Bio


Dr. Gabriel Mannis is Assistant Professor of Medicine in the Division of Hematology at Stanford University School of Medicine, and Medical Director of Stanford’s Inpatient Leukemia Service. He specializes in the treatment of acute myeloid leukemia (AML), high-risk myelodysplastic syndromes (MDS), and other hematologic malignancies. As a clinical scientist, Dr. Mannis divides his time between caring for patients, teaching trainees, and researching novel therapies for AML and MDS. Dr. Mannis has co-authored numerous publications on topics including AML, hematopoietic cell transplantation, and advanced care planning for patients with hematologic malignancies. Currently, Dr. Mannis serves on the National Comprehensive Cancer Network AML panel, helping to write evidence-based guidelines for how AML is best treated. He oversees the AML clinical trial portfolio at Stanford, with multiple clinical trials of novel drugs actively enrolling for both newly diagnosed and relapsed or refractory AML.

Clinical Focus


  • Hematology
  • Leukemia
  • Medical Oncology

Academic Appointments


Administrative Appointments


  • Medical Director, Stanford Hospital Inpatient Hematology Service (2021 - Present)
  • Panel Member, Acute Leukemia Working Group, Southwest Oncology Group (SWOG) (2019 - Present)
  • Panel Member, Acute Myeloid Leukemia Guidelines Committee, National Comprehensive Cancer Network (2019 - Present)
  • Member, Stanford Cancer Institute (2019 - Present)

Professional Education


  • Board Certification: American Board of Internal Medicine, Hematology (2015)
  • Board Certification: American Board of Internal Medicine, Medical Oncology (2014)
  • Board Certification: American Board of Internal Medicine, Internal Medicine (2011)
  • Fellowship: UCSF Hematology and Medical Oncology Fellowship (2014) CA
  • Residency: UCSF Internal Medicine Residency (2011) CA
  • Medical Education: University of California Davis School of Medicine (2008) CA

Current Research and Scholarly Interests


My research focuses on the development of more effective, less toxic therapies for patients with AML and other high-risk hematologic malignancies. We study biologic correlates that predict response to therapy as well as factors/interventions that improve quality-of-life for patients struggling with blood-borne cancers.

Clinical Trials


  • A Study of SNDX-5613 in R/R Leukemias Including Those With an MLLr/KMT2A Gene Rearrangement or NPM1 Mutation Recruiting

    Phase 1 dose escalation will determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of SNDX-5613 in patients with acute leukemia. In Phase 2, patients will be enrolled in 3 indication-specific expansion cohorts to determine the efficacy, short- and long-term safety, and tolerability of SNDX-5613.

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  • Feasibility of Telehealth Palliative Care and Digital Symptom Monitoring for Patients With Acute Myeloid Leukemia Recruiting

    AML is the most common leukemia diagnosed in adults. In spite of recent low-intensity therapies that have improved outcomes for older AML patients, AML remains associated with poor prognosis as well as high symptom burden. While the benefits of early palliative care as well as electronic PROs have been well-described in the oncology population, neither have been well-studied in the AML population, and have never been studied in combination. We propose a prospective, single-center, single-arm trial to evaluate the feasibility of a virtually-mediated supportive care model utilizing both electronic PROs and palliative care for patients with AML being treated with low-intensity therapy. AIM1: is to evaluate and describe the feasibility of implementing early specialty palliative care referrals carried out via telehealth/video-based modalities in combination with digital symptom monitoring for patients recently diagnosed with acute myeloid leukemia (AML) and starting low intensity induction therapy. AIM2: study the differences in health-related quality-of-life (HRQoL) metrics using patient-reported outcomes (PROs) in patients recently diagnosed with AML and starting low intensity induction therapy who receive early referral to telehealth/video-based palliative care visits compared to standard care. AIM3: to explore the patient experience of patients with AML on low-intensity therapy, capture rates of advance care planning, hospice utilization, and hospital utilization.

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  • Pharmacokinetics, Safety, and Efficacy of ASTX727 in Combination With Venetoclax in Acute Myeloid Leukemia (AML) Recruiting

    The Phase 1 portion of this study is a single-arm, open-label, multicenter, non-randomized interventional study to evaluate the pharmacokinetic (PK) interaction, safety, and efficacy of ASTX727 when given in combination with venetoclax for the treatment of newly diagnosed acute myeloid leukemia (AML) in adults who are age 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy. The primary purpose of the study is to rule out drug-drug interactions between ASTX727 and venetoclax combination therapy by evaluating area under the curve (AUC) and maximum plasma concentration (Cmax) exposure. The Phase 2 portion of the study is to assess the efficacy of ASTX727 and venetoclax when given in combination and to evaluate potential PK interactions. Phase 2 will follow the same overall study design as Phase 1.

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  • Study of Magrolimab Combinations in Participants With Myeloid Malignancies Recruiting

    The primary objectives of this study are to evaluate the safety, tolerability and to determine the recommended Phase 2 dose (RP2D) of magrolimab (Mag) in combination with the anti-leukemia therapies of venetoclax (Ven) and azacitidine (Aza) (Cohort 1), mitoxantrone, etoposide, and cytarabine (MEC) (Cohort 2) and CC-486 (Cohort 3) respectively in participants with acute myeloid leukemia (AML), to evaluate the efficacy of magrolimab in combination with the anti-leukemia therapies as determined by the rate of complete remission (CR) (Phase 2 Cohorts 1 and 2), and/or complete remission with incomplete hematologic recovery (CRi) (CR/CRi) (Phase 2 Cohort 2) and to evaluate the efficacy of magrolimab in combination with anti-leukemia therapy CC-486 as determined by the minimal residual disease (MRD) negative CR rate (Phase 2 Cohort 3).

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  • A Phase 1b Master Trial to Investigate CPX-351 in Subjects With Previously Untreated Acute Myeloid Leukemia Not Recruiting

    JZP025-101 is an open-label, multicenter, multi-arm, nonrandomized phase 1b master trial to determine the recommended phase 2 dose (RP2D) of CPX-351 when administered in combination with various targeted agents in previously untreated subjects with Acute Myeloid Leukemia (AML) who are fit to receive intensive chemotherapy (ICT). Subjects will be assigned to treatment arms based on results of AML mutation testing.

    Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.

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  • Magrolimab Monotherapy or Magrolimab in Combination With Azacitidine in Participants With Hematological Malignancies Not Recruiting

    The primary objectives of this study are: - To confirm the safety and tolerability of magrolimab monotherapy in a relapsed/refractory (R/R) acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) population, and of magrolimab in combination with azacitidine in previously untreated participants with AML or MDS and participants with R/R AML and MDS - To evaluate the efficacy of magrolimab monotherapy in R/R AML/MDS, and of magrolimab in combination with azacitidine in previously untreated participants with AML/MDS, or R/R AML/MDS as measured by complete remission (CR) rate for participants with AML and higher-risk MDS, and duration of complete response for participants with AML and higher-risk MDS, and duration of CR for participants with AML and higher-risk MDS - To evaluate the safety, tolerability, and efficacy of magrolimab monotherapy or combination with azacitidine in low-risk MDS participants as measured by red blood cell (RBC) transfusion independence rate

    Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.

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  • Study to Determine the Efficacy of Uproleselan (GMI-1271) in Combination With Chemotherapy to Treat Relapsed/Refractory Acute Myeloid Leukemia Not Recruiting

    This study will evaluate the efficacy of uproleselan (GMI-1271), a specific E-selectin antagonist, in combination with chemotherapy to treat relapsed/refractory AML, compared to chemotherapy alone. The safety of uproleselan when given with chemotherapy will also be investigated in patients with relapsed/refractory AML

    Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.

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All Publications


  • Gilteritinib Clinical Activity in Relapsed/Refractory FLT3 Mutated AML Previously Treated with FLT3 inhibitors. American journal of hematology Numan, Y., Abdel Rahman, Z., Grenet, J., Boisclair, S., Bewersdorf, J. P., Collins, C., Barth, D., Fraga, M., Bixby, D. L., Zeidan, A. M., Yilmaz, M., Desai, P., Mannis, G., Deutsch, Y. E., Abaza, Y., Dinner, S., Frankfurt, O., Litzow, M., Al-Kali, A., Foran, J. M., Sproat, L. Z., Jovanovic, B., Daver, N., Perl, A. E., Altman, J. K. 2022

    Abstract

    Gilteritinib is approved for the treatment of relapsed/refractory (R/R) acute myeloid leukemia (AML) with a FLT3-mutation (FLT3mut+ ). However, the gilteritinib phase 3 ADMIRAL study (Perl et al NEJM 2019) was conducted prior to widespread adoption of either midostaurin as a component of standard intensive induction and consolidation or post-transplant FLT3 inhibitor maintenance. We performed a retrospective analysis using data from 11 US centers and where we identified 113 patients who received gilteritinib alone or as combination therapy for the treatment of R/R FLT3mut+ AML. The composite CR rate (CRc, defined as CR + CRi + CRp) was 48.7% (n= 55). The CRc rate after treatment with gilteritinib in patients who were treated with only prior 7+3 and midostaurin with or without consolidation was 58% with a median survival of 7.8 months. Survival was longest in patients who obtained a CR, particularly a cMRD (Clinical minimal or measurable residual disease) negative response; this remained significant after censoring at the time of SCT. MAPK pathway activating mutations that are known for gilteritinib resistance (NRAS, KRAS, and PTPN11) had lower CRc (35% vs 60.5%) and lower mOS than patients' whose leukemia did not express these mutations (4.9 months vs 7.8 months) (HR 2.4- 95% CI 1.1-5.4) p value <0.01. This article is protected by copyright. All rights reserved.

    View details for DOI 10.1002/ajh.26447

    View details for PubMedID 34981560

  • Patterns and predictors of functional decline after alloHCT in older adults. Transplantation and cellular therapy Huang, L. W., Sheng, Y., Andreadis, C., Logan, A. C., Mannis, G. N., Smith, C. C., Gaensler, K. M., Martin, T. G., Damon, L. E., Huang, C. Y., Olin, R. L. 2022

    Abstract

    As allogeneic hematopoietic cell transplantation (alloHCT) is increasingly offered to older adults, geriatric assessments (GA) have been identified as a useful tool for predicting outcomes, particularly functional status. However, very few studies have examined the longitudinal change in GA measures in the post-alloHCT period.The objectives of this study are to 1) describe the longitudinal change in GA and QOL measures after alloHCT and to 2) identify predictors of greater functional decline post-transplant.In this single-center prospective cohort study, patients aged 50 years or older planning to undergo alloHCT completed a cancer-specific GA and the Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) survey at baseline prior to alloHCT and then at 3, 6, and 12 months after transplant. Changes in GA and QOL measures at each post-transplant time point (3, 6, or 12 months) compared to baseline were analyzed using paired t-tests. Exploration of potential predictors of greater post-transplant functional decline, as measured by instrumental activities of daily living (IADL) and Medical Outcomes Study Physical Health scale (MOS-PH), were examined using linear regressions and chi-squared two-sample test of proportions.Mean functional status generally exhibited a pattern of decline at 3 to 6 months post-alloHCT, with recovery to near baseline by 12 months. Mean mental health and emotional QOL were lowest at baseline and improved at all time points post-transplant. Differences in baseline clinical characteristics were not associated with any differences in functional trajectories. Differences in baseline GA measures (patient-rated KPS, IADL, MOS-PH, Timed-Up-and-Go, Blessed Orientation-Memory-Concentration test, Mental Health Inventory 5) also did not predict greater functional decline at 3 months. Patients whose IADL was improved or maintained at 3 months generally maintained their functional status at 6 and 12 months. Similarly, most patients who had IADL decline at 3 months still had functional decline at 6 months, though a portion did have functional recovery by 12 months. Compared to those with improved/maintained IADL at 3 months, those with declined IADL at 3 months were significantly more likely to have persistent functional decline at 6 months (p<0.0001) and 12 months (p=0.02).In older alloHCT patients, mean functional status declines short-term after alloHCT with possibility of recovery by 6 to 12 months, while mean mental and emotional health improve post-alloHCT. Functional decline at 3 months post-alloHCT is associated with persistent functional decline at 12 months.

    View details for DOI 10.1016/j.jtct.2022.02.022

    View details for PubMedID 35247612

  • Characterisation of infections in patients with acute myeloid leukaemia receiving venetoclax and a hypomethylating agent. British journal of haematology On, S., Rath, C. G., Lan, M., Wu, B., Lau, K. M., Cheung, E., Alegria, W., Young, R., Tan, M., Kim, C., Phun, J., Patel, N., Mannis, G., Logan, A. C., Kennedy, V., Goodman, A., Taplitz, R. A., Young, P. A., Wen, R., Saunders, I. M. 2022

    Abstract

    We investigated the incidence of invasive fungal infections (IFIs) and other infectious complications in patients receiving venetoclax and hypomethylating agent therapy for acute myeloid leukaemia (AML). This retrospective, multicentre cohort study included adult patients with AML who received at least one cycle of venetoclax and either azacitidine or decitabine between January 2016 and August 2020. The primary outcome was the incidence of probable or confirmed IFI. Secondary outcomes included antifungal prophylaxis prescribing patterns, incidence of bacterial infections, and incidence of neutropenic fever hospital admissions. Among 235 patients, the incidence of probable or confirmed IFI was 5.1%. IFI incidence did not differ significantly according to age, antifungal prophylaxis use, or disease status. In the subgroup of patients with probable or confirmed IFIs, six (50%) were receiving antifungal prophylaxis at the time of infection. The overall incidence of developing at least one bacterial infection was 33.6% and 127 (54%) patients had at least one hospital admission for febrile neutropenia. This study demonstrated an overall low risk of developing probable or confirmed IFI as well as a notable percentage of documented bacterial infections and hospital admissions due to neutropenic fever.

    View details for DOI 10.1111/bjh.18051

    View details for PubMedID 35174480

  • Outcomes of Allogeneic Transplantation after Hypomethylating Agents with Venetoclax in Acute Myeloid Leukemia. American journal of hematology Kennedy, V. E., Hui, G., Azenkot, T., Gaut, D., Wieduwilt, M. J., Oliai, C., Jonas, B. A., Mittal, V., Logan, A. C., Muffly, L. S., Mannis, G. N. 2022

    View details for DOI 10.1002/ajh.26524

    View details for PubMedID 35266185

  • The First-in-Class Anti-CD47 Antibody Magrolimab in Combination with Azacitidine Is Well Tolerated and Effective in AML Patients: Phase 1b Results Sallman, D., Asch, A., Kambhampati, S., Al Malki, M., Zeidner, J., Donnellan, W., Lee, D., Vyas, P., Jeyakumar, D., Mannis, G., Tanaka, T., Chai-Ho, W., Larson, R., Whiteley, A., Marcucci, G., Komrokji, R., Garcia-Manero, G., Van Elk, J., Lin, M., Maute, R., Volkmer, J., Takimoto, C., Chao, M., Daver, N. CIG MEDIA GROUP, LP. 2021: S290
  • Measurable Residual Disease Status and FLT3 Inhibitor Therapy in Patients with FLT3-ITD-Mutated AML Following Allogeneic Hematopoietic Cell Transplantation Liang, E. C., Chen, C., Lu, R., Mannis, G. N., Muffly, L. CIG MEDIA GROUP, LP. 2021: S278-S279
  • Feasibility Study Integrating Electronic Patient-Reported Outcomes (PROs) and Palliative Care for High-Risk Acute Myeloid Leukemia (AML) Patients Tan, I., Choi, J., Cunanan, K., Fronk, J., Zhang, T., Mannis, G. N., Ramchandran, K. CIG MEDIA GROUP, LP. 2021: S279-S280
  • Preliminary results of V-FAST, a phase 1b master trial to investigate CPX-351 combined with targeted agents in newly diagnosed AML. Pullarkat, V., Levis, M. J., Mannis, G. N., Strickland, S., Lin, T. L., Faderl, S., Chakravarthy, D., Chandrasekaran, V., Cheung, R., Erba, H. LIPPINCOTT WILLIAMS & WILKINS. 2021
  • 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
  • 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

  • Inhibition of MET Signaling with Ficlatuzumab in Combination with Chemotherapy in Refractory AML: Clinical Outcomes and High-Dimensional Analysis. Blood cancer discovery Wang, V. E., Blaser, B. W., Patel, R. K., Behbehani, G. K., Rao, A. A., Durbin-Johnson, B., Jiang, T., Logan, A. C., Settles, M., Mannis, G. N., Olin, R., Damon, L. E., Martin, T. G., Sayre, P. H., Gaensler, K. M., McMahon, E., Flanders, M., Weinberg, V., Ye, C. J., Carbone, D. P., Munster, P. N., Fragiadakis, G. K., McCormick, F., Andreadis, C. 2021; 2 (5): 434-449

    Abstract

    Acute myeloid leukemia patients refractory to induction therapy or relapsed within one year have poor outcomes. Autocrine production of hepatocyte growth factor by myeloid blasts drives leukemogenesis in pre-clinical models. A phase Ib trial evaluated ficlatuzumab, a first-in-class anti-HGF antibody, in combination with cytarabine in this high-risk population. Dose-limiting toxicities were not observed, and 20 mg/kg was established as the recommended phase II dose. The most frequent treatment-related adverse event was febrile neutropenia. Among 17 evaluable patients, the overall response rate was 53%, all complete remissions. Phospho-proteomic mass cytometry showed potent on-target suppression of p-MET after ficlatuzumab treatment and that attenuation of p-S6 was associated with clinical response. Multiplexed single cell RNA sequencing using prospectively acquired patient specimens identified interferon response genes as adverse predictive factors. The ficlatuzumab and cytarabine combination is well-tolerated with favorable efficacy. High-dimensional analyses at single-cell resolution represent promising approaches for identifying biomarkers of response and mechanisms of resistance in prospective clinical studies.

    View details for DOI 10.1158/2643-3230.bcd-21-0055

    View details for PubMedID 34514432

    View details for PubMedCentralID PMC8425277

  • Measurable residual disease status and FLT3 inhibitor therapy in patients with FLT3-ITD mutated AML following allogeneic hematopoietic cell transplantation. Bone marrow transplantation Liang, E. C., Chen, C., Lu, R., Mannis, G. N., Muffly, L. 2021

    Abstract

    Measurable residual disease (MRD) is associated with poor prognosis in acute myeloid leukemia (AML), even after allogeneic hematopoietic cell transplantation (HCT). New next-generation sequencing (NGS) methods have emerged as a highly sensitive and specific method to detect MRD. In addition to defining the role of post-HCT MRD monitoring in FLT3-ITD mutated AML, there is great interest in the optimal use of oral FLT3 tyrosine kinase inhibitors (FLT3 inhibitors) to maintain remission following HCT. In this study, we evaluated the clinical impact of sensitive FLT3 MRD testing early after HCT and maintenance FLT3 inhibitor use at our transplant center. We found that there was a trend towards inferior progression-free survival (PFS) for patients with early post-HCT MRD, but that overall survival (OS) was not significantly impacted by MRD. The use of maintenance FLT3 inhibitors led to a significantly superior PFS and OS in our cohort, and improved PFS and OS in both MRD-negative and MRD-positive patients. Altogether, our results demonstrate the prognostic significance of NGS-based MRD monitoring for FLT3-ITD and the ability of post-HCT maintenance therapy to prevent relapse and death in FLT3-ITD mutated AML.

    View details for DOI 10.1038/s41409-021-01475-8

    View details for PubMedID 34584238

  • Epstein-Barr virus-positive lymphoproliferative disorder manifesting as pulmonary disease in a patient with acute myeloid leukemia: a case report. Journal of medical case reports Dutta, R. n., Miao, S. Y., Phan, P. n., Fernandez-Pol, S. n., Shiraz, P. n., Ho, D. n., Mannis, G. N., Zhang, T. Y. 2021; 15 (1): 170

    Abstract

     Patients with lymphoproliferative disorders following hematopoietic stem cell transplant (HSCT) most commonly present with fever and lymphadenopathy within the first 5 months of transplant. Pulmonary post-transplant lymphoproliferative disorder (PTLD) is a particularly aggressive and rapidly progressive disease, with high morbidity and mortality. There are a very limited number of reported pulmonary PTLD cases following HSCT in patients with acute myeloid leukemia (AML). Early diagnosis and detection of pulmonary PTLD is critical given its high lethality. However, variable clinical presentations and nonspecific radiographic findings make pulmonary PTLD difficult to distinguish from other more common causes of pulmonary disease in AML patients.Here, we describe a 68-year-old Caucasian man who presented for salvage induction therapy following relapse of his AML after a haploidentical allogeneic HSCT 10 months earlier. He developed recurrent fevers, dry cough, and hypoxemia, with chest computed tomography (CT) showing bibasilar consolidations and increased nodularity without increased lymphadenopathy. His symptoms initially improved with antibiotic and antifungal therapy, but his follow-up chest CT showed progression of disease despite symptomatic improvement. Epstein-Barr virus (EBV) was detected in his blood by polymerase chain reaction (PCR), and a lung biopsy revealed monomorphic PTLD with B cells positive for EBV. Unfortunately, the patient's condition rapidly deteriorated, and he passed away prior to treatment initiation. To our knowledge, this is the first reported case of an AML patient developing pulmonary PTLD relatively late in his post-transplant course in the setting of relapsed disease and salvage therapy. Pulmonary PTLD, a rare but highly lethal disorder, can imitate the symptoms and radiographic findings of pneumonia, a common diagnosis in immunocompromised AML patients. This case illustrates the importance of considering pulmonary PTLD in the differential diagnosis for pulmonary disease in AML patients with a history of HSCT, especially in the setting of progressive radiographic findings despite broad antibacterial and antifungal therapy. Further, our case demonstrates the importance of biopsy and uninterrupted EBV DNA monitoring in the definitive diagnosis of PTLD, given nonspecific symptomatology and radiographic findings.

    View details for DOI 10.1186/s13256-021-02744-2

    View details for PubMedID 33773605

  • NCCN Guidelines Insights: Acute Myeloid Leukemia, Version 2.2021. Journal of the National Comprehensive Cancer Network : JNCCN Pollyea, D. A., Bixby, D. n., Perl, A. n., Bhatt, V. R., Altman, J. K., Appelbaum, F. R., de Lima, M. n., Fathi, A. T., Foran, J. M., Gojo, I. n., Hall, A. C., Jacoby, M. n., Lancet, J. n., Mannis, G. n., Marcucci, G. n., Martin, M. G., Mims, A. n., Neff, J. n., Nejati, R. n., Olin, R. n., Percival, M. E., Prebet, T. n., Przespolewski, A. n., Rao, D. n., Ravandi-Kashani, F. n., Shami, P. J., Stone, R. M., Strickland, S. A., Sweet, K. n., Vachhani, P. n., Wieduwilt, M. n., Gregory, K. M., Ogba, N. n., Tallman, M. S. 2021; 19 (1): 16–27

    Abstract

    The NCCN Guidelines for Acute Myeloid Leukemia (AML) provide recommendations for the diagnosis and treatment of adults with AML based on clinical trials that have led to significant improvements in treatment, or have yielded new information regarding factors with prognostic importance, and are intended to aid physicians with clinical decision-making. These NCCN Guidelines Insights focus on recent select updates to the NCCN Guidelines, including familial genetic alterations in AML, postinduction or postremission treatment strategies in low-risk acute promyelocytic leukemia or favorable-risk AML, principles surrounding the use of venetoclax-based therapies, and considerations for patients who prefer not to receive blood transfusions during treatment.

    View details for DOI 10.6004/jnccn.2021.0002

    View details for PubMedID 33406488

  • Hypomethylating agents super-responders: challenging the dogma of long-term remission for acute myeloid leukemia. Annals of hematology Maakaron, J. E., Ozga, M. P., Mannis, G. N., Pulley, W., Foster, M. C., Zeidner, J. F., Mims, A. S. 2020

    View details for DOI 10.1007/s00277-020-04054-x

    View details for PubMedID 32377815

  • Hepatic veno-occlusive disease in allogeneic stem cell transplant recipients with prior exposure to gemtuzumab ozogamicin or inotuzumab ozogamicin. Leukemia & lymphoma Ladha, A. n., Mannis, G. n., Muffly, L. n. 2020: 1–7

    Abstract

    Hepatic veno-occlusive disease (VOD/sinusoidal obstructive syndrome) represents a constellation of clinical findings including right upper quadrant pain, jaundice, hepatomegaly, and ascites. In the post-hematopoietic stem cell transplant (SCT) setting, the reported incidence has been 10-15%, with severe VOD historically resulting in high mortality rates. Novel agents including calicheamicin conjugated with CD33 (gemtuzumab ozogamicin; GO) and CD22 (inotuzumab ozogamicin; InO) are increasingly used for the treatment of acute myeloid leukemia and acute lymphoblastic leukemia, respectively. Both GO and InO are highly active, but also have unique hepatotoxicity profiles, including a higher risk of VOD in recipients of SCT. Introduction of GO and InO into pre-SCT leukemia management adds additional complexity to SCT patient selection and toxicity monitoring. In this article, we describe and review the risks and management associated with VOD in SCT recipients exposed to GO and InO.

    View details for DOI 10.1080/10428194.2020.1827247

    View details for PubMedID 32988266

  • Hematopoietic Cell Transplantation in the Treatment of Newly Diagnosed Adult Acute Myeloid Leukemia: An Evidence-Based Review from the American Society of Transplantation and Cellular Therapy. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation Dholaria, B. n., Savani, B. N., Hamilton, B. K., Oran, B. n., Liu, H. D., Tallman, M. S., Ciurea, S. O., Holtzman, N. G., Ii, G. L., Devine, S. M., Mannis, G. n., Grunwald, M. R., Appelbaum, F. n., Rodriguez, C. n., Chaer, F. E., Shah, N. n., Hashmi, S. K., Kharfan-Dabaja, M. A., DeFilipp, Z. n., Aljurf, M. n., Inamoto, Y. n., Jain, T. n., Majhail, N. n., Perales, M. A., Mohty, M. n., Hamadani, M. n., Carpenter, P. A., Nagler, A. n. 2020

    Abstract

    The role of hematopoietic cell transplantation (HCT) in the management of newly diagnosed adult acute myeloid leukemia (AML) is reviewed and critically evaluated in this evidence-based review. An AML expert panel, consistent of both transplant and non-transplant experts was invited to develop clinically relevant frequently asked questions covering disease- and HCT-related topics. A systematic literature review was conducted to generate core recommendations that were graded based on the quality and strength of underlying evidence based on the standardized criteria established by American Society of Transplantation and Cellular Therapy Steering Committee for evidence-based reviews. Allogeneic HCT offers a survival benefit in patients with intermediate and high-risk AML and is currently a part of standard clinical care. We recommend the preferential use of myeloablative conditioning in eligible patients. A haploidentical related donor marrow graft is preferred over a cord blood unit in the absence of a fully HLA-matched donor. The evolving role of allogeneic HCT in the context of measurable residual disease monitoring and recent therapeutic advances in AML with regards to maintenance therapy after HCT are also discussed.

    View details for DOI 10.1016/j.bbmt.2020.09.020

    View details for PubMedID 32966881

  • Venetoclax and hypomethylating agent therapy in high risk myelodysplastic syndromes: a retrospective evaluation of a real-world experience. Leukemia & lymphoma Azizi, A. n., Ediriwickrema, A. n., Dutta, R. n., Patel, S. A., Shomali, W. n., Medeiros, B. n., Iberri, D. n., Gotlib, J. n., Mannis, G. n., Greenberg, P. n., Majeti, R. n., Zhang, T. n. 2020: 1–8

    Abstract

    Treatment with hypomethylating agents (HMAs) azacitidine or decitabine is the current standard of care for high risk myelodysplastic syndromes (MDSs) but is associated with low rates of response. The limited number of treatment options for patients with high risk MDS highlights a need for new therapeutic options. Venetoclax is an inhibitor of the BCL-2 protein which, when combined with an HMA, has shown high response rates in unfit and previously untreated acute myeloid leukemia. We performed a retrospective study of high risk MDS patients receiving combination HMA plus venetoclax in order to determine their effectiveness in this context. We show that in our cohort, the combination results in high response rates but is associated with a high frequency of myelosuppression. These data highlight the efficacy of combination HMA plus venetoclax in high risk MDS, warranting further prospective evaluation in clinical trials.

    View details for DOI 10.1080/10428194.2020.1775214

    View details for PubMedID 32543932

  • Improved Outcomes of Octogenarians and Nonagenarians with Acute Myeloid Leukemia in the Era of Novel Therapies. American journal of hematology Jeng, M. Y., Dutta, R. n., Tan, I. T., Zhang, T. Y., Mannis, G. N. 2020

    View details for DOI 10.1002/ajh.25949

    View details for PubMedID 32744731

  • Venetoclax monotherapy for cutaneous blastic plasmacytoid dendritic cell neoplasm. Annals of hematology Schwede, M. n., Tan, I. T., Atibalentja, D. F., Dickman, M. M., Rieger, K. E., Mannis, G. N. 2020

    View details for DOI 10.1007/s00277-020-04276-z

    View details for PubMedID 32968828

  • Serial comprehensive geriatric and quality of life assessments in adults age ≥ 50 years undergoing autologous hematopoietic cell transplantation. Journal of geriatric oncology Nawas, M. T., Sheng, Y. n., Huang, C. Y., Andreadis, C. n., Martin, T. G., Wolf, J. L., Ai, W. Z., Kaplan, L. D., Mannis, G. N., Logan, A. C., Damon, L. E., Olin, R. L. 2020

    Abstract

    We sought to examine the natural history of geriatric assessment (GA) and quality of life (QOL) domains among adults age ≥ 50 years undergoing autologous hematopoietic cell transplantation (autoHCT).A QOL tool and cancer-specific GA were completed before autoHCT in patients ≥50 years, and at 100 days, six months, and one year post-transplant.One hundred eighty-four patients completed the pre-transplant QOL/GA assessment, 169 (92%) completed the 100-day assessment, 162 (88%) completed the six-month assessment, and 145 (79%) completed the twelve-month assessment. Functional status, as measured by instrumental activities of daily living (IADL), decreased from baseline to day 101 (mean change -0.42 points, 95% CI, -0.75 to -0.09, p = 0.01) but returned to baseline by one year. Physical function as measured by Medical Outcomes Study-Physical Health (MOS-PH) increased by mean of 3.27 points (95% CI, -0.02 to 6.56, p = 0.05) by one year. Physician-rated KPS improved by one year, but patient-rated KPS did not. No QOL metric deteriorated from baseline. Baseline factors predictive of IADL and MOS-PH as measured over time included comorbidities and disease status at transplant. IADL and MOS-PH as measured over time were not significantly associated with age.AutoHCT for adults age ≥ 50 years resulted in an initial decrease in functional status, with subsequent improvement back to baseline by one year. Physical health and QOL measures were improved or unchanged over time. AutoHCT is well tolerated in well selected older patients, using patient reported geriatric metrics as outcomes.

    View details for DOI 10.1016/j.jgo.2020.09.027

    View details for PubMedID 33059999

  • Maintenance Lenalidomide in Primary CNS Lymphoma. Annals of oncology : official journal of the European Society for Medical Oncology Rubenstein, J. L., Geng, H., Vu, K., Mannis, G., Formaker, P., Hwang, J., Munster, P. N., Damato, B. 2019

    View details for DOI 10.1093/annonc/mdz142

    View details for PubMedID 31046114

  • Low-dose lenalidomide maintenance after induction therapy in older patients with primary central nervous system lymphoma. British journal of haematology Vu, K., Mannis, G., Hwang, J., Geng, H., Rubenstein, J. L. 2019

    View details for DOI 10.1111/bjh.15787

    View details for PubMedID 30714128

  • Limitation in Patient-Reported Function Is Associated with Inferior Survival in Older Adults Undergoing Autologous Hematopoietic Cell Transplantation. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation Nawas, M. T., Andreadis, C., Martin, T. G., Wolf, J. L., Ai, W. Z., Kaplan, L. D., Mannis, G. N., Logan, A. C., Damon, L. E., Huang, C., Olin, R. L. 2019

    Abstract

    Although the use of geriatric assessment (GA) in the allogeneic hematopoietic cell transplantation (HCT) setting has been reported, few studies have evaluated the impact of patient-reported function on autologous HCT (autoHCT) outcomes. In this study, GA, including the administration of Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) quality of life tool, was performed in 184 patients age ≥50 years (median age, 61 years; range, 50 to 75 years) before autoHCT. Associations among GA findings, quality of life metrics, and post-transplantation outcomes were evaluated using Cox regression. Indications for autoHCT included multiple myeloma (73%), non-Hodgkin lymphoma (20%), and other disorders (7%). The median progression-free survival (PFS) was 28 months, whereas the median overall survival (OS) was not reached. In unadjusted analysis, both PFS and OS were significantly associated with 5 GA components: limitation in instrumental activities of daily living, patient-reported Karnofsky Performance Status (KPS), and the Physical, Functional, and BMT subscale scores of the FACT-BMT. In multivariate analysis, 3 components-limitation in instrumental activities of daily living, patient-reported KPS, and FACT-BMT Physical subscale-remained predictive of both PFS and OS when adjusted for age, provider-reported KPS, disease status, and HCT comorbidity index. In older adults undergoing autoHCT, limitation in any 1 of 3 patient-reported measures of functional status was independently associated with inferior PFS and OS, even after adjusting for known prognostic factors.

    View details for DOI 10.1016/j.bbmt.2019.01.028

    View details for PubMedID 30708189

  • Allogeneic HSCT for adult-onset leukoencephalopathy with spheroids and pigmented glia. Brain : a journal of neurology Gelfand, J. M., Greenfield, A. L., Barkovich, M. n., Mendelsohn, B. A., Van Haren, K. n., Hess, C. P., Mannis, G. N. 2019

    Abstract

    Adult-onset leukoencephalopathy with spheroids and pigmented glia (ALSP) is an autosomal dominant leukoencephalopathy caused by mutations in colony stimulating factor 1 receptor (CSF1R). Here we report clinical and imaging outcomes following allogeneic haematopoietic stem cell transplantation (HSCT) in two patients with ALSP at the University of California, San Francisco between January 2016 and December 2017. Patient 1 proceeded to transplantation at age 53 with a haplo-identical sibling donor. Patient 2, whose sister and mother had died of the disease, proceeded to transplantation at age 49 with a 12/12 human leukocyte antigen-matched unrelated donor. Both patients received reduced intensity conditioning regimens. At 28 and 26 months post-HSCT, respectively, both patients were alive, without evidence of graft-versus-host disease, with major infection at 1 year in one and new-onset seizures in the other. In both cases, neurological worsening continued post-HSCT; however, the progression in cognitive deficits, overall functional status and gait impairment gradually stabilized. There was continued progression of parkinsonism in both patients. On brain MRI, within 1 year there was stabilization of T2/FLAIR abnormalities, and after 2 years there was complete resolution of abnormal multifocal reduced diffusion. In summary, after >2 years of follow-up, allogeneic HSCT in ALSP led to interval resolution of diffusion MRI abnormalities, stabilization of T2/FLAIR MRI abnormalities, and partial clinical stabilization, supportive of treatment response. Allogeneic HSCT may be beneficial in ALSP by providing a supply of bone marrow-derived brain-engrafting myeloid cells with donor wild-type CSF1R to repopulate the microglial niche.

    View details for DOI 10.1093/brain/awz390

    View details for PubMedID 31840744

  • Functional status as measured by geriatric assessment predicts inferior survival in older allogeneic hematopoietic cell transplant recipients. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation Huang, L. W., Sheng, Y. n., Andreadis, C. n., Logan, A. C., Mannis, G. N., Smith, C. C., Gaensler, K. M., Martin, T. G., Damon, L. E., Steinman, M. A., Huang, C. Y., Olin, R. L. 2019

    Abstract

    Allogeneic hematopoietic cell transplantation (alloHCT) has been increasingly offered to older adults with hematologic malignancies. However, optimal methods to determine fitness for alloHCT have yet to be defined. We evaluated the ability of a comprehensive geriatric assessment (CGA) to predict post-alloHCT outcomes in a single-center prospective cohort study of patients aged 50 and older. Outcomes included overall survival (OS), progression-free survival (PFS), and non-relapse mortality (NRM). A total of 148 patients were included, with median age 62 years (range 50-76). In multivariate regression analysis, several CGA measures of functional status were predictive of post-alloHCT outcomes, after adjusting for traditional prognostic factors. Any deficit in Instrumental Activities of Daily Living (IADL) was associated with inferior OS (hazard ratio [HR] 1.81, 95% confidence interval [CI] 1.07-3.08, p=0.03) and PFS (HR 1.85, 95% CI 1.15-2.99, p=0.01). Medical Outcomes Study Physical Health scale (MOS-PH) score <85 was associated with inferior OS (HR 1.96, 95% CI 1.13-3.40, p=0.02), PFS (HR 1.75, 95% CI 1.07-2.88, p=0.03), and increased NRM (subdistribution HR 2.57, 95% CI 1.12-5.92, p=0.03). MOS-PH was also associated with the number of non-hematologic grade ≥3 adverse events within the first 100 days after alloHCT (rate ratio 1.61, 95% CI 1.04-2.49, p=0.03). These findings support previous work suggesting that IADL is an important prognostic tool prior to alloHCT. MOS-PH is newly identified as an additional metric to identify older patients at higher risk of poor post-alloHCT outcomes, including toxicity and NRM.

    View details for DOI 10.1016/j.bbmt.2019.08.022

    View details for PubMedID 31493541

  • Acute Myeloid Leukemia, Version 3.2019, NCCN Clinical Practice Guidelines in Oncology. Journal of the National Comprehensive Cancer Network : JNCCN Tallman, M. S., Wang, E. S., Altman, J. K., Appelbaum, F. R., Bhatt, V. R., Bixby, D. n., Coutre, S. E., De Lima, M. n., Fathi, A. T., Fiorella, M. n., Foran, J. M., Hall, A. C., Jacoby, M. n., Lancet, J. n., LeBlanc, T. W., Mannis, G. n., Marcucci, G. n., Martin, M. G., Mims, A. n., O'Donnell, M. R., Olin, R. n., Peker, D. n., Perl, A. n., Pollyea, D. A., Pratz, K. n., Prebet, T. n., Ravandi, F. n., Shami, P. J., Stone, R. M., Strickland, S. A., Wieduwilt, M. n., Gregory, K. M., Hammond, L. n., Ogba, N. n. 2019; 17 (6): 721–49

    Abstract

    Acute myeloid leukemia (AML) is the most common form of acute leukemia among adults and accounts for the largest number of annual deaths due to leukemias in the United States. Recent advances have resulted in an expansion of treatment options for AML, especially concerning targeted therapies and low-intensity regimens. This portion of the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for AML focuses on the management of AML and provides recommendations on the workup, diagnostic evaluation and treatment options for younger (age <60 years) and older (age ≥60 years) adult patients.

    View details for DOI 10.6004/jnccn.2019.0028

    View details for PubMedID 31200351

  • Ivosidenib induces deep durable remissions in patients with newly diagnosed IDH1-mutant acute myeloid leukemia. Blood Roboz, G. J., DiNardo, C. D., Stein, E. M., de Botton, S. n., Mims, A. S., Prince, G. T., Altman, J. K., Arellano, M. L., Donnellan, W. n., Erba, H. P., Mannis, G. N., Pollyea, D. A., Stein, A. S., Uy, G. L., Watts, J. M., Fathi, A. T., Kantarjian, H. M., Tallman, M. S., Choe, S. n., Dai, D. n., Fan, B. n., Wang, H. n., Zhang, V. n., Yen, K. E., Kapsalis, S. M., Hickman, D. n., Liu, H. n., Agresta, S. V., Wu, B. n., Attar, E. C., Stone, R. M. 2019

    Abstract

    Ivosidenib (AG-120) is an oral, targeted agent that suppresses production of the oncometabolite 2-hydroxyglutarate via inhibition of the mutant isocitrate dehydrogenase 1 (mIDH1) enzyme. From a phase 1 study of 258 patients with IDH1-mutant advanced hematologic malignancies, we report results for 34 patients with newly diagnosed acute myeloid leukemia (AML) ineligible for standard therapy who received ivosidenib 500 mg once daily. Median age was 76.5 years, 26 (76%) patients had secondary AML and 16 (47%) had received {greater than or equal to}1 hypomethylating agent for an antecedent hematologic disorder. The most common all-grade adverse events were diarrhea (n=18; 53%), fatigue (n=16; 47%), nausea (n=13; 38%), and decreased appetite (n=12; 35%). Differentiation syndrome was reported in 6 (18%) patients (grade {greater than or equal to}3 in 3 [9%]) and did not require treatment discontinuation. Complete remission (CR) + CR with partial hematologic recovery (CRh) rate was 42.4% (95% confidence interval [CI], 25.5-60.8%); CR rate was 30.3% (95% CI, 15.6-48.7%). Median durations of CR+CRh and CR were not reached, with 95% CI lower bounds of 4.6 and 4.2 months, respectively; 61.5% and 77.8% of patients remained in remission at 1 year. With median follow-up of 23.5 months (range, 0.6-40.9), median overall survival was 12.6 months (95% CI, 4.5-25.7). Of 21 (63.6%) patients who were transfusion dependent at baseline, 9 (42.9%) became transfusion independent. IDH1 mutation clearance was seen in 9/14 patients achieving CR+CRh (5/10 CR, 4/4 CRh). Ivosidenib monotherapy was well tolerated and induced durable remissions and transfusion independence in patients with newly diagnosed AML. (Trial registered at www.clinicaltrials.gov #NCT02074839.).

    View details for DOI 10.1182/blood.2019002140

    View details for PubMedID 31841594

  • Durable Remissions with Ivosidenib in IDH1-Mutated Relapsed or Refractory AML NEW ENGLAND JOURNAL OF MEDICINE DiNardo, C. D., Stein, E. M., de Botton, S., Roboz, G. J., Altman, J. K., Mims, A. S., Swords, R., Collins, R. H., Mannis, G. N., Pollyea, D. A., Donnellan, W., Fathi, A. T., Pigneux, A., Erba, H. P., Prince, G. T., Stein, A. S., Uy, G. L., Foran, J. M., Traer, E., Stuart, R. K., Arellano, M. L., Slack, J. L., Sekeres, M. A., Willekens, C., Choe, S., Wang, H., Zhang, V., Yen, K. E., Kapsalis, S. M., Yang, H., Dai, D., Fan, B., Goldwasser, M., Liu, H., Agresta, S., Wu, B., Attar, E. C., Tallman, M. S., Stone, R. M., Kantarjian, H. M. 2018; 378 (25): 2386–98

    Abstract

    Mutations in the gene encoding isocitrate dehydrogenase 1 ( IDH1) occur in 6 to 10% of patients with acute myeloid leukemia (AML). Ivosidenib (AG-120) is an oral, targeted, small-molecule inhibitor of mutant IDH1.We conducted a phase 1 dose-escalation and dose-expansion study of ivosidenib monotherapy in IDH1-mutated AML. Safety and efficacy were assessed in all treated patients. The primary efficacy population included patients with relapsed or refractory AML receiving 500 mg of ivosidenib daily with at least 6 months of follow-up.Overall, 258 patients received ivosidenib and had safety outcomes assessed. Among patients with relapsed or refractory AML (179 patients), treatment-related adverse events of grade 3 or higher that occurred in at least 3 patients were prolongation of the QT interval (in 7.8% of the patients), the IDH differentiation syndrome (in 3.9%), anemia (in 2.2%), thrombocytopenia or a decrease in the platelet count (in 3.4%), and leukocytosis (in 1.7%). In the primary efficacy population (125 patients), the rate of complete remission or complete remission with partial hematologic recovery was 30.4% (95% confidence interval [CI], 22.5 to 39.3), the rate of complete remission was 21.6% (95% CI, 14.7 to 29.8), and the overall response rate was 41.6% (95% CI, 32.9 to 50.8). The median durations of these responses were 8.2 months (95% CI, 5.5 to 12.0), 9.3 months (95% CI, 5.6 to 18.3), and 6.5 months (95% CI, 4.6 to 9.3), respectively. Transfusion independence was attained in 29 of 84 patients (35%), and patients who had a response had fewer infections and febrile neutropenia episodes than those who did not have a response. Among 34 patients who had a complete remission or complete remission with partial hematologic recovery, 7 (21%) had no residual detectable IDH1 mutations on digital polymerase-chain-reaction assay. No preexisting co-occurring single gene mutation predicted clinical response or resistance to treatment.In patients with advanced IDH1-mutated relapsed or refractory AML, ivosidenib at a dose of 500 mg daily was associated with a low frequency of grade 3 or higher treatment-related adverse events and with transfusion independence, durable remissions, and molecular remissions in some patients with complete remission. (Funded by Agios Pharmaceuticals; ClinicalTrials.gov number, NCT02074839 .).

    View details for PubMedID 29860938

  • Venetoclax in Combination with Decitabine for Relapsed T-Cell Acute Lymphoblastic Leukemia after Allogeneic Hematopoietic Cell Transplant CASE REPORTS IN HEMATOLOGY Rahmat, L. T., Nguyen, A., Abdulhaq, H., Prakash, S., Logan, A. C., Mannis, G. N. 2018: 6092646

    Abstract

    Long-term disease-free survival in adults with T-cell acute lymphoblastic leukemia (T-ALL) remains poor, particularly after relapse, with few available salvage options. Preclinical data suggest that inhibition of the antiapoptotic protein BCL-2 (B-cell lymphoma 2) either alone or in combination with other agents, may be a unique therapeutic approach for the treatment of T-ALL. We present a case of a young male with T-ALL, relapsed after allogeneic hematopoietic stem cell transplant, who achieved a second complete remission following salvage therapy with combined venetoclax and decitabine. Assessment of measurable residual disease by next generation sequencing showed no evidence of residual disease of a sensitivity of 1 × 10-6. While the combination of venetoclax and hypomethylating agents has shown promise in the treatment of relapsed/refractory AML, and to our knowledge, this is the first report of this combination demonstrating clinical activity in relapsed/refractory T-ALL.

    View details for DOI 10.1155/2018/6092646

    View details for Web of Science ID 000444206900001

    View details for PubMedID 30225152

    View details for PubMedCentralID PMC6129347

  • Discussion on reply to Foley et al., 'Acute myeloid leukemia with t(14;21) involving RUNX1 and SYNE2: A novel favorable-risk translocation?' CANCER GENETICS Mannis, G. N. 2018; 220: 77–78
  • Acute myeloid leukemia with t(14;21) involving RUNX1 and SYNE2: A novel favorable-risk translocation? CANCER GENETICS Foley, N., Van Ziffle, J., Yu, J., Qi, Z., Grenert, J. P., Yeh, I., Bastian, B., Kogan, S., Mannis, G. N. 2017; 216: 74–78

    Abstract

    In acute myeloid leukemia (AML), a translocation between chromosomes 8q22 and 21q22 leads to the RUNX1-RUNXT1 fusion gene which, in the absence of a concomitant KIT mutation, generally portends a more favorable prognosis. Translocations at 21q22, other than those involving 8q22, are uncommon, and the specific prognostic and therapeutic implications are accordingly limited by the small number of reported cases. In this report, we describe the case of a 67-year-old gentleman who presented with AML harboring t(14;21)(q23;q22). Subsequent molecular analysis revealed mutations in RUNX1, ASXL1, and SF3B1, with translocation breakpoints identified within SYNE2 on chromosome 14 and RUNX1 on chromosome 21. The functional consequence of the DNA fusion between SYNE2 and RUNX1 is unclear. Nonetheless, despite several adverse risk factors associated with this patient's AML, he achieved a long-lasting remission with standard chemotherapy alone, potentially suggestive of a novel favorable-risk translocation in AML involving 21q22.

    View details for DOI 10.1016/j.cancergen.2017.07.002

    View details for Web of Science ID 000414382900010

    View details for PubMedID 29025598

  • Advance care planning and end-of-life care for patients with hematologic malignancies who die after hematopoietic cell transplant. Bone marrow transplantation Eckhert, E. E., Schoenbeck, K. L., Galligan, D., McNey, L. M., Hwang, J., Mannis, G. N. 2017; 52 (6): 929-931

    View details for DOI 10.1038/bmt.2017.41

    View details for PubMedID 28287642

  • Regression of methotrexate-resistant AIDS-related primary central nervous system lymphoma with lenalidomide plus combination anti-retroviral therapy LEUKEMIA & LYMPHOMA Gupta, N. K., Wang, C., Mannis, G. N., Yu, J. J., Rubenstein, J. L. 2017; 58 (11): 2748–51

    View details for DOI 10.1080/10428194.2017.1312374

    View details for Web of Science ID 000406274600034

    View details for PubMedID 28395565

    View details for PubMedCentralID PMC6026016

  • Multigene Measurable Residual Disease Assessment Improves Acute Myeloid Leukemia Relapse Risk Stratification in Autologous Hematopoietic Cell Transplantation BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION Mule, M. P., Mannis, G. N., Wood, B. L., Radich, J. R., Hwang, J., Ramos, N. R., Andreadis, C., Damon, L., Logan, A. C., Martin, T. G., Hourigan, C. S. 2016; 22 (11): 1974–82

    Abstract

    We report here the largest study to date of adult patients with acute myeloid leukemia (AML) tested for measurable residual disease (MRD) at the time of autologous hematopoietic cell transplantation (auto-HCT). Seventy-two adult patients who underwent transplantation between 2004 and 2013 at a single academic medical center (University of California San Francisco) were eligible for this retrospective study based on availability of cryopreserved granulocyte colony-stimulating factor (GCSF)-mobilized autologous peripheral blood progenitor cell (PBPC) leukapheresis specimens ("autografts"). Autograft MRD was assessed by molecular methods (real-time quantitative PCR [RQ-PCR] for Wilms tumor 1 (WT1) alone or a multigene panel) and by multiparameter flow cytometry (MPFC). WT1 RQ-PCR testing of the autograft had low sensitivity for relapse prediction (14%) and a negative predictive value of 51%. MPFC failed to identify MRD in any of 34 autografts tested. Combinations of molecular MRD assays, however, improved prediction of post-auto-HCT relapse. In multivariate analysis of clinical variables, including age, gender, race, cytogenetic risk category, and CD34+ cell dose, only autograft multigene MRD as assessed by RQ-PCR was statistically significantly associated with relapse. One year after transplantation, only 28% patients with detectable autograft MRD were relapse free, compared with 67% in the MRD-negative cohort. Multigene MRD, while an improvement on other methods tested, was however suboptimal for relapse prediction in unselected patients, with specificity of 83% and sensitivity of 46%. In patients with known chromosomal abnormalities or mutations, however, better predictive value was observed with no relapses observed in MRD-negative patients in the first year after auto-HCT compared with 83% incidence of relapse in the MRD-positive patients (hazard ratio, 12.45; P = .0016). In summary, increased personalization of MRD monitoring by use of a multigene panel improved the ability to risk stratify patients for post-auto-HCT relapse. WT1 RQ-PCR and flow cytometric assessment for AML MRD in autograft samples had limited value for predicting relapse after auto-HCT. We demonstrate that cryopreserved autograft material presents unique challenges for AML MRD testing because of the masking effects of previous GCSF exposure on gene expression and flow cytometry signatures. In the absence of information regarding diagnostic characteristics, sources other than GCSF-stimulated PBSC leukapheresis specimens should be considered as alternatives for MRD testing in AML patients undergoing auto-HCT.

    View details for DOI 10.1016/j.bbmt.2016.08.014

    View details for Web of Science ID 000386544200010

    View details for PubMedID 27544285

    View details for PubMedCentralID PMC5072749

  • Paraproteinemic keratopathy as the presenting sign of hematologic malignancy AMERICAN JOURNAL OF HEMATOLOGY Mannis, T. E., Mannis, G. N., Waterhouse, E. G., Aldave, A. J., Rose-Nussbaumer, J. 2016; 91 (9): 961–62

    View details for DOI 10.1002/ajh.24327

    View details for Web of Science ID 000385237100167

    View details for PubMedID 26872417

    View details for PubMedCentralID PMC6038815

  • Quantification of Acute Lymphoblastic Leukemia Clonotypes in Leukapheresed Peripheral Blood Progenitor Cells Predicts Relapse Risk after Autologous Hematopoietic Stem Cell Transplantation BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION Mannis, G. N., Martin, T. G., Damon, L. E., Andreadis, C., Olin, R. L., Kong, K. A., Faham, M., Hwang, J., Ai, W. Z., Gaensler, K. L., Sayre, P. H., Wolf, J. L., Logan, A. C. 2016; 22 (6): 1030–36

    Abstract

    Since the incorporation of tyrosine kinase inhibitors into the treatment of Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL), the notion that all patients with "high-risk" ALL uniformly require allogeneic (allo) hematopoietic cell transplantation (HCT) has received increasing scrutiny. Although multiple studies have shown superiority of alloHCT over autologous (auto) hematopoietic cell transplantation for high-risk patients, these findings may be explained, in part, by contamination of the peripheral blood progenitor cell (PBPC) leukapheresis product by residual leukemic cells in patients undergoing autoHCT. We retrospectively evaluated minimal residual disease (MRD) using next-generation sequencing (NGS) in the PBPC leukapheresis product of 32 ALL patients who underwent autoHCT. Twenty-eight patients (88%) had diagnostic samples with quantifiable immunoreceptor rearrangements to follow for MRD. Twelve (38%) patients had Ph+ B-ALL, 12 (38%) had Philadelphia chromosome-negative (Ph-) B-ALL, and 4 (14%) had T cell ALL. With a median follow-up of 41 months (range, 3 to 217), median relapse-free survival (RFS) and overall survival for the entire cohort were 3.2 and 4.2 years, respectively; at 5 years after transplantation, 42% of patients remain alive and relapse free. Using MRD detection at a threshold of ≥ 1 × 10(-6), median RFS for patients with detectable MRD was 6.5 months and was not reached for patients without detectable disease (P = .0005). In multivariate analysis, the only factor significantly associated with relapse was the presence of MRD ≥1 × 10(-6) (odds ratio, 23.8; confidence interval, 1.8 to 312.9; P = .0158). Our findings suggest that NGS for MRD detection can predict long-term RFS in patients undergoing autoHCT for high-risk ALL.

    View details for DOI 10.1016/j.bbmt.2016.02.004

    View details for Web of Science ID 000376814000010

    View details for PubMedID 26899561

  • Inferior vena cava filter thrombosis CLINICAL CASE REPORTS Byrne, M., Mannis, G. N., Nair, J., Andreadis, C. 2016; 4 (2): 162–64

    Abstract

    Patients with inferior vena cava (IVC) filters - particularly permanent filters - are at increased risk for recurrent deep venous thrombosis (DVT). Judicious use of IVC filters, as well as the prompt retrieval of temporary IVC filters, substantially reduces the risk of IVC thrombosis.

    View details for DOI 10.1002/ccr3.418

    View details for Web of Science ID 000369149200015

    View details for PubMedID 26862415

    View details for PubMedCentralID PMC4736520

  • The Transfusion Tether: Bridging the Gap Between End-Stage Hematologic Malignancies and Optimal End-of-Life Care. American journal of hematology Mannis, G. N., McNey, L. M., Gupta, N. K., Gross, D. M. 2016

    View details for PubMedID 26799788

  • Long-term outcomes of patients with intermediate-risk acute myeloid leukemia treated with autologous hematopoietic cell transplant in first complete remission LEUKEMIA & LYMPHOMA Mannis, G. N., Martin, T. G., Damon, L. E., Logan, A. C., Olin, R. L., Flanders, M. D., Ai, W. Z., Gaensler, K. L., Kaplan, L. D., Sayre, P. H., Smith, C. C., Wolf, J. L., Andreadis, C. 2016; 57 (7): 1560–66

    Abstract

    In 2014, autologous hematopoietic cell transplant (autoHCT) was removed from the National Comprehensive Cancer Network guidelines as a recommended treatment for patients with intermediate-risk AML in first complete remission (CR1). We reviewed the outcomes of all patients with intermediate-risk AML treated with autoHCT in CR1 at our institution. Of 334 patients who underwent autoHCT for AML between 1988 and 2013, 133 patients with intermediate-risk AML in CR1 were identified. Cytogenetics were diploid in 97 (73%). With a median follow-up of 4.1 years (range 0.1-17), median overall survival (OS) is 6.7 years; at 5 years post-transplant, 59% of patients remain alive and 43% remain relapse-free. Forty-eight percent of relapsing patients proceeded to salvage alloHCT. Our findings demonstrate that nearly half of patients with intermediate-risk AML in CR1 achieve sustained remissions, and that salvage alloHCT is feasible in those who relapse. AutoHCT therefore remains a reasonable option for intermediate-risk patients with AML in CR1.

    View details for DOI 10.3109/10428194.2015.1088646

    View details for Web of Science ID 000377265000013

    View details for PubMedID 26490487

  • Long-term survival in AIDS-related primary central nervous system lymphoma. Neuro-oncology Gupta, N. K., Nolan, A. n., Omuro, A. n., Reid, E. G., Wang, C. C., Mannis, G. n., Jaglal, M. n., Chavez, J. C., Rubinstein, P. G., Griffin, A. n., Abrams, D. I., Hwang, J. n., Kaplan, L. D., Luce, J. A., Volberding, P. n., Treseler, P. A., Rubenstein, J. L. 2016

    Abstract

    The optimal therapeutic approach for patients with AIDS-related primary central nervous system lymphoma (AR-PCNSL) remains undefined. While its incidence declined substantially with combination antiretroviral therapy (cART), AR-PCNSL remains a highly aggressive neoplasm for which whole brain radiotherapy (WBRT) is considered a standard first-line intervention.To identify therapy-related factors associated with favorable survival, we first retrospectively analyzed outcomes of AR-PCNSL patients treated at San Francisco General Hospital, a public hospital with a long history of dedicated care for patients with HIV and AIDS-related malignancies. Results were validated in a retrospective, multicenter analysis that evaluated all newly diagnosed patients with AR-PCNSL treated with cART plus high-dose methotrexate (HD-MTX).We provide evidence that CD4+ reconstitution with cART administered during HD-MTX correlates with long-term survival among patients with CD4 <100. This was confirmed in a multicenter analysis which demonstrated that integration of cART regimens with HD-MTX was generally well tolerated and resulted in longer progression-free survival than other treatments. No profound differences in immunophenotype were identified in an analysis of AR-PCNSL tumors that arose in the pre- versus post-cART eras. However, we detected evidence for a demographic shift, as the proportion of minority patients with AR-PCNSL increased since advent of cART.Long-term disease-free survival can be achieved in AR-PCNSL, even among those with histories of opportunistic infections, limited access to health care, and medical non-adherence. Given this, as well as the long-term toxicities of WBRT, we recommend that integration of cART plus first-line HD-MTX be considered for all patients with AR-PCNSL.

    View details for DOI 10.1093/neuonc/now155

    View details for PubMedID 27576871

  • A Phase I Study of Targeted, Dose-Escalated Intravenous Busulfan in Combination With Etoposide as Myeloablative Therapy for Autologous Stem Cell Transplantation in Acute Myeloid Leukemia CLINICAL LYMPHOMA MYELOMA & LEUKEMIA Mannis, G. N., Andreadis, C., Logan, A. C., Damon, L. E., Benet, L. Z., Ai, W. Z., Gaensler, K. L., Kaplan, L. D., Koplowicz, Y. B., Linker, C. A., Olin, R. L., Sayre, P. H., Smith, C. C., Sudhindra, A., Venstrom, J. M., Wolf, J. L., Martin, T. G. 2015; 15 (6): 377–83

    Abstract

    Busulfan and etoposide have been used as myeloablative therapy for autologous hematopoietic stem cell transplantation (HSCT) in adults with acute myeloid leukemia (AML) for > 20 years. The use of targeted intravenous (I.V.) busulfan has significantly improved the tolerability and efficacy of this regimen. We designed a dose-escalation study to examine the maximum tolerated dose (MTD) of targeted I.V. busulfan with bolus etoposide as preparative therapy for autologous HSCT in AML.In this single-center, phase I study, adult AML patients received I.V. busulfan targeted to either an area under the curve (AUC) of 1250 (cohort 1) or 1400 (cohort 2) μmol/min over 16 doses. Dose adjustments based on plasma pharmacokinetics occurred before doses 2 and 11. Etoposide 60 mg/kg I.V. was administered 24 hours after the last busulfan dose and 3 days before stem cell infusion.Twelve patients with intermediate-risk AML in first complete remission were treated. All patients in cohort 1 and 5 patients (83%) in cohort 2 were within 10% of the target AUC. The MTD was not reached, although Grade ≥ 3 mucositis occurred in 3 patients (50%) in cohort 1 and in 4 patients (66%) in cohort 2, limiting further dose escalation. Two-year relapse-free survival was 33% in cohort 1 versus 67% in cohort 2 (P = .08).Etoposide and targeted, dose-escalated I.V. busulfan as myeloablative therapy for autologous HSCT in AML is safe, with mucositis being the most significant toxicity. A phase II study is warranted to further evaluate the activity and safety of busulfan targeted to AUC 1400 μmol/min.

    View details for DOI 10.1016/j.clml.2015.02.016

    View details for Web of Science ID 000356397700010

    View details for PubMedID 25776193

  • Ibrutinib rash in a patient with 17p del chronic lymphocytic leukemia. American journal of hematology Mannis, G., Wu, D., Dea, T., Mauro, T., Hsu, G. 2015; 90 (2): 179

    View details for DOI 10.1002/ajh.23775

    View details for PubMedID 24890909

    View details for PubMedCentralID PMC4548957

  • Delayed hematopoietic recovery after auto-SCT in patients receiving arsenic trioxide-based therapy for acute promyelocytic leukemia: a multi-center analysis BONE MARROW TRANSPLANTATION Mannis, G. N., Logan, A. C., Leavitt, A. D., Yanada, M., Hwang, J., Olin, R. L., Damon, L. E., Andreadis, C., Ai, W. Z., Gaensler, K. M., Greene, C. C., Gupta, N. K., Kaplan, L. D., MAHINDRA, A., Miyazaki, Y., Naoe, T., Ohtake, S., Sayre, P. H., Smith, C. C., Venstrom, J. M., Wolf, J. L., Caballero, L., Emi, N., Martin, T. G. 2015; 50 (1): 40-44

    Abstract

    A potential link between arsenic (ATO)-based therapy and delayed hematopoietic recovery after autologous hematopoietic SCT (HSCT) for acute promyelocytic leukemia (APL) has previously been reported. We retrospectively reviewed the clinical histories of 58 patients undergoing autologous HSCT for APL at 21 institutions in the United States and Japan. Thirty-three (56%) of the patients received ATO-based therapy prior to stem cell collection. Delayed neutrophil engraftment occurred in 10 patients (17%): 9 of the 10 patients (90%) received prior ATO (representing 27% of all ATO-treated patients), compared with 1 of the 10 patients (10%) not previously treated with ATO (representing 4% of all ATO-naïve patients; P<0.001). Compared with ATO-naïve patients, ATO-treated patients experienced significantly longer times to ANC recovery (median 12 days vs 9 days, P<0.001). In multivariate analysis, the only significant independent predictor of delayed neutrophil engraftment was prior treatment with ATO (hazard ratio 4.87; P<0.001). Of the available stem cell aliquots from APL patients, the median viable post-thaw CD34+ cell recovery was significantly lower than that of cryopreserved autologous stem cell products from patients with non-APL AML. Our findings suggest that ATO exposure prior to CD34+ cell harvest has deleterious effects on hematopoietic recovery after autologous HSCT.

    View details for DOI 10.1038/bmt.2014.201

    View details for Web of Science ID 000347806800008

    View details for PubMedID 25243620

  • How I treat CNS lymphomas BLOOD Rubenstein, J. L., Gupta, N. K., Mannis, G. N., LaMarre, A. K., Treseler, P. 2013; 122 (14): 2318-2330

    Abstract

    The pathogenesis of primary and secondary central nervous system (CNS) lymphoma poses a unique set of diagnostic, prognostic, and therapeutic challenges. During the past 10 years, there has been significant progress in the elucidation of the molecular properties of CNS lymphomas and their microenvironment, as well as evolution in the development of novel treatment strategies. Although a CNS lymphoma diagnosis was once assumed to be uniformly associated with a dismal prognosis, it is now reasonable to anticipate long-term survival, and possibly a cure, for a significant fraction of CNS lymphoma patients. The pathogenesis of CNS lymphomas affects multiple compartments within the neuroaxis, and proper treatment of the CNS lymphoma patient requires a multidisciplinary team with expertise not only in hematology/oncology but also in neurology, neuroradiology, neurosurgery, clinical neuropsychology, ophthalmology, pathology, and radiation oncology. Given the evolving principles of management and the evidence for improvements in survival, our goal is to provide an overview of current knowledge regarding the pathogenesis of CNS lymphomas and to highlight promising strategies that we believe to be most effective in establishing diagnosis, staging, and therapeutic management.

    View details for DOI 10.1182/blood-2013-06-453084

    View details for Web of Science ID 000326078200015

    View details for PubMedID 23963042

    View details for PubMedCentralID PMC3790503

  • Risk-Reducing Salpingo-oophorectomy and Ovarian Cancer Screening in 1077 Women After BRCA Testing JAMA INTERNAL MEDICINE Mannis, G. N., Fehniger, J. E., Creasman, J. S., Jacoby, V. L., Beattie, M. S. 2013; 173 (2): 96–103

    Abstract

    For women at potentially increased risk for ovarian cancer, data regarding screening and risk reduction are limited. Previous studies have reported on the behaviors of BRCA mutation carriers, but less is known about the behaviors of non- BRCA carriers. We surveyed a large cohort of women after BRCA testing to identify the prevalence and posttest predictors of risk-reducing and screening interventions.A median of 3.7 years after BRCA testing, 1447 women who received genetic counseling and BRCA testing at 2 hospital sites were surveyed, with a 77.6% response rate. We analyzed data from 1077 survey respondents. We performed univariate and multivariate logistic regression analyses to identify predictors of risk-reducing salpingo-oophorectomy (RRSO), screening transvaginal ultrasonography (TVUS), and screening serum cancer antigen 125 (CA-125).Among the respondents, 201 women (18.7%) received positive test results for a deleterious mutation, 103 women (9.6%) received true-negative results, and 773 women (71.8%) received uninformative results. Overall, 19.1% of eligible women underwent RRSO and 39.6% used screening procedures. A positive BRCA result predicted RRSO (odds ratio [OR], 28.1; 95% CI, 16.2-48.6), TVUS (9.5 [4.3-21.0]), and serum CA-125 (13.0 [5.5-29.0]). Similarly, a true-negative BRCA result reduced the OR for RRSO (0.1 [0.0-0.6]), TVUS (0.2 [0.1-0.5]), and serum CA-125 (0.3 [0.1-0.7]). Of the 71.8% of women who received uninformative results after BRCA testing, 12.3% subsequently underwent RRSO, 33.8% reported ever having undergone screening serum CA-125 since BRCA testing, and 37.3% reported ever having undergone screening TVUS since BRCA testing.Results of BRCA testing strongly predict RRSO and ovarian cancer screening. Use of RRSO and ovarian screening was reported in a sizable percentage of non- BRCA carriers despite insufficient data to determine the effectiveness of these interventions.

    View details for DOI 10.1001/2013.jamainternmed.962

    View details for Web of Science ID 000317239700004

    View details for PubMedID 23247828

    View details for PubMedCentralID PMC4989513