Vanessa Kennedy

All Publications

• Prevalence of hypersensitivity reactions in various forms of mastocytosis: A pilot study of 2485 adult patients with mastocytosis collected in the ECNM registry. Allergy Niedoszytko, M., Gorska, A., Brockow, K., Bonadonna, P., Lange, M., Kluin-Nelemans, H., Oude-Elberink, H., Sabato, V., Shoumariyeh, K., von Bubnoff, D., Müller, S., Illerhaus, A., Doubek, M., Angelova-Fischer, I., Hermine, O., Arock, M., Elena, C., Malcovati, L., Yavuz, A. S., Schug, T. D., Fortina, A. B., Judit, V., Gotlib, J., Panse, J., Vucinic, V., Reiter, A., Schwaab, J., Triggiani, M., Mattsson, M., Breynaert, C., Romantowski, J., Zanotti, R., Olivieri, E., Zink, A., van de Ven, A., Stefan, A., Barete, S., Caroppo, F., Perkins, C., Kennedy, V., Christen, D., Jawhar, M., Luebke, J., Parente, R., Levedahl, K., Hadzijusufovic, E., Hartmann, K., Nedoszytko, B., Sperr, W. R., Valent, P. 2024

  Abstract

  Hypersensitivity reactions (HR) are common in mastocytosis. However, little is known about triggers and risk factors. The registry of the European Competence Network on Mastocytosis (ECNM) enables reliable studies in a larger cohort of mastocytosis patients. We assessed prevalence, triggers and risk factors of HR in adults with mastocytosis in the ECNM registry.Data were collected in 27 ECNM centers. We analyzed potential triggers (Hymenoptera venoms, food, drug, inhalant and others) and risk factors at diagnosis and during follow-up. The study group consisted of 2485 adults with mastocytosis, 1379 women (55.5%) and 1106 men (44.5%). Median age was 48.2 years (range 18-91 years).Nine hundred and forty eight patients (38.1%) reported one or more HR`. Most common triggers were Hymenoptera venoms in cutaneous mastocytosis (CM) and indolent systemic mastocytosis (ISM), whereas in advanced SM (advSM), most common elicitors were drugs, including nonsteroidal anti-inflammatory agents and penicillin. In multivariate analyses, tryptase level < 90 ng/mL, <15% infiltration by mast cells in bone marrow biopsy-sections, and diagnosis of ISM were identified as independent risk factors for HR. For drug-induced HR, prominent risk factors were advSM and high tryptase levels. New reactions were observed in 4.8% of all patients during 4 years follow-up.HR are mainly triggered by Hymenoptera venoms in patients with CM and ISM and by drugs in patients with advSM. Tryptase levels <90 ng/mL, mast cell bone marrow infiltration <15%, and WHO category ISM are predictors of HR. New HR occur in 4.8% of all patients within 4 years.

  View details for DOI 10.1111/all.16132

  View details for PubMedID 38651829

• Long-Term Clinical Outcomes and B Cell Immune Reconstitution following Allo-HCT with Prophylactic, Post-Transplant Rituximab. Transplantation and cellular therapy Kennedy, V. E., Sahaf, B., Wu, F., Ehlinger, Z. J., Arai, S., Miklos, D. B. 2024

  Abstract

  Chronic graft-versus-host disease (cGVHD) remains a significant source of morbidity and mortality following allogeneic hematopoietic cell transplantation (HCT). Post-transplant, prophylactic rituximab has successfully decreased cGHVD rates in clinical trials, but the durability of this strategy is uncertain. The long-terms effect of post-HCT B cell depletion on immune reconstitution, B cell function, and infectious complications are also unknown.In this study, we provide 10 year follow-up and correlative analyses on patients given post-HCT, prophylactic rituximab. The objective of the study is to examine the durability of cGVHD protection as well as the long-term effect of rituximab prophylaxis on protective immune reconstitution, B cell function, and alloantibody formation.We analyzed 35 patients given prophylactic rituximab on phase II clinical trial. Clinical outcomes included cGVHD development, relapse and survival outcomes, and infectious outcomes. Correlative analyses included B cell subset analysis, development of antibodies to infectious antigens, and, for male patients receiving female donor grafts, development of antibodies to HY antigens. To further investigate the effect of rituximab on immune reconstitution and function, we also analyzed 43 similarly transplanted patients who did not receive post- or peri-HCT rituximab as a comparator group.For patients who received rituximab, the 8-year cumulative incidence of cGHVD and freedom from immunosuppression were 20.0% and 76.2%, respectively. Importantly, no late incidences of cGVHD developed beyond 14 months post-HCT. Relative to patients who did not receive rituximab, post-HCT rituximab was associated with increased B cell aplasia at 1 year post-HCT (42.9% vs 11% of patients, p = 0.037); by 3 years post-HCT, this aplasia resolved. Patients who received rituximab also had a significantly lower proportion of IgD+/CD38+ transitional B cells at 3 years post-HCT (78.8% vs 89.9%, p = 0.039); at 10 years post-HCT, this percentage remained markedly decreased at 50.7%. Rituximab prophylaxis altered B cell function. In male patients receiving female donor grafts, fewer patients developed HY antibodies at 3 years post-HCT (20% vs 78%, p = 0.04). At 10 years post-HCT, HY antibody production remained decreased at 33%. Rituximab prophylaxis was also associated with significantly lower antibody response to tetanus and EBV infectious antigens as well as lower IgG levels. Despite these changes, post-HCT was not associated with increased infections, although patients who received rituximab required intravenous immunoglobulin (IVIG) supplementation more frequently than those who did not (62.9% vs 32.6% of patients, p = 0.01).Prior data on the efficacy and feasibility of rituximab prophylaxis are durable, with persistent reduction in cGVHD. Rituximab prophylaxis also results in lasting B cell immunologic changes, with altered B cell subset composition and decreased alloantibody formation. Associated infectious risks were not increased, perhaps mitigated by high IVIG use.

  View details for DOI 10.1016/j.jtct.2024.02.025

  View details for PubMedID 38458479

• LNK/SH2B3 as a novel driver in juvenile myelomonocytic leukemia. Haematologica Wintering, A., Hecht, A., Meyer, J., Wong, E. B., Hübner, J., Abelson, S., Feldman, K., Kennedy, V. E., Peretz, C. A., French, D. L., Maguire, J. A., Jobaliya, C., Vasquez, M. R., Desai, S., Dulman, R., Nemecek, E., Haines, H., Hammad, M., El Haddad, A., Kogan, S. C., Abdullaev, Z., Chehab, F. F., Tasian, S. K., Smith, C. C., Loh, M. L., Stieglitz, E. 2023

  Abstract

  Mutations in five canonical Ras pathway genes (NF1, NRAS, KRAS, PTPN11 and CBL) are detected in nearly 90% of patients with juvenile myelomonocytic leukemia (JMML), a frequently fatal malignant neoplasm of early childhood. In this report, we describe seven patients diagnosed with SH2B3-mutated JMML, including five patients who were found to have initiating, loss of function mutations in the gene. SH2B3 encodes the adaptor protein LNK, a negative regulator of normal hematopoiesis upstream of the Ras pathway. These mutations were identified to be germline, somatic or a combination of both. Loss of function of LNK, which has been observed in other myeloid malignancies, results in abnormal proliferation of hematopoietic cells due to cytokine hypersensitivity and activation of the JAK/STAT signaling pathway. In vitro studies of induced pluripotent stem cell-derived JMML-like hematopoietic progenitor cells (HPCs) also demonstrated sensitivity of SH2B3- mutated HPCs to JAK inhibition. Lastly, we describe two patients with JMML and SH2B3 mutations who were treated with the JAK1/2 inhibitor ruxolitinib. This report expands the spectrum of initiating mutations in JMML and raises the possibility of targeting the JAK/STAT pathway in patients with SH2B3 mutations.

  View details for DOI 10.3324/haematol.2023.283776

  View details for PubMedID 38152053

• The FLT3N701K mutation causes clinical AML resistance to gilteritinib and triggers TKI sensitivity switch to quizartinib. American journal of hematology Joshi, S. K., Pittsenbarger, J., Kennedy, V. E., Peretz, C. A., Perl, A. E., Smith, C. C., Tyner, J. W., Druker, B. J., Traer, E. 2023

  View details for DOI 10.1002/ajh.27096

  View details for PubMedID 37815132

• Measurable residual disease conversion rate with consolidation chemotherapy in acute myeloid leukemia. Leukemia & lymphoma Gaut, D., Oliai, C., Boiarsky, J., Zhang, S., Salhotra, A., Azenkot, T., Kennedy, V. E., Khanna, V., Olmedo Gutierrez, K., Shukla, N., Moskoff, B., Park, G., Afkhami, M., Patel, A., Jeyakumar, D., Mannis, G., Logan, A. C., Jonas, B. A., Schiller, G. 2023: 1-9

  Abstract

  The rate of MRD clearance in AML with standard consolidation chemotherapy is not well defined. A multi-institution retrospective analysis was performed on 107 consecutively treated AML patients in morphologic complete remission with detectable MRD post-induction therapy who received standard chemotherapy consolidation. In response to standard intermediate/high-dose cytarabine consolidation therapy, 26 of 60 patients (43.3%) with MRD threshold of detection of at least 0.1% converted to MRD-negative status (undetectable with assay used), and 6 of 47 patients (12.8%) with MRD threshold of detection > 0.1% converted to MRD-negative status. Multivariable logistic regression for patients with MRD threshold of detection of at least 0.1% showed that, when controlling for age, ELN risk category, dose of cytarabine, and use of a combination agent, treatment with 1 cycle of consolidation cytarabine versus ≥2 cycles decreased the odds of conversion of AML to MRD-negative (OR = 0.24, 95% CI 0.07-0.85, p = 0.03).

  View details for DOI 10.1080/10428194.2023.2264426

  View details for PubMedID 37801340

• Daratumumab Plus Bortezomib and Dexamethasone in Newly Diagnosed Systemic Light Chain Amyloidosis. Current problems in cancer Kennedy, V. E., Natsuhara, K., Maringanti, S. A., Shah, N. D., Arora, S., Wolf, J., Martin, T. G., Aras, M. A., Chung, A., Wong, S. W. 2023; 47 (3): 100953

  Abstract

  Light chain amyloidosis (AL) is a plasma cell dyscrasia characterized by organ dysfunction, morbidity, and early mortality. Daratumumab in combination with cyclophosphamide, bortezomib, and dexamethasone is now standard frontline AL therapy; however, not all patients are candidates for this intensive regimen. Given the potency of Daratumumab, we evaluated an alternative frontline regimen: daratumumab, bortezomib, and limited-duration dexamethasone (Dara-Vd). Over a 3 year period, we treated 21 patients with Dara-Vd. At baseline, all patients had cardiac and/or renal dysfunction, including 30% of patients with Mayo stage IIIB cardiac disease. Nineteen of 21 patients (90%) achieved a hematologic response with 38% achieving a complete response. The median time to response was 11 days. Ten of 15 (67%) evaluable patients achieved a cardiac response and 7 of 9 (78%) achieved a renal response. The 1-year overall survival was 76%. In untreated systemic AL amyloidosis, Dara-Vd produces rapid and deep hematologic and organ responses. Dara-Vd was well-tolerated and efficacious, even among patients with extensive cardiac dysfunction.

  View details for DOI 10.1016/j.currproblcancer.2023.100953

  View details for PubMedID 36807996

• Microfluidics-free single-cell genomics with templated emulsification. Nature biotechnology Clark, I. C., Fontanez, K. M., Meltzer, R. H., Xue, Y., Hayford, C., May-Zhang, A., D'Amato, C., Osman, A., Zhang, J. Q., Hettige, P., Ishibashi, J. S., Delley, C. L., Weisgerber, D. W., Replogle, J. M., Jost, M., Phong, K. T., Kennedy, V. E., Peretz, C. A., Kim, E. A., Song, S., Karlon, W., Weissman, J. S., Smith, C. C., Gartner, Z. J., Abate, A. R. 2023

  Abstract

  Current single-cell RNA-sequencing approaches have limitations that stem from the microfluidic devices or fluid handling steps required for sample processing. We develop a method that does not require specialized microfluidic devices, expertise or hardware. Our approach is based on particle-templated emulsification, which allows single-cell encapsulation and barcoding of cDNA in uniform droplet emulsions with only a vortexer. Particle-templated instant partition sequencing (PIP-seq) accommodates a wide range of emulsification formats, including microwell plates and large-volume conical tubes, enabling thousands of samples or millions of cells to be processed in minutes. We demonstrate that PIP-seq produces high-purity transcriptomes in mouse-human mixing studies, is compatible with multiomics measurements and can accurately characterize cell types in human breast tissue compared to a commercial microfluidic platform. Single-cell transcriptional profiling of mixed phenotype acute leukemia using PIP-seq reveals the emergence of heterogeneity within chemotherapy-resistant cell subsets that were hidden by standard immunophenotyping. PIP-seq is a simple, flexible and scalable next-generation workflow that extends single-cell sequencing to new applications.

  View details for DOI 10.1038/s41587-023-01685-z

  View details for PubMedID 36879006

  View details for PubMedCentralID 48793

• Mast Cell Leukemia: Clinical and Molecular Features and Survival Outcomes of Patients in the ECNM Registry. Blood advances Kennedy, V. E., Perkins, C., Reiter, A., Jawhar, M., Lubke, J., Kluin-Nelemans, H. C., Shomali, W., Langford, C., Abuel, J., Hermine, O., Niedoszytko, M., Gorska, A., Mital, A., Bonadonna, P., Zanotti, R., Tanasi, I., Mattsson, M., Hagglund, H. G., Triggiani, M., Yavuz, A. S., Panse, J. P., Christen, D., Heizmann, M., Shoumariyeh, K., Muller, S., Elena, C., Malcovati, L., Fiorelli, N., Wortmann, F., Vucinic, V., Brockow, K., Fokoloros, C., Papageorgiou, S. G., Breynaert, C., Bullens, D., Doubek, M., Ilerhaus, A., Angelova-Fischer, I., Solomianyi, O., Varkonyi, J., Sabato, V., Rufer, A., Schug, T., Hermans, M. A., Belloni Fortina, A., Caroppo, F., Bumbea, H., Gulen, T., Hartmann, K., Oude Elberink, H., Schwaab, J., Arock, M., Valent, P., Sperr, W., Gotlib, J. 2022

  Abstract

  Mast cell leukemia (MCL) is a rare subtype of systemic mastocytosis (SM) defined by >20% mast cells (MC) on a bone marrow aspirate. We evaluated 92 patients with MCL from the European Competence Network on Mastocytosis registry. Thirty-one (34%) patients had a diagnosis of MCL with an associated hematologic neoplasm (MCL-AHN). Chronic MCL (lack of C-findings) comprised 14% of patients, and only 4.5% had 'leukemic MCL' (≥ 10% circulating MCs). KIT D816V was found in 62/85 (73%) evaluable patients; 9 (11%) individuals exhibited alternative KIT mutations, and no KIT variants were detected in 14 (17%) subjects. Ten evaluable patients (17%) had an abnormal karyotype and the poor-risk SRSF2, ASXL1, and RUNX1 (S/A/R) mutations were identified in 16/36 (44%) patients who underwent next-generation sequencing. Midostaurin was the most common therapy, administered to 65% of patients, and 45% as first-line therapy. The median overall survival (OS) was 1.6 years. In multivariate analysis (S/A/R mutations excluded due to low event rates), a diagnosis of MCL-AHN (HR 4.7, 95% CI 1.7 - 13.0, p = 0.001) and abnormal karyotype (HR 5.6, 95% CI 1.4 - 13.3, p = 0.02) were associated with inferior OS; KIT D816V positivity (HR 0.33, 95% CI 0.11 - 0.98, p = 0.04) and midostaurin treatment (HR 0.32, 95% CI 0.08 - 0.72, p = 0.008) were associated with superior OS. These data provide the most comprehensive snapshot of the clinicopathologic, molecular, and treatment landscape of MCL to date, and should help further inform subtyping and prognostication of MCL.

  View details for DOI 10.1182/bloodadvances.2022008292

  View details for PubMedID 36094848

• Geriatric assessment in adults age 50 years and older undergoing autologous hematopoietic cell transplantation for lymphoma. Journal of geriatric oncology Kennedy, V. E., Huang, C. Y., Kaplan, L. D., Andreadis, C., Ai, W. Z., Olin, R. L. 2022; 13 (5): 644-647

  View details for DOI 10.1016/j.jgo.2022.02.016

  View details for PubMedID 35256304

• Infectious complications in patients with relapsed refractory multiple myeloma after BCMA CAR T-cell therapy. Blood advances Kambhampati, S., Sheng, Y., Huang, C. Y., Bylsma, S., Lo, M., Kennedy, V., Natsuhara, K., Martin, T., Wolf, J., Shah, N., Wong, S. W. 2022; 6 (7): 2045-2054

  Abstract

  B-cell maturation antigen-targeted chimeric antigen receptor T-cell therapy (BCMA CAR-T) is an effective treatment of relapsed refractory multiple myeloma (MM). However, the pattern of infectious complications is not well elucidated. We performed a single-center retrospective analysis of infection outcomes up to 1 year after BCMA CAR-T for MM from 2018 to 2020. Fifty-five patients with MM were treated with BCMA CAR-T. Before lymphodepletion (LD), 35% of patients had severe hypogammaglobulinemia and 18% had severe lymphopenia. Most patients (68%) received bridging chemotherapy (BC) before LD. In the first month after CAR-T, 98% patients had grade 3 to 4 neutropenia. At 1 year after infusion, 76% patients had hypogammaglobulinemia. With a median follow-up of 6.0 months (95% confidence interval, 4.7-7.4), there were a total of 47 infection events in 29 (53%) patients: 40% bacterial, 53% viral, and 6% fungal. Most (92%) were mild-moderate and of the lower/upper respiratory tract system (68%). Half of the infections (53%) occurred in the first 100 days after CAR-T infusion. Although no statistically significant risk factors for infection were identified, prior lines of therapy, use of BC, recent infections, and post-CAR-T lymphopenia were identified as possible risk factors that need to be further explored. This is the largest study to date to assess infectious complications after BCMA CAR-T. Despite multiple risk factors for severe immunosuppression in this cohort, relatively few life-threatening or severe infections occurred. Further larger studies are needed to better characterize the risk factors for and occurrence of infections after BCMA CAR-T.

  View details for DOI 10.1182/bloodadvances.2020004079

  View details for PubMedID 34543400

  View details for PubMedCentralID PMC9006279

• 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

• 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

• Macrophage activation syndrome-like (MAS-L) manifestations following BCMA-directed CAR T cells in multiple myeloma. Blood advances Kennedy, V. E., Wong, C., Huang, C. Y., Kambhampati, S., Wolf, J., Martin, T. G., Shah, N., Wong, S. W. 2021; 5 (23): 5344-5348

  View details for DOI 10.1182/bloodadvances.2021005020

  View details for PubMedID 34644387

  View details for PubMedCentralID PMC9153014

• VITT following Ad26.COV2.S vaccination presenting without radiographically demonstrable thrombosis. Blood advances Kennedy, V. E., Wong, C. C., Hong, J. M., Peng, T., Brondfield, S., Reilly, L. M., Cornett, P., Leavitt, A. D. 2021; 5 (22): 4662-4665

  Abstract

  We report a case of vaccine-induced immune thrombotic thrombocytopenia (VITT) in a young man diagnosed 13 days after Ad26.COV2.S COVID-19 (Johnson & Johnson/Janssen) vaccination. He presented to us with 5 days of progressive left leg pain, thrombocytopenia, hypofibrinogenemia, and markedly elevated d-dimers, but without radiographically demonstrable thrombosis. Despite negative imaging, we initiated treatment of presumptive VITT given the striking clinical picture that included the timing of his recent adenovirus-based COVID-19 vaccine, leg symptoms, marked thrombocytopenia, and consumptive coagulopathy. He received intravenous immune globulin, prednisone, and argatroban and was discharged 7 days later much improved. His positive platelet factor 4 enzyme-linked immunosorbent assay antibody test returned after treatment was initiated. To our knowledge, this is the first reported case of VITT following Ad26.COV2.S vaccination presenting without radiographically demonstrable thrombosis. Our patient highlights the importance of knowing vaccine status and initiating treatment as soon as possible in the right clinical setting, even in the absence of radiographic evidence of thrombus. Early VITT recognition and treatment provide an opportunity to prevent serious thrombotic complications.

  View details for DOI 10.1182/bloodadvances.2021005388

  View details for PubMedID 34587255

  View details for PubMedCentralID PMC8483979

• Haematopoietic stem-cell transplantation in older adults: geriatric assessment, donor considerations, and optimisation of care. The Lancet. Haematology Kennedy, V. E., Olin, R. L. 2021; 8 (11): e853-e861

  Abstract

  Haematopoietic stem-cell transplantation (HSCT) has seen substantial growth among older adults. Chronological age is no longer viewed as an absolute barrier to HSCT, and alternative methods for assessing pre-transplantation fitness are increasingly used. In this Series paper, we summarise the metrics for pre-transplantation risk assessment in older adults, including both traditional metrics and geriatric assessment, and the ability of these metrics to predict post-transplantation outcomes. We also discuss strategies to broaden the utility of geriatric assessment, including in chronologically younger HSCT candidates and to guide individualised pre-transplantation interventions. Finally, we discuss donor considerations in older adults, including use of older sibling donors, haploidentical donors, and emerging data for donor-associated clonal haematopoiesis of indeterminate potential.

  View details for DOI 10.1016/S2352-3026(21)00231-3

  View details for PubMedID 34624239

• Frontline treatment patterns and outcomes among older adults with acute myeloid leukemia: A population-based analysis in the modern era. Cancer Kennedy, V. E., Keegan, T. H., Li, Q., Maguire, F. B., Muffly, L. S. 2021

  Abstract

  BACKGROUND: Traditionally, conventional induction chemotherapy has been the primary frontline treatment for acute myeloid leukemia (AML); however, older adults are often poor chemotherapy candidates. Recently, several nonconventional frontline AML regimens, including hypomethylating agents, the BCL-2 inhibitor venetoclax, and targeted therapies, have emerged, and they may offer new options for older adults. This study was aimed at describing treatment patterns and outcomes of older adult AML in a modern population-based cohort.METHODS: This study evaluated patients aged ≥60 years with a first primary diagnosis of AML (2014-2017) in the California Cancer Registry linked to inpatient hospitalizations. Multivariable regression examined factors associated with the frontline treatment regimen and survival.RESULTS: In all, 3068 patients were included; 36% received frontline therapy with a conventional chemotherapy backbone, 42% received nonconventional therapy, and 22% received no treatment. The use of nonconventional therapy increased over time from 38% of patients in 2014 to 47% in 2017 (P < .001). In multivariable analyses, receipt of treatment was associated with an age younger than 80 years, fewer than 2 comorbidities, and care at a National Cancer Institute-designated cancer center (NCI-CC). Compared with conventional chemotherapy, nonconventional therapy was associated with Black race/ethnicity, public health insurance, fewer hospital admissions, and fewer inpatient days. Receiving frontline therapy at an NCI-CC was independently associated with superior overall survival.CONCLUSIONS: Using a population-based approach, this study has demonstrated that patterns of care for frontline AML treatment in older adults are changing, with increasing use of nonconventional therapies. A significant proportion of older adults remain untreated. At the population level, there remain opportunities to increase therapy access for older adults with AML.

  View details for DOI 10.1002/cncr.33873

  View details for PubMedID 34436782

• Early Time-to-Tocilizumab after B Cell Maturation Antigen-Directed Chimeric Antigen Receptor T Cell Therapy in Myeloma. Transplantation and cellular therapy Banerjee, R., Marsal, J., Huang, C. Y., Lo, M., Kambhampati, S., Kennedy, V. E., Arora, S., Wolf, J. L., Martin, T. G., Wong, S. W., Shah, N. 2021; 27 (6): 477.e1-477.e7

  Abstract

  Preemptive administration of tocilizumab (toci) to manage cytokine release syndrome (CRS) after chimeric antigen receptor T cell (CAR-T) therapy may reduce rates of serious CRS but conversely may worsen neurotoxicity or risk of infections. Optimal toci administration strategies for patients with relapsed/refractory multiple myeloma (RRMM) receiving B cell maturation antigen (BCMA)-directed CAR-T therapies have not been evaluated. The objective of this study was to identify whether shorter time-to-toci intervals (hours between first fever attributed to CRS and first dose of toci) have any impact on therapy-related toxicities or clinical outcomes among patients with RRMM receiving BCMA-directed CAR-T therapies. We retrospectively analyzed our institution's experience with 4 BCMA-directed CAR-T therapies (idecabtagene vicleucel, bb21217, ciltacabtagene autoleucel, and orvacabtagene autoceucel) for RRMM over a 3-year period ending in June 2020. We divided patients based on the administration of toci and median time-to-toci interval into early-toci (time-to-toci ≤50th percentile), late-toci (time-to-toci >50th percentile), and no-toci (no toci received) groups. We compared the early-toci and late-toci groups with regard to patient characteristics, weight-based CAR-T toxicities, selected toxicities (CRS, neurotoxicity, macrophage activation syndrome, or infections), and clinical outcomes. Of 50 analyzed patients with a median follow-up of 15.3 months, 76% (n = 38) received ≥1 dose of toci (range, 1 to 3) and were classified into early-toci (time-to-toci ≤12 hours) or late-toci (time-to-toci >12 hours) groups. The 2 groups (n = 19 each) had similar CRS grade distributions, hours to CRS onset, CRS-related biomarkers, and incidences of neurotoxicity or severe infections; however, weight-adjusted CAR-T cell doses were higher in the early-toci group (median 5.99 versus 3.80 × 106 cells/kg, P < 0.01). Peak CRS grades (range, 0 to 2) using American Society for Transplantation and Cellular Therapy consensus criteria, neurotoxicity rates, and rates of severe infections were similar between groups; however, the median CRS duration was 18.6 hours for the early-toci group versus 84.7 hours for the late-toci group. The median progression-free survival was 35.7 months in the early-toci group and 13.2 months in the late-toci group. While limited by small sample size and known confounders such as CAR-T cell dose, our analysis suggests that preemptive toci strategies for CRS management with BCMA-directed CAR-T therapy-specifically, toci administration within 12 hours of the first fever attributed to CRS-do not appear to increase rates of therapy-related toxicities or compromise efficacy. However, total CRS duration may be shorter with early-toci workflows. Prospective validation of our findings may lead to improved safety and cost-effectiveness profiles for CAR-T therapy in RRMM.

  View details for DOI 10.1016/j.jtct.2021.03.004

  View details for PubMedID 33831353

• A Case of EBV-Negative Aggressive NK-cell Leukemia: Use of Next-Generation Sequencing in Demystifying a Diagnostic Dilemma and Guiding Clinical Care. Clinical lymphoma, myeloma & leukemia Kennedy, V. E., Ruiz-Cordero, R., Jangam, D., Wen, K. W., Dunavin, N., Ohgami, R. S., Bhargava, P., Ai, W., Fakhri, B. 2021

  View details for DOI 10.1016/j.clml.2021.02.010

  View details for PubMedID 33814335

• Cytogenetic and molecular aberrations and worse outcome for male patients in systemic mastocytosis. Theranostics Kluin-Nelemans, H. C., Jawhar, M., Reiter, A., van Anrooij, B., Gotlib, J., Hartmann, K., Illerhaus, A., Oude Elberink, H. N., Gorska, A., Niedoszytko, M., Lange, M., Scaffidi, L., Zanotti, R., Bonadonna, P., Perkins, C., Elena, C., Malcovati, L., Shoumariyeh, K., von Bubnoff, N., Müller, S., Triggiani, M., Parente, R., Schwaab, J., Kundi, M., Fortina, A. B., Caroppo, F., Brockow, K., Zink, A., Fuchs, D., Angelova-Fischer, I., Yavuz, A. S., Doubek, M., Mattsson, M., Hagglund, H., Panse, J., Simonowski, A., Sabato, V., Schug, T., Jentzsch, M., Breynaert, C., Várkonyi, J., Kennedy, V., Hermine, O., Rossignol, J., Arock, M., Valent, P., Sperr, W. R. 2021; 11 (1): 292-303

  Abstract

  In systemic mastocytosis (SM), the clinical features and survival vary greatly. Patient-related factors determining the outcome in SM are largely unknown. Methods: We examined the impact of sex on the clinical features, progression-free survival (PFS), and overall survival (OS) in 3403 patients with mastocytosis collected in the registry of the European Competence Network on Mastocytosis (ECNM). The impact of cytogenetic and molecular genetic aberrations on sex differences was analyzed in a subset of patients. Results: Of all patients enrolled, 55.3% were females. However, a male predominance was found in a subset of advanced SM (AdvSM) patients, namely SM with an associated hematologic neoplasm (SM-AHN, 70%; p < 0.001). Correspondingly, organomegaly (male: 23% vs. female: 13%, p = 0.007) was more, whereas skin involvement (male: 71% vs. female: 86%, p = 0.001) was less frequent in males. In all patients together, OS (p < 0.0001) was significantly inferior in males, and also within the WHO sub-categories indolent SM, aggressive SM (ASM) and SM-AHN. PFS was significantly (p = 0.0002) worse in males when all patients were grouped together; due to low numbers of events, this significance persisted only in the subcategory smoldering SM. Finally, prognostically relevant cytogenetic abnormalities (10% vs. 5%, p = 0.006) or molecular aberrations (SRSF2/ASXL1/RUNX1 profile; 63% vs. 40%, p = 0.003) were more frequently present in males. Conclusions: Male sex has a major impact on clinical features, disease progression, and survival in mastocytosis. Male patients have an inferior survival, which seems related to the fact that they more frequently develop a multi-mutated AdvSM associated with a high-risk molecular background.

  View details for DOI 10.7150/thno.51872

  View details for PubMedID 33391475

  View details for PubMedCentralID PMC7681091

• FLT3 Mutations in Acute Myeloid Leukemia: Key Concepts and Emerging Controversies. Frontiers in oncology Kennedy, V. E., Smith, C. C. 2020; 10: 612880

  Abstract

  The FLT3 receptor is overexpressed on the majority of acute myeloid leukemia (AML) blasts. Mutations in FLT3 are the most common genetic alteration in AML, identified in approximately one third of newly diagnosed patients. FLT3 internal tandem duplication mutations (FLT3-ITD) are associated with increased relapse and inferior overall survival. Multiple small molecule inhibitors of FLT3 signaling have been identified, two of which (midostaurin and gilteritinib) are currently approved in the United States, and many more of which are in clinical trials. Despite significant advances, resistance to FLT3 inhibitors through secondary FLT3 mutations, upregulation of parallel pathways, and extracellular signaling remains an ongoing challenge. Novel therapeutic strategies to overcome resistance, including combining FLT3 inhibitors with other antileukemic agents, development of new FLT3 inhibitors, and FLT3-directed immunotherapy are in active clinical development. Multiple questions regarding FLT3-mutated AML remain. In this review, we highlight several of the current most intriguing controversies in the field including the role of FLT3 inhibitors in maintenance therapy, the role of hematopoietic cell transplantation in FLT3-mutated AML, use of FLT3 inhibitors in FLT3 wild-type disease, significance of non-canonical FLT3 mutations, and finally, emerging concerns regarding clonal evolution.

  View details for DOI 10.3389/fonc.2020.612880

  View details for PubMedID 33425766

  View details for PubMedCentralID PMC7787101

• Marked Hyperbilirubinemia-Silent No More! The American journal of medicine Kennedy, V. E., Leavitt, A. D., Cornett, P. 2020; 133 (12): e733-e734

  View details for DOI 10.1016/j.amjmed.2020.04.031

  View details for PubMedID 32473870

• Late Effects in Survivors of Adolescent and Young Adult Acute Lymphoblastic Leukemia. JNCI cancer spectrum Muffly, L., Maguire, F. B., Li, Q., Kennedy, V., Keegan, T. H. 2020; 4 (4): pkaa025

  Abstract

  Background: Knowledge regarding late effects (medical conditions and subsequent neoplasms) in survivors of adolescent and young adult (AYA) acute lymphoblastic leukemia (ALL) is lacking.Methods: Using the population-based California Cancer Registry linked with California hospitalization data, we evaluated late effects in 1069 AYAs (aged 15-39years) diagnosed with ALL in California between 1995 and 2012 and surviving a minimum of 3 years from diagnosis.Results: The estimated 10-year cumulative incidence of subsequent endocrine disease (28.7%, 95% confidence interval [CI] = 25.8% to 31.6%) and cardiac disease (17.0%, 95% CI = 14.6% to 19.5%) were strikingly high; avascular necrosis (9.6%, 95% CI = 7.8% to 11.6%), liver disease (6.5%, 95% CI = 5.0% to 8.3%), respiratory disease (6.2%, 95% CI = 4.8% to 8.0%), seizure and/or stroke (4.3%, 95% CI = 3.1% to 5.8%), renal disease (3.1%, 95% CI = 2.1% to 4.4%), and second neoplasms (1.4%, 95% CI = 0.7% to 2.4%) were estimated to occur at 10years with the reported frequencies. Multivariable analyses including the entire patient cohort demonstrated that public or no insurance (vs private and/or military insurance) and receipt of hematopoietic cell transplantation were independently associated with the occurrence of all late effects considered. In multivariable analyses limited to the 766 AYAs who were not transplanted, we continued to find a statistically significant association between public and no insurance and the occurrence of all late effects. Frontline regimen type (pediatric vs adult) was not statistically significantly associated with any of the late effect categories.Conclusions: This large population-based analysis is among the first to describe late effects in survivors of AYA ALL. The strong association between insurance type and late effects suggests that AYAs with public or no insurance may have reduced access to survivorship care following completion of ALL therapy.

  View details for DOI 10.1093/jncics/pkaa025

  View details for PubMedID 32704618

• MARS: Mutation-Adjusted Risk Score for Advanced Systemic Mastocytosis Jawhar, M., Schwaab, J., Alvarez-Twose, I., Shoumariyeh, K., Naumann, N., Luebke, J., Perkins, C., Munoz-Gonzalez, J. I., Meggendorfer, M., Kennedy, V., Metzgeroth, G., Fabarius, A., Pfeifer, D., Sotlar, K., Horny, H., von Bubnoff, N., Haferlach, T., Cross, N. P., Hofmann, W., Sperr, W. R., Garcia-Montero, A. C., Valent, P., Gotlib, J., Orfao, A., Reiter, A. KARGER. 2020: 107–8

  View details for Web of Science ID 000517158700262

• Prognostic impact of eosinophils in mastocytosis: analysis of 2350 patients collected in the ECNM Registry. Leukemia Kluin-Nelemans, H. C., Reiter, A., Illerhaus, A., van Anrooij, B., Hartmann, K., Span, L. F., Gorska, A., Niedoszytko, M., Lange, M., Scaffidi, L., Zanotti, R., Bonadonna, P., Perkins, C., Elena, C., Malcovati, L., Shoumariyeh, K., von Bubnoff, N., Parente, R., Triggiani, M., Schwaab, J., Jawhar, M., Caroppo, F., Fortina, A. B., Brockow, K., Zink, A., Fuchs, D., Kilbertus, A., Yavuz, A. S., Doubek, M., Mattsson, M., Hagglund, H., Panse, J., Sabato, V., Aberer, E., Niederwieser, D., Breynaert, C., Varkonyi, J., Kennedy, V., Lortholary, O., Jakob, T., Hermine, O., Rossignol, J., Arock, M., Gotlib, J., Valent, P., Sperr, W. R. 2019

  Abstract

  Systemic mastocytosis (SM) is frequently associated with eosinophilia. To examine its prevalence and clinical impact in all WHO classification-based subcategories, we analyzed eosinophil counts in 2350 mastocytosis patients using the dataset of the European Competence Network on Mastocytosis. Ninety percent of patients had normal eosinophil counts, 6.8% mild eosinophilia (0.5-1.5*109/l), and 3.1% hypereosinophilia (HE; >1.5*109/l). Eosinophilia/HE were mainly present in patients with advanced SM (17%/19%), and only rarely recorded in patients with indolent and smoldering SM (5%/1%), and some patients with cutaneous mastocytosis. The eosinophil count correlated with organomegaly, dysmyelopoiesis, and the WHO classification, but not with mediator-related symptoms or allergy. Eosinophilia at diagnosis had a strong prognostic impact (p<0.0001) on overall survival (OS) and progression-free survival (PFS), with a 10-year OS of 19% for patients with HE, 70% for those with mild eosinophilia, and 88% for patients with normal eosinophil counts. In 89% of patients with follow-up data (n=1430, censored at start of cytoreductive therapy), eosinophils remained stable. In those with changing eosinophil counts (increase/decrease or mixed pattern), OS and PFS were inferior compared with patients with stable eosinophil counts. In conclusion, eosinophilia and HE are more prevalent in advanced SM and are predictors of a worse outcome.

  View details for DOI 10.1038/s41375-019-0632-4

  View details for PubMedID 31740811

• Immune Reconstitution and Long-Term Outcomes Following Allo-HCT with TLI-ATG and Post-Transplant Rituximab Kennedy, V. E., Arai, S., Miklos, D. B., Wu, F. AMER SOC HEMATOLOGY. 2019

  View details for DOI 10.1182/blood-2019-129804

  View details for Web of Science ID 000577160403269

• Late Effects and Subsequent Neoplasms in Survivors of Adolescent and Young Adult Acute Lymphoblastic Leukemia: A Population-Based Analysis Including Impact of Front-Line Regimen Type Muffly, L. S., Maguire, F., Li, Q., Kennedy, V., Keegan, T. M. AMER SOC HEMATOLOGY. 2019

  View details for DOI 10.1182/blood-2019-124992

  View details for Web of Science ID 000518218500312

• Differential Interaction of Peripheral Blood Lymphocyte Counts (ALC) With Different in vivo Depletion Strategies in Predicting Outcomes of Allogeneic Transplant: An International 2 Center Experience FRONTIERS IN ONCOLOGY Sheth, V., Kennedy, V., de lavallade, H., Mclornan, D., Potter, V., Engelhardt, B. G., Savani, B., Chinratanalab, W., Goodman, S., Greer, J., Kassim, A., York, S., Kenyon, M., Gandhi, S., Kulasekararaj, A., Marsh, J., Mufti, G., Pagliuca, A., Jagasia, M., Raj, K. 2019; 9

  View details for DOI 10.3389/fonc.2019.00623

  View details for Web of Science ID 000474725600001

• Differential Interaction of Peripheral Blood Lymphocyte Counts (ALC) With Different in vivo Depletion Strategies in Predicting Outcomes of Allogeneic Transplant: An International 2 Center Experience. Frontiers in oncology Sheth, V., Kennedy, V., de Lavallade, H., Mclornan, D., Potter, V., Engelhardt, B. G., Savani, B., Chinratanalab, W., Goodman, S., Greer, J., Kassim, A., York, S., Kenyon, M., Gandhi, S., Kulasekararaj, A., Marsh, J., Mufti, G., Pagliuca, A., Jagasia, M., Raj, K. 2019; 9: 623

  Abstract

  Dosing regimens for antithymocyte globulin (ATG) and anti-CD52 antibody (alemtuzumab) for graft vs. host disease prophylaxis (GVHD) are empiric or weight-based, and do not account for individual patient factors. Recently, it has been shown that recipient peripheral blood absolute lymphocyte count (ALC) on the day of ATG administration interacts with the dose of ATG administered to predict transplantation outcome. Similarly, we wanted to analyze if the recipient ALC interacts with alemtuzumab dosing to predict outcomes. We retrospectively compared 364 patients, 124 patients receiving ATG (anti-thymocyte globulin) for GVHD prophylaxis, and undergoing unrelated first allogeneic transplant for myeloid and lymphoid malignancies (group 1) to 240 patients receiving alemtuzumab (group 2), in similar time period. There was no difference in survival or acute and chronic GVHD between 60 and 100 mg of alemtuzumab dosing. Unlike ATG (where the pre-transplant recipient ALC interacted with ATG dose on day of its administration (day 1) to predict OS and DFS (p = 0.05), within alemtuzumab group, the recipient ALC on second day of alemtuzumab administration (day 2) and its interaction with alemtuzumab dose strongly predicted OS, DFS and relapse (p = 0.05, HR-1.81, 1.1-3.3; p = 0.002, HR-2.41, CI, 1.3-4.2; and p = 0.003, HR-2.78, CI, 1.4-5.2), respectively. ALC (day 2) of 0.08 × 109/lit or higher, had a specificity of 96% in predicting inferior DFS. Like ATG, there is definite but differential interaction between the recipient peripheral blood ALC and alemtuzumab dose to predict OS, DFS, and relapses.

  View details for DOI 10.3389/fonc.2019.00623

  View details for PubMedID 31355140

  View details for PubMedCentralID PMC6636242

• Assessment of older adult candidates for allogeneic hematopoietic cell transplantation: updates and remaining questions EXPERT REVIEW OF HEMATOLOGY Kennedy, V. E., Muffly, L. S. 2019; 12 (2): 99-106

  View details for DOI 10.1080/17474086.2019.1568236

  View details for Web of Science ID 000459541000003

• Assessment of Older Adult Candidates for Allogeneic Hematopoietic Cell Transplantation: Updates and Remaining Questions. Expert review of hematology Kennedy, V. E., Muffly, L. S. 2019

  Abstract

  INTRODUCTION: Allogeneic hematopoietic cell transplantation (allo-HCT) has seen marked growth among older adults, where chronological age is no longer a barrier to transplant. As allo-HCT expands to older and potentially less fit individuals, prognosticating transplant outcomes in this population remains an ongoing need. Areas Covered: This review summarizes pre-transplant assessment tools in optimizing patient selection and predicting transplant outcomes in older adults, including comorbidity indices, psychosocial assessment, geriatric assessment, serum biomarkers, and disease risk. This review also discusses the impact of donor age and clonal hematopoiesis of indeterminate significance on transplant outcomes. Expert Opinion: Determining which patients should be referred for transplant remains challenging, especially in older adults. Chronological age is an insufficient prognostic metric, and refining, validating, and developing novel pre-transplant risk assessment tools for geriatric patients offers great potential benefit to the field.

  View details for PubMedID 30632411

• Nonmyeloablative TLI-ATG conditioning for allogeneic transplantation: mature follow-up from a large single-center cohort. Blood advances Spinner, M. A., Kennedy, V. E., Tamaresis, J. S., Lavori, P. W., Arai, S. n., Johnston, L. J., Meyer, E. H., Miklos, D. B., Muffly, L. S., Negrin, R. S., Rezvani, A. R., Shizuru, J. A., Weng, W. K., Hoppe, R. T., Strober, S. n., Lowsky, R. n. 2019; 3 (16): 2454–64

  Abstract

  Nonmyeloablative total lymphoid irradiation and antithymocyte globulin (TLI-ATG) conditioning is protective against graft-versus-host disease (GVHD), while retaining graft-versus-tumor activity across various hematologic malignancies. We report our comprehensive experience using TLI-ATG conditioning in 612 patients with hematologic malignancies who underwent allogeneic transplantation at Stanford University from 2001 to 2016. All patients received granulocyte colony-stimulating factor-mobilized peripheral blood grafts and cyclosporine and mycophenolate mofetil for GVHD prophylaxis. The median age was 60 years (range, 21-78), with a median follow-up of 6.0 years (range, 1.0-16.4). Common diagnoses included acute myeloid leukemia (AML; n = 193), myelodysplastic syndrome (MDS; n = 94), chronic lymphocytic leukemia (CLL; n = 80), non-Hodgkin lymphoma (NHL; n = 175), and Hodgkin lymphoma (HL; n = 35). Thirty-four percent of patients had a comorbidity index ≥3, 30% had a high to very high disease risk index, and 56% received unrelated donor grafts, including 15% with HLA-mismatched donors. Ninety-eight percent underwent transplant in the outpatient setting, and 57% were never hospitalized from days 0 through 100. The 1-year rates of nonrelapse mortality (NRM), grade II-IV acute GVHD, and extensive chronic GVHD were 9%, 14%, and 22%, respectively. The 4-year estimates for overall and progression-free survival were 42% and 32% for AML, 30% and 21% for MDS, 67% and 43% for CLL, 68% and 45% for NHL, and 78% and 49% for HL. Mixed chimerism correlated with the risk of relapse. TLI-ATG conditioning was well tolerated, with low rates of GVHD and NRM. Durable remissions were observed across hematologic malignancies, with particularly favorable outcomes for heavily pretreated lymphomas. Several efforts are underway to augment donor chimerism and reduce relapse rates while maintaining the favorable safety and tolerability profile of this regimen.

  View details for DOI 10.1182/bloodadvances.2019000297

  View details for PubMedID 31427277

• MARS: Mutation-Adjusted Risk Score for Advanced Systemic Mastocytosis. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Jawhar, M. n., Schwaab, J. n., Álvarez-Twose, I. n., Shoumariyeh, K. n., Naumann, N. n., Lübke, J. n., Perkins, C. n., Muñoz-González, J. I., Meggendorfer, M. n., Kennedy, V. n., Metzgeroth, G. n., Fabarius, A. n., Pfeifer, D. n., Sotlar, K. n., Horny, H. P., von Bubnoff, N. n., Haferlach, T. n., Cross, N. C., Hofmann, W. K., Sperr, W. R., García-Montero, A. C., Valent, P. n., Gotlib, J. n., Orfao, A. n., Reiter, A. n. 2019: JCO1900640

  Abstract

  To develop a risk score for patients with advanced systemic mastocytosis (AdvSM) that integrates clinical and mutation characteristics.The study included 383 patients with AdvSM from the German Registry on Disorders of Eosinophils and Mast Cells (training set; n = 231) and several centers for mastocytosis in the United States and Europe, all within the European Competence Network on Mastocytosis (validation set; n = 152). A Cox multivariable model was used to select variables that were predictive of overall survival (OS).In multivariable analysis, the following risk factors were identified as being associated with OS: age greater than 60 years, anemia (hemoglobin < 10 g/dL), thrombocytopenia (platelets < 100 × 109/L), presence of one high molecular risk gene mutation (ie, in SRSF2, ASXL1, and/or RUNX1), and presence of two or more high molecular risk gene mutations. By assigning hazard ratio-weighted points to these variables, the following three risk categories were defined: low risk (median OS, not reached), intermediate risk (median OS, 3.9 years; 95% CI, 2.1 to 5.7 years), and high risk (median OS, 1.9 years; 95% CI, 1.3 to 2.6 years; P < .001). The mutation-adjusted risk score (MARS) was independent of the WHO classification and was confirmed in the independent validation set. During a median follow-up time of 2.2 years (range, 0 to 23 years), 63 (16%) of 383 patients experienced a leukemic transformation to secondary mast cell leukemia (32%) or secondary acute myeloid leukemia (68%). The MARS was also predictive for leukemia-free survival (P < .001).The MARS is a validated, five-parameter, WHO-independent prognostic score that defines three risk groups among patients with AdvSM and may improve up-front treatment stratification for these rare hematologic neoplasms.

  View details for DOI 10.1200/JCO.19.00640

  View details for PubMedID 31509472

• Nonmyeloablative Allogeneic Transplantation Using TLI-ATG Conditioning for Lymphoid and Myeloid Malignancies: Mature Follow-up from a Large, Single Institution Cohort Spinner, M. A., Kennedy, V. E., Tamaresis, J. S., Lavori, P. W., Elder, L. V., Arai, S., Johnston, L. J., Meyer, E. H., Miklos, D. B., Muffly, L. S., Negrin, R. S., Rezvani, A. R., Shizuru, J. A., Weng, W., Hoppe, R. T., Strober, S., Lowsky, R. AMER SOC HEMATOLOGY. 2018

  View details for DOI 10.1182/blood-2018-99-113597

  View details for Web of Science ID 000454842804265

• The Data Registry of the European Competence Network on Mastocytosis (ECNM): Set Up, Projects, and Perspectives. The journal of allergy and clinical immunology. In practice Valent, P., Oude Elberink, J. N., Gorska, A., Lange, M., Zanotti, R., van Anrooij, B., Bonifacio, M., Bonadonna, P., Gleixner, K. V., Hadzijusufovic, E., Perkins, C., Hartmann, K., Illerhaus, A., Merante, S., Elena, C., Shoumariyeh, K., von Bubnoff, N., Parente, R., Triggiani, M., Schwaab, J., Jawhar, M., Caroppo, F., Fortina, A. B., Brockow, K., David Fuchs, Greul, R., Yavuz, A. S., Doubek, M., Mattsson, M., Hagglund, H., Panse, J., Sabato, V., Aberer, E., Al-Ali, H. K., Morren, M., Varkonyi, J., Zink, A., Niedoszytko, M., Niederwieser, D., Malcovati, L., Reiter, A., Kennedy, V., Gotlib, J., Lortholary, O., Hermine, O., Arock, M., Kluin-Nelemans, H., Sperr, W. R., Study Group of the European Competence Network on Mastocytosis (ECNM) 2018

  Abstract

  Mastocytosis is a unique hematologic neoplasm with complex biology and pathology and a variable clinical course. The disease can essentially be divided into cutaneous mastocytosis (CM) and systemic mastocytosis (SM). In adults, SM is diagnosed in most cases and manifests as either indolent or advanced disease. Patients with advanced SM have an unfavorable prognosis with reduced survival. However, so far, little is known about the prevalence of various categories of SM and about prognostic factors. In an attempt to learn more about the behavior and evolution of various forms of CM and SM, the European Competence Network on Mastocytosis (ECNM) initiated a mastocytosis registry in 2012. In this article, the set up and start phase of this registry are described. Until 2018, more than 3000 patients from 12 countries and 25 centers have been enrolled. In a majority of all patients, robust follow-up data and relevant clinical end points are available. Using this data set, a series of registry projects have been launched, with the aim to validate previously identified diagnostic and prognostic variables and to identify new disease-related and patient-related parameters in various forms of mastocytosis. Moreover, the core data set of the registry will be useful to establish multiparametric scoring systems through which prognostication and individualized management of patients with mastocytosis should improve in the foreseeable future.

  View details for PubMedID 30416055

• Importance of peripheral blood absolute lymphocyte counts (ALC) in predicting transplant outcomes in preparative regimens using anti-thymocyte globulin or alemtuzumab: an international 2 centre experience Sheth, V., Kennedy, V., de Lavallade, H., Mclornan, D., Potter, V., Savani, B., Chinratanalab, W., Engelhardt, B., Goodman, S., Greer, J., Kassim, A., York, S., Kulasekararaj, A., Marsh, J., Mufti, G., Pagliuca, A., Jagasia, M., Raj, K. NATURE PUBLISHING GROUP. 2018: 425–26

  View details for Web of Science ID 000487702804067

• Strongyloides Hyperinfection After Immunosuppression in an Immigrant From El Salvador: A Case for Early Diagnosis and Treatment. Journal of clinical rheumatology : practical reports on rheumatic & musculoskeletal diseases Hoppenfeld, M. S., Kennedy, V., Sheth, K., Chang, A., Nelson, J., Fairchild, R. M. 2018

  View details for PubMedID 30074914

• Defining the complex phenotype of severe systemic loxoscelism using a large electronic health record cohort PLOS ONE Robinson, J. R., Kennedy, V. E., Doss, Y., Bastarache, L., Denny, J., Warner, J. L. 2017; 12 (4)

  Abstract

  Systemic loxoscelism is a rare illness resulting from the bite of the recluse spider and, in its most severe form, can lead to widespread hemolysis, coagulopathy, and death. We aim to describe the clinical features and outcomes of the largest known cohort of individuals with moderate to severe loxoscelism.We performed a retrospective, cross sectional study from January 1, 1995, to December 31, 2015, at a tertiary-care academic medical center, to determine individuals with clinical records consistent with moderate to severe loxoscelism. Age-, sex-, and race-matched controls were compared. Demographics, clinical characteristics, laboratory measures, and outcomes of individuals with loxoscelism are described. Case and control groups were compared with descriptive statistics and phenome-wide association study (PheWAS).During the time period, 57 individuals were identified as having moderate to severe loxoscelism. Of these, only 33% had an antecedent spider bite documented. Median age of individuals diagnosed with moderate to severe loxoscelism was 14 years old (IQR 9.0-24.0 years). PheWAS confirmed associations of systemic loxoscelism with 29 other phenotypes, e.g., rash, hemolytic anemia, and sepsis. Hemoglobin level dropped an average of 3.1 g/dL over an average of 2.0 days (IQR 2.0-6.0). Lactate dehydrogenase and total bilirubin levels were on average over two times their upper limit of normal values. Eighteen individuals of 32 tested had a positive direct antiglobulin (Coombs') test. Mortality was 3.5% (2/57 individuals).Systemic loxoscelism is a rare but devastating process with only a minority of patients recalling the toxic exposure; hemolysis reaches a peak at 2 days after admission, with some cases taking more than a week before recovery. In endemic areas, suspicion for systemic loxoscelism should be high in individuals, especially children and younger adults, presenting with a cutaneous ulcer and hemolysis or coagulopathy, even in the absence of a bite exposure history.

  View details for DOI 10.1371/journal.pone.0174941

  View details for Web of Science ID 000399875600024

  View details for PubMedID 28422977

• Allogeneic Hematopoietic Cell Transplantation for Adult T Cell Acute Lymphoblastic Leukemia. Biology of blood and marrow transplantation Hamilton, B. K., Rybicki, L., Abounader, D., Adekola, K., Advani, A., Aldoss, I., Bachanova, V., Bashey, A., Brown, S., DeLima, M., Devine, S., Flowers, C. R., Ganguly, S., Jagasia, M., Kennedy, V. E., Kim, D. D., McGuirk, J., Pullarkat, V., Romee, R., Sandhu, K., Smith, M., Ueda, M., Viswabandya, A., Vu, K., Wall, S., Zeichner, S. B., Perales, M., Majhail, N. S. 2017

  Abstract

  Allogeneic hematopoietic cell transplantation (HCT) is recommended for patients with T cell acute lymphoblastic leukemia (T-ALL) in second or later complete remission (CR) and high-risk patients in first CR. Given its relative rarity, data on outcomes of HCT for T-ALL are limited. We conducted a multicenter retrospective cohort study using data from 208 adult patients who underwent HCT between 2000 and 2014 to describe outcomes of allogeneic HCT for T-ALL in the contemporary era. The median age at HCT was 37 years, and the majority of patients underwent HCT in CR, using total body irradiation (TBI)-based myeloablative conditioning regimens. One-quarter of the patients underwent alternative donor HCT using a mismatched, umbilical cord blood, or haploidentical donor. With a median follow up of 38 months, overall survival at 5 years was 34%. The corresponding cumulative incidence of non-relapse mortality and relapse was 26% and 41%, respectively. In multivariable analysis, factors significantly associated with overall survival were the use of TBI (HR, 0.57; P = .021), age >35 years (HR, 1.55; P = .025), and disease status at HCT (HR, 1.98; P = .005 for relapsed/refractory disease compared with CR). Relapse was the most common cause of death (58% of patients). Allogeneic HCT remains a potentially curative option in selected patients with adult T-ALL, although relapse is a major cause of treatment failure.

  View details for DOI 10.1016/j.bbmt.2017.04.003

  View details for PubMedID 28396160

• Rituximab-containing reduced-intensity conditioning improves progression-free survival following allogeneic transplantation in B cell non-Hodgkin lymphoma. Journal of hematology & oncology Epperla, N. n., Ahn, K. W., Ahmed, S. n., Jagasia, M. n., DiGilio, A. n., Devine, S. M., Jaglowski, S. n., Kennedy, V. n., Rezvani, A. R., Smith, S. M., Sureda, A. n., Fenske, T. S., Kharfan-Dabaja, M. A., Armand, P. n., Hamadani, M. n. 2017; 10 (1): 117

  Abstract

  In B cell non-Hodgkin lymphoma (B-NHL), rituximab-containing reduced-intensity conditioning regimens (R-RIC) have been shown to provide favorable outcomes in single-arm studies; however, large multicenter studies comparing R-RIC and non-rituximab-containing reduced-intensity conditioning regimens (nonR-RIC) have not been performed. Using the CIBMTR database, we report the outcomes of R-RIC versus nonR-RIC regimens in B-NHL.We evaluated 1401 adult B-NHL patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) who received nonR-RIC (n = 1022) or R-RIC (n = 379) regimens. Graft-versus-host disease (GVHD) prophylaxis was limited to calcineurin inhibitor-based approaches.Median follow-up of survivors in the R-RIC and nonR-RIC groups was 47 and 37 months, respectively. On multivariate analysis, no difference was seen between the R-RIC and nonR-RIC cohorts in terms of acute GVHD grade II-IV (RR = 1.14, 95%CI = 0.83-1.56, p = 0.43) or grade III-IV (RR = 1.16, 95%CI = 0.72-1.89, p = 0.54), chronic GVHD (RR = 1.15, 95%CI = 0.92-1.46, p = 0.22), non-relapse mortality (RR = 0.90; 95%CI = 0.67-1.22; p = 0.51), relapse/progression (RR = 0.79; 95%CI = 0.63-1.01; p = 0.055), and mortality (RR = 0.84, 95%CI = 0.69-1.02, p = 0.08) risk. However, R-RIC was associated with a significantly improved progression-free survival (RR = 0.76; 95%CI 0.62-0.92; p = 0.006). On subgroup analysis, mortality benefit was noted in the R-RIC group patients not receiving busulfan-based RIC (RR = 0.76; 95%CI = 0.60-0.96; p = 0.02) and with the use of a higher cumulative rituximab dose (RR = 0.43; 95%CI = 0.21-0.90; p = 0.02).Our analysis shows that inclusion of rituximab in RIC regimens improves progression-free survival in patients with B cell NHL. These data supports the use of R-RIC in B-NHL patients undergoing allo-HCT.

  View details for PubMedID 28606176

• Optimizing Anti-Thymocyte Globulin Dosing for Unrelated Donor Allogeneic Hematopoietic Cell Transplant Based on Recipient Absolute Lymphocyte Count. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation Kennedy, V. E., Chen, H. n., Savani, B. N., Greer, J. n., Kassim, A. A., Engelhardt, B. G., Goodman, S. n., Sengsayadeth, S. n., Chinratanalab, W. n., Jagasia, M. n. 2017

  Abstract

  Anti-thymocyte globulin (ATG) is used as prophylaxis against graft-versus-host-disease (GVHD). Current dosing regimens for ATG are empiric, weight-based, and do not account for patient-specific factors. Furthermore, the target of ATG, recipient T cells post-cytotoxic chemotherapy, is not a function of recipient weight. We hypothesized the recipient peripheral blood absolute lymphocyte count (ALC) on day of ATG administration would interact with the amount of ATG administered to predict transplant outcomes. We retrospectively analyzed 135 patients who received ATG for GVHD prophylaxis for unrelated allogeneic hematopoietic cell transplantation at three different doses: 10 mg/kg, 7.5 mg/kg, and 5 mg/kg. There was no difference in the 2-year overall survival among ATG dosing groups; however, deaths from infectious complications were significantly higher with higher doses of ATG (3.7% vs 19% vs 26.7%, p = 0.02). Severity of chronic GVHD was lower with higher doses of ATG (28% vs. 24% vs. 4%, p = 0.03). In multivariate analysis, the median peripheral blood ALC on day of ATG administration and the total amount of ATG interacted to predict overall survival (HR 0.09, p = 0.03). For low recipient ALC (10(th) percentile or 0.56 x 10(2)/µL), increasing total ATG was associated with a higher risk of death, while for high recipient ALC (90(th) percentile or 24.96 x 10(2)/µL), increasing ATG was associated with a lower risk of death. Our findings suggest the interaction between ATG and its target, the recipient lymphocyte, could represent a new paradigm for ATG dosing.

  View details for PubMedID 28864139

• Reduced-Intensity Conditioning with Fludarabine, Cyclophosphamide, and Rituximab Is Associated with Improved Outcomes Compared with Fludarabine and Busulfan after Allogeneic Stem Cell Transplantation for B Cell Malignancies BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION Kennedy, V. E., Savani, B. N., Greer, J. P., Kassim, A. A., Engelhardt, B. G., Goodman, S. A., Sengsayadeth, S., Chinratanalab, W., Jagasia, M. 2016; 22 (10): 1801-1807

  Abstract

  Reduced-intensity conditioning (RIC) has been used increasingly for allogeneic hematopoietic cell transplantation to minimize transplant-related mortality while maintaining the graft-versus-tumor effect. In B cell lymphoid malignancies, reduced-intensity regimens containing rituximab, an antiCD20 antibody, have been associated with favorable survival; however, the long-term outcomes of rituximab-containing versus nonrituximab-containing regimens for allogeneic hematopoietic cell transplantation in B cell lymphoid malignancies remain to be determined. We retrospectively analyzed 94 patients who received an allogeneic transplant for a B cell lymphoid malignancy. Of these, 33 received RIC with fludarabine, cyclophosphamide, and rituximab (FCR) and graft-versus-host disease (GVHD) prophylaxis with a calcineurin inhibitor and mini-methotrexate, and 61 received RIC with fludarabine and busulfan (FluBu) and GVHD prophylaxis with a calcineurin inhibitor and mycophenolate mofetil. The 2-year overall survival was superior in patients who received FCR versus FluBu (72.7% versus 54.1%, P = .031), and in multivariable analysis adjusted for Disease Risk Index and donor type, only the conditioning regimen (FluBu versus FCR: HR, 2.06; 95% CI, 1.04 to 4.08; P = .037) and Disease Risk Index (low versus intermediate/high: HR, .38; 95% CI, .17 to .86; P = .02) were independent predictors of overall survival. The 2-year cumulative incidence of chronic GVHD was lower in patients who received FCR versus FluBu (24.2% versus 51.7%, P = .01). There was no difference in rate of relapse/progression or acute GVHD. Our results demonstrate that the use of RIC with FCR and GVHD prophylaxis with a calcineurin inhibitor and mini-methotrexate is associated with decreased chronic GVHD and improved overall survival.

  View details for DOI 10.1016/j.bbmt.2016.06.029

  View details for Web of Science ID 000384965200010

  View details for PubMedID 27377900

• Does adherence to epilepsy quality measures correlate with reduced epilepsy-related adverse hospitalizations? A retrospective experience EPILEPSIA Ladner, T. R., Morgan, C. D., Pomerantz, D. J., Kennedy, V. E., Azar, N., Haas, K., Lagrange, A., Gallagher, M., Singh, P., Abou-Khalil, B. W., Arain, A. M. 2015; 56 (5): E63-E67

  Abstract

  In 2011, the American Academy of Neurology (AAN) established eight epilepsy quality measures (EQMs) for chronic epilepsy treatment to address deficits in quality of care. This study assesses the relationship between adherence to these EQMs and epilepsy-related adverse hospitalizations (ERAHs). A retrospective chart review of 475 new epilepsy clinic patients with an ICD-9 code 345.1-9 between 2010 and 2012 was conducted. Patient demographics, adherence to AAN guidelines, and annual number of ERAHs were assessed. Fisher's exact test was used to assess the relationship between adherence to guidelines (as well as socioeconomic variables) and the presence of one or more ERAH per year. Of the eight measures, only documentation of seizure frequency, but not seizure type, correlated with ERAH (relative risk [RR] 0.343, 95% confidence interval [CI] 0.176-0.673, p = 0.010). Among patients in the intellectually disabled population (n = 70), only review/request of neuroimaging correlated with ERAH (RR 0.128, 95% CI 0.016-1.009, p = 0.004). ERAHs were more likely in African American patients (RR 2.451, 95% CI 1.377-4.348, p = 0.008), Hispanic/Latino patients (RR 4.016, 95% CI 1.721-9.346, p = 0.016), Medicaid patients (RR 2.217, 95% CI 1.258-3.712, p = 0.009), and uninsured patients (RR 2.667, 95% CI 1.332-5.348, p = 0.013). In this retrospective series, adherence to the eight AAN quality measures did not strongly correlate with annual ERAH.

  View details for DOI 10.1111/epi.12965

  View details for Web of Science ID 000354641700004

  View details for PubMedID 25809720

• Hyaluronan Contributes to Bronchiolitis Obliterans Syndrome and Stimulates Lung Allograft Rejection through Activation of Innate Immunity AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Todd, J. L., Wang, X., Sugimoto, S., Kennedy, V. E., Zhang, H. L., Pavlisko, E. N., Kelly, F. L., Huang, H., Kreisel, D., Palmer, S. M., Gelman, A. E. 2014; 189 (5): 556-566

  Abstract

  Although innate immunity is increasingly recognized to contribute to lung allograft rejection, the significance of endogenous innate ligands, such as hyaluronan (HA) fragments, in clinical or experimental lung transplantation is uncertain.To determine if HA is associated with clinical bronchiolitis obliterans syndrome (BOS) in lung transplant recipients, and evaluate the effect of low- or high-molecular-weight HA on experimental lung allograft rejection, including dependence on innate signaling pathways or effector cells.HA concentrations were measured in bronchoalveolar lavage and plasma samples from lung recipients with or without established BOS. BOS and normal lung tissues were assessed for HA localization and expression of HA synthases. Murine orthotopic lung recipients with established tolerance were treated with low- or high-molecular-weight HA under varied experimental conditions, including Toll-like receptor (TLR) 2/4 and myeloid differentiation protein 88 deficiency and neutrophil depletion.HA localized within areas of intraluminal small airways fibrosis in BOS lung tissue. Moreover, transcripts for HA synthase enzymes were significantly elevated in BOS versus normal lung tissues and both lavage fluid and plasma HA concentrations were increased in recipients with BOS. Treatment with low-molecular-weight HA abrogated tolerance in murine orthotopic lung recipients in a TLR2/4- and myeloid differentiation protein 88-dependent fashion and drove expansion of alloantigen-specific T lymphocytes. Additionally, TLR-dependent signals stimulated neutrophilia that promoted rejection. In contrast, high-molecular-weight HA attenuated basal allograft inflammation.These data suggest that accumulation of HA could contribute to BOS by directly activating innate immune signaling pathways that promote allograft rejection and neutrophilia.

  View details for DOI 10.1164/rccm.201308-1481OC

  View details for Web of Science ID 000332512500010

  View details for PubMedID 24471427

  View details for PubMedCentralID PMC3977710

• Bronchoalveolar Lavage as a Tool to Predict, Diagnose and Understand Bronchiolitis Obliterans Syndrome AMERICAN JOURNAL OF TRANSPLANTATION KENNEDY, V. E., Todd, J. L., Palmer, S. M. 2013; 13 (3): 552-561

  Abstract

  Bronchiolitis obliterans syndrome (BOS), a condition of irreversible small airway fibrosis, is the principal factor limiting long-term survival after lung transplantation. Bronchoscopy and bronchoalveolar lavage (BAL), techniques central to lung transplant clinical practice, provide a unique opportunity to interrogate the lung allograft during BOS development and identify potential disease mechanisms or biomarkers. Over the past 20 years, numerous studies have evaluated the BAL cellular composition, cytokine profiles and protein constituents in lung transplant recipients with BOS. To date, however, no summative evaluation of this literature has been reported. We developed and applied objective criteria to qualitatively rank the strength of associations between BAL parameters and BOS in order to provide a comprehensive and systematic assessment of the literature. Our analysis indicates that several BAL parameters, including neutrophil count, interleukin-8, alpha defensins and MMP-9, demonstrate highly replicable associations with BOS. Additionally, we suggest that considerable opportunity exists to increase the knowledge gained from BAL analyses in BOS through increased sample sizes, covariant adjustment and standardization of the BAL technique. Further efforts to leverage analysis of BAL constituents in BOS may offer great potential to provide additional in-depth and mechanistic insights into the pathogenesis of this complex disease.

  View details for DOI 10.1111/ajt.12091

  View details for Web of Science ID 000315452600007

  View details for PubMedID 23356456

  View details for PubMedCentralID PMC3582805

• Epithelial clara cell injury occurs in bronchiolitis obliterans syndrome after human lung transplantation. American journal of transplantation Kelly, F. L., KENNEDY, V. E., Jain, R., Sindhwani, N. S., Finlen Copeland, C. A., Snyder, L. D., Eu, J. P., Meltzer, E. B., Brockway, B. L., Pavlisko, E., Stripp, B. R., Palmer, S. M. 2012; 12 (11): 3076-3084

  Abstract

  Bronchiolitis obliterans syndrome (BOS) is a condition of progressive airflow obstruction that affects a majority of lung transplant recipients and limits long-term posttransplant survival. Although epithelial injury appears central to the development of BOS, little is known regarding the specific epithelial cell types that are affected in this condition. We hypothesized that BOS would involve preferential injury to the secretory Clara cells that function in innate defense and epithelial repair. To test this hypothesis, we assessed tissue transcript, tissue protein and lung fluid protein expression of Clara cell secretory protein (CCSP), a marker for Clara cells, in lung transplant recipients with BOS, BOS-free patients and in donor controls. Our results demonstrate that CCSP tissue transcript and protein expression are significantly reduced in lung transplant recipients with BOS compared to BOS-free or donor controls. In addition, we demonstrate that CCSP protein levels are significantly reduced in the lung fluid of patients with BOS compared to BOS-free controls, in cross-sectional and longitudinal analysis. Collectively, these complementary results illustrate that BOS involves a selective alteration in the distribution and function of bronchiolar Clara cells.

  View details for DOI 10.1111/j.1600-6143.2012.04201.x

  View details for PubMedID 22883104

  View details for PubMedCentralID PMC3484196