E., Patel, S., Ho, M., Owen, T., Pollyea, D. A., Majeti, R., Gotlib, J., Coutre, S., Liedtke, M., Berube, C., Alizadeh, A. A., Medeiros, B. C. 2010; 85 (11): 877-881

  Abstract

  The majority of patients with acute myeloid leukemia (AML) will require second-line chemotherapy for either relapsed or refractory disease. Currently, only allogeneic hematopoietic cell transplantation (HCT) offers a curative option in this setting and no preferred regimen has been established. The reported efficacy of second-line regimens is widely disparate, thus limiting informed clinical decision making. A retrospective review of 77 patients receiving therapy between 2001 and 2008 with relapsed, 42, and refractory, 35, AML was performed to determine overall response rate and survival following mitoxantrone (8 mg/m(2)/day), etoposide (100 mg/m(2)/day), and cytarabine (1,000 mg/m(2)/day) chemotherapy administered over 5 days. Among 77 patients (median age of 54 years and 64% intermediate risk karyotype) with median follow-up of 153 days, 18% achieved a complete response and 8% a morphologic leukemia-free state. Fifty-seven (74%) experienced treatment failure, 10 of whom achieved a remission after additional therapy. Median overall survival (OS) was 6.8 months. Among patients achieving a response, 50% received consolidation with allogeneic HCT, autologous HCT (5%), or consolidation chemotherapy alone (45%). A nonsignificant trend in overall response (50%, 27%, and 23.8%) and median OS (8.3, 6.8, and 4.7 months) was observed by cytogenetic stratification into favorable, intermediate, and unfavorable risk. Patients with refractory versus relapsed disease had similar overall responses (20% and 31%, P = 0.41) and median OS (5.3 and 7.6 months, P = 0.36). Despite risk stratification by the European Prognostic Index, our series demonstrates inferior rates of response and survival, illustrating the limited activity of this regimen in our cohort.

  View details for DOI 10.1002/ajh.21857

  View details for Web of Science ID 000283568200010

  View details for PubMedID 20872554

• Plasma cell leukemia: concepts and management. Expert review of hematology Liedtke, M., Medeiros, B. C. 2010; 3 (5): 543-549

  Abstract

  Plasma cell leukemia (PCL) is a rare and aggressive plasma cell dyscrasia. Patients with PCL have a very poor prognosis with median survival measured in months. PCL can present de novo or following a prodrome of plasma cell myeloma. Patients with PCL tend to present with aggressive clinical features, such as extramedullary disease, bone marrow failure, advanced stage disease and expression of distinct immunophenotypic markers, such as lack of CD56 and presence of CD20. Historically, the treatment of PCL has primarily been palliative, with only a small minority of patients achieving a durable remission. The impact of newer agents, such as bortezomib and lenalidomide, in conjunction with autologous and allogeneic stem cell transplantation is uncertain, but emerging data suggest that use of these modalities may help improve the poor prognosis of patients with PCL.

  View details for DOI 10.1586/ehm.10.52

  View details for PubMedID 21083471

• Self-association mediated by the Ras association 1 domain of AF6 activates the oncogenic potential of MLL-AF6 BLOOD Liedtke, M., Ayton, P. M., Somervaille, T. C., Smith, K. S., Cleary, M. L. 2010; 116 (1): 63-70

  Abstract

  MLL is a common target for chromosomal translocations associated with acute leukemia resulting in its fusion with a large variety of nuclear or cytoplasmic proteins that may activate its oncogenic properties by distinct but poorly understood mechanisms. The MLL-AF6 fusion gene represents the most common leukemogenic fusion of mixed lineage leukemia (MLL) to a cytoplasmic partner protein. Here, we identified a highly conserved Ras association (RA1) domain at the amino-terminus of AF6 as the minimal region sufficient for MLL-AF6 mediated myeloid progenitor immortalization in vitro and short latency leukemogenesis in vivo. Moreover, the ability of RA1 to activate MLL oncogenesis is conserved with its Drosophila ortholog, Canoe. Although the AF6 RA1 domain has previously been defined as an interaction surface for guanosine triphosphate-bound Ras, single amino acid substitutions known to abolish the AF6-Ras interaction did not abrogate MLL-AF6-mediated oncogenesis. Furthermore, fusion of MLL to heterologous RA domains of c-Raf1 or RalGDS, or direct fusion of MLL to constitutively active K-RAS, H-RAS, or RAP1 was not sufficient for oncogenic activation of MLL. Rather, the AF6 RA1 domain efficiently mediated self-association, suggesting that constitutive MLL self-association is a more common pathogenic mechanism for MLL oncogenesis than indicated by previous studies of rare MLL fusion partners.

  View details for DOI 10.1182/blood-2009-09-243386

  View details for Web of Science ID 000279641400012

  View details for PubMedID 20395419

  View details for PubMedCentralID PMC2904581

• Therapeutic targeting of MLL BLOOD Liedtke, M., Cleary, M. L. 2009; 113 (24): 6061-6068

  Abstract

  Treatment of hematologic malignancies is evolving from a uniform approach to targeted therapies directed at the underlying molecular abnormalities of disease. The mixed lineage leukemia (MLL) proto-oncogene is a recurrent site of genetic rearrangements in acute leukemias; and since its discovery in 1992, many advances have been made in understanding its role in leukemogenesis. A variety of MLL translocation partners have been described, and detailed structure/function studies have identified functional domains that are required for transformation. Proteins associated with the MLL core complex or its fusion partners have been isolated and characterized for their critical roles in leukemia pathogenesis. Downstream mediators of MLL transcriptional regulation and multiple collaborating signaling pathways have been described and characterized. These advances in our understanding of MLL-related leukemogenesis provide a foundation for ongoing and future efforts to develop novel therapeutic strategies that will hopefully result in better treatment outcomes.

  View details for DOI 10.1182/blood-2008-12-197061

  View details for Web of Science ID 000267147100009

  View details for PubMedID 19289854

  View details for PubMedCentralID PMC2699228

• Reversible high-output cardiac failure, an unusual marker of disease status in multiple myeloma LEUKEMIA & LYMPHOMA Kohrt, H., Logan, A., Temmins, C., Witteles, R., Liedtke, M., Medeiros, B. 2008; 49 (3): 581-585

  View details for DOI 10.1080/10428190701861702

  View details for Web of Science ID 000253513300029

  View details for PubMedID 18297538

• Surveillance imaging during remission identifies a group of patients with more favorable aggressive NHL at time of relapse: a retrospective analysis of a uniformly-treated patient population ANNALS OF ONCOLOGY Liedtke, M., Hamlin, P. A., Moskowitz, C. H., Zelenetz, A. D. 2006; 17 (6): 909-913

  Abstract

  Approximately one-third of the patients with relapsed aggressive non-Hodgkin's lymphoma (NHL) are cured by second-line chemotherapy followed by high-dose consolidation. The age-adjusted international prognostic index determined at the time of relapse (sAAIPI) predicts outcome in relapsed diffuse large B-cell lymphoma, suggesting that the success of salvage therapy could be enhanced by early relapse detection. This study evaluated the role of surveillance imaging in detection of relapsed disease and its impact on outcome of salvage treatment.One hundred and eight patients with relapsed aggressive NHL were treated with ICE-based second-line chemotherapy. Relapses were categorized as detected by imaging, examination, or patient-reported symptoms.Twenty per cent of relapses were detected by routine imaging while 80% were identified by reported symptoms or abnormalities on exam. Patients were 4.1 times (95% CI: 1.7-10.2) more likely to have low risk disease if relapse was diagnosed by routine imaging (group 1) compared with those diagnosed by reported symptoms or physical findings (group 2). Median overall 5-year survival for group 1 versus group 2 was 54% and 43% respectively (P = 0.13).These results suggest that routine surveillance imaging can identify a population of patients with a more favorable outcome based on the sAAIPI.

  View details for DOI 10.1093/annonc/mdl049

  View details for Web of Science ID 000237696000005

  View details for PubMedID 16672295

• Regulation of Bcr-Abl-induced SAP kinase activity and transformation by the SHPTP1 protein tyrosine phosphatase ONCOGENE Liedtke, M., Pandey, P., Kumar, S., KHARBANDA, S., Kufe, D. 1998; 17 (15): 1889-1892

  Abstract

  The oncogenic Bcr-Abl variant of the c-Abl tyrosine kinase transforms cells by a mechanism dependent on activation of the stress-activated protein kinase (SAPK). Other work has shown that c-Abl interacts with the SHPTP1 protein tyrosine phosphatase in induction of SAPK activity by genotoxic stress. The present studies demonstrate that Bcr-Abl binds constitutively to SHPTP1. We show that Bcr-Abl phosphorylates SHPTP1 on C-terminal Y536 and Y564 sites. The functional significance of the Bcr-Abl/SHPTP1 interaction is supported by the finding that SHPTP1 regulates Bcr-Abl-induced SAPK activity. Importantly, SHPTP1 also decreases Bcr-Abl-dependent transformation of fibroblasts. These findings indicate that SHPTP1 functions as a tumor suppressor in cells transformed by Bcr-Abl.

  View details for Web of Science ID 000076423500001

  View details for PubMedID 9788431

• A SITE-DIRECTED MUTAGENESIS STUDY TO IDENTIFY AMINO-ACID-RESIDUES INVOLVED IN THE CATALYTIC FUNCTION OF THE RESTRICTION ENDONUCLEASE ECORV BIOCHEMISTRY SELENT, U., RUTER, T., Kohler, E., Liedtke, M., THIELKING, V., Alves, J., Oelgeschlager, T., Wolfes, H., Peters, F., Pingoud, A. 1992; 31 (20): 4808-4815

  Abstract

  We have used site-directed mutagenesis of the EcoRV restriction endonuclease to change amino acid side chains that have been shown crystallographically to be in close proximity to the scissile phosphodiester bond of the DNA substrate. DNA cleavage assays of the resulting mutant proteins indicate that the largest effects on nucleolytic activity result from substitution of Asp74, Asp90, and Lys92. We suggest on the basis of structural information, mutagenesis data, and analogies with other nucleases that Asp74 and Asp90 might be involved in Mg2+ binding and/or catalysis and that Lys92 probably stabilizes the pentacovalent phosphorus in the transition state. These amino acids are part of a sequence motif, Pro-Asp...Asp/Glu-X-Lys, which is also present in EcoRI. In both enzymes, it is located in a structurally similar context near the scissile phosphodiester bond. A preliminary mutational analysis with EcoRI indicates that this sequence motif is of similar functional importance for EcoRI and EcoRV. On the basis of these results, a proposal is made for the mechanism of DNA cleavage by EcoRV and EcoRI.

  View details for Web of Science ID A1992HW13800010

  View details for PubMedID 1591242