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Little is known about the central nervous system (CNS) risk in high-grade B-cell lymphoma, not otherwise specified (HGBL, NOS). Hence, we sought to describe the rates of baseline CNS involvement, risk of CNS recurrence after primary therapy, and management strategies in HGBL, NOS. In this multicenter retrospective study, we included 160 adults with newly diagnosed HGBL, NOS treated between 2016 and 2021 at 20 US institutions. Eleven patients (7%) had baseline CNS involvement at diagnosis (leptomeningeal=6, parenchymal=4, and both=1). Baseline CNS involvement was significantly associated only with MYC rearrangement (OR=3.5) and testicular (in men) or female pelvic (in women) involvement (OR=8.1). There was no significant difference in survival outcomes between HGBL, NOS patients with (median PFS=4 years) or without (median PFS=2.4 years) baseline CNS involvement (p=0.45). The cumulative incidence of CNS recurrence at 3 years was 11%. Patients with baseline CNS involvement were at the highest risk (48.5% versus 8% for those without baseline CNS involvement) and were excluded from the risk factors analysis for CNS recurrence. The risk for CNS recurrence was significantly associated with blood or bone marrow involvement, CD5 expression, non-GCB subtype, and DEL phenotype, however, high CNS-IPI was not. The prognosis of relapsed HGBL, NOS was poor, regardless of whether recurrence was systemic or limited to the CNS, and with currently available salvage strategies, including autologous transplantation and CAR T-cell modalities, almost all patients with CNS recurrence ultimately succumbed to their disease. These patients represent an unmet need and should be prioritized for experimental approaches., (Copyright © 2024 American Society of Hematology.)

Patients with B-cell lymphomas have altered cellular components of vaccine responses due to malignancy and therapy, and the optimal timing of vaccination relative to therapy remains unknown. Severe acute respiratory syndrome coronavirus 2 vaccines created an opportunity for new insights in vaccine timing because patients were challenged with a novel antigen across multiple phases of treatment. We studied serologic messenger RNA vaccine response in retrospective and prospective cohorts with lymphoma and chronic lymphocytic leukemia, paired with clinical and research immune parameters. Reduced serologic response was observed more frequently during active treatment, but nonresponse was also common within observation and posttreatment groups. Total immunoglobulin A and immunoglobulin M correlated with successful vaccine response. In individuals treated with anti-CD19-directed chimeric antigen receptor-modified T cells, nonresponse was associated with reduced B and T follicular helper cells. Predictors of vaccine response varied by disease and therapeutic group, and therefore further studies of immune health during and after cancer therapies are needed to individualize vaccine timing., Competing Interests: Potential conflicts of interest. E. A. C. receives research support from Genentech/Roche and AbbVie and has served as a consultant for Beigene, AstraZeneca, and TG Therapeutics. J. S. has served as a consultant for ATARA, AstraZeneca, Celgene Corporation, Adaptive, and Genmab, and receives research support from AstraZeneca, Merck, Incyte, Bristol-Myers Squibb, Pharmacyclics, TG Therapeutics, Seattle Genetics, and Adaptive. S. K. B. received honoraria from Acrotech, Seagen, Kyowa Kirin, and Daiichi Sankyo. S. D. N. receives research support from Roche, Rafael, ATARA, Pharmacyclics, and Takeda/Millennium; is a data monitoring committee member for Merck; and has served as a consultant for Epizyme and Morphosys. D. J. L. received research funding from Curis and Triphase; is a data and safety monitoring board member for Karyopharm; and has served as a consultant for Morphosys/Incyte, Epizyme, and ADC Therapeutics. J. N. G. received research funding from Loxo and has served as a consultant for Genentech, AbbVie, and Kite. E. L. P. received funding from Roche Diagnostics Corporation for the evaluation of serologic tests for SARS-CoV-2. E. J. W. is consulting or is an advisor for Merck, Marengo, Janssen, Related Sciences, Synthekine, and Surface Oncology; is a founder of Surface Oncology, Danger Bio, and Arsenal Biosciences; and is an inventor on a patent (US patent number 10,370,446) submitted by Emory University that covers the use of PD-1 blockade to treat infections and cancer. S. J. S. reports research funding from Acerta, Celgene, Genentech/Roche, Merck, Novartis, Pharmacyclics, and TG Therapeutics; received honoraria/consulting fees from Acerta, AstraZeneca, Celgene, Incyte, Janssen, Loxo Oncology, Morphosys, and Nordic Nanovector; is a steering committee member for Celgene, Nordic Nanovector, and Novartis; and has a patent for combination therapies of CAR T cells and PD-1 inhibitors. M. R. holds patents related to CAR T cells; has served as a consultant for nanoString, BMS, GSK, Bayer, Sana Therapeutics, and AbClon; receives research funding from AbClon, nanoString, viTToria biotherapeutics, Oxford Nanoimaging, and Beckman Coulter; and is the scientific founder of viTToria Biotherapeutics. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Abstract: Little is known about risk factors for central nervous system (CNS) relapse in mature T-cell and natural killer cell neoplasms (MTNKNs). We aimed to describe the clinical epidemiology of CNS relapse in patients with MTNKN and developed the CNS relapse In T-cell lymphoma Index (CITI) to predict patients at the highest risk of CNS relapse. We reviewed data from 135 patients with MTNKN and CNS relapse from 19 North American institutions. After exclusion of leukemic and most cutaneous forms of MTNKNs, patients were pooled with non-CNS relapse control patients from a single institution to create a CNS relapse-enriched training set. Using a complete case analysis (n = 182), including 91 with CNS relapse, we applied a least absolute shrinkage and selection operator Cox regression model to select weighted clinicopathologic variables for the CITI score, which we validated in an external cohort from the Swedish Lymphoma Registry (n = 566). CNS relapse was most frequently observed in patients with peripheral T-cell lymphoma, not otherwise specified (25%). Median time to CNS relapse and median overall survival after CNS relapse were 8.0 and 4.7 months, respectively. We calculated unique CITI risk scores for individual training set patients and stratified them into risk terciles. Validation set patients with low-risk (n = 158) and high-risk (n = 188) CITI scores had a 10-year cumulative risk of CNS relapse of 2.2% and 13.4%, respectively (hazard ratio, 5.24; 95% confidence interval, 1.50-18.26; P = .018). We developed an open-access web-based CITI calculator (https://redcap.link/citicalc) to provide an easy tool for clinical practice. The CITI score is a validated model to predict patients with MTNKN at the highest risk of developing CNS relapse., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Brexucabtagene autoleucel (brexu-cel) is an autologous CD19-directed chimeric antigen receptor (CAR) T-cell therapy approved for treatment of relapsed/refractory mantle cell lymphoma (MCL). During a fludarabine shortage, we used bendamustine as an alternative to standard cyclophosphamide/fludarabine (cy/flu) lymphodepletion (LD) prior to brexu-cel. We assessed MCL patient outcomes as well as CAR T-cell expansion and persistence after brexu-cel following bendamustine or cy/flu LD at our center. This was a retrospective single institution study that utilized prospectively banked blood and tissue samples. Clinical efficacy was assessed by 2014 Lugano guidelines. CAR T-cell expansion and persistence in peripheral blood were assessed on day 7 and at ≥month 6 for patients with available samples. Seventeen patients received bendamustine and 5 received cy/flu. For the bendamustine cohort, 14 (82%) received bridging therapy and 4 (24%) had CNS involvement. Fifteen patients (88%) developed CRS with 4 (24%) ≥grade 3 events. Six (35%) patients developed ICANS with 4 (24%) events ≥grade 3. No patient had ≥grade 3 cytopenias at day 90. Best objective (BOR) and complete response (CRR) rates were 82% and 65%, respectively. At 24.5 months median follow-up, 12-month progression-free survival (PFS) was 45%, 24-month PFS was 25%, and median duration of response was 19 months. Median OS was not reached. BOR was 25% (1/4) for patients with CNS involvement. CAR transgene expansion after bendamustine LD was observed on day 7 in all (4/4) patients tested and persisted at ≥6 months (2/2), regardless of response. Bendamustine LD before brexu-cel for MCL is feasible and safe with a lower frequency and shorter duration of cytopenias than reported for cy/flu. Both CAR T-cell expansion and persistence were observed after bendamustine LD. Outcomes appear comparable to the real world outcomes reported with cy/flu LD., (Copyright © 2024. Published by Elsevier Inc.)

Background: Administration of anti-CD19 chimeric antigen receptor T-cell (CART19) immunotherapy for large B-cell lymphomas (LBCLs), a subset of non-Hodgkin lymphoma (NHL), involves high costs and access to specialized tertiary care centers. We investigated whether minority health populations (MHPs) have equal access to CART19 and whether their outcomes are similar to those of non-MHPs., Methods: We analyzed the prevalence and clinical outcomes of patients treated with commercial CART19 at two geographically and socioeconomically different institutions: the Abramson Cancer Center (ACC, Philadelphia, Pennsylvania) and the Knight Cancer Institute (KCI, Portland, Oregon)., Results: In the ACC catchment area, 8956 patients were diagnosed with NHL between 2015 and 2019 (latest available data from the state registry), including 17.9% MHPs. In the ACC, between 2018 and 2022 (CART became available in 2018), 1492 patients with LBCL were treated, and 194 received CART19. The proportion of MHPs was 15.7% for the entire LBCL cohort but only 6.7% for the CART19 cohort. During the same time, in the KCI catchment area, 4568 patients were diagnosed with NHL, including 4.2% MHPs. In the KCI, 396 patients with LBCL were treated, and 47 received CART19. The proportion of MHPs was 6.6% for the entire LBCL cohort and 4.2% for the CART19 cohort. The 3-month response, survival, and toxicities after CART19 infusion showed similar results, although the number of patients who were treated was limited., Conclusions: This study shows that the access of MHPs to tertiary centers for LBCL care was preserved but appeared reduced for commercial CART19 immunotherapy. Although clinical outcomes of MHPs seemed similar to those of non-MHPs, the small sample size precludes drawing firm conclusions. Further studies are needed. (Funded by the Laffey McHugh Foundation and others.).

We report a T cell lymphoma (TCL) occurring 3 months after anti-CD19 chimeric antigen receptor (CAR) T cell immunotherapy for non-Hodgkin B cell lymphoma. The TCL was diagnosed from a thoracic lymph node upon surgery for lung cancer. The TCL exhibited CD8 + cytotoxic phenotype and a JAK3 variant, while the CAR transgene was very low. The T cell clone was identified at low levels in the blood before CAR T infusion and in lung cancer. To assess the overall risk of secondary primary malignancy after commercial CAR T (CD19, BCMA), we analyzed 449 patients treated at the University of Pennsylvania. At a median follow-up of 10.3 months, 16 patients (3.6%) had a secondary primary malignancy. The median onset time was 26.4 and 9.7 months for solid and hematological malignancies, respectively. The projected 5-year cumulative incidence is 15.2% for solid and 2.3% for hematological malignancies. Overall, one case of TCL was observed, suggesting a low risk of TCL after CAR T., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Abstract: Lymphodepletion (LD) is an integral component of chimeric antigen receptor T-cell (CART) immunotherapies. In this study, we compared the safety and efficacy of bendamustine (Benda) to standard fludarabine/cyclophosphamide (Flu/Cy) LD before CD19-directed, CD28-costimulated CART axicabtagene ciloleucel (axi-cel) for patients with large B-cell lymphoma (LBCL) and follicular lymphoma (FL). We analyzed 59 patients diagnosed with LBCL (n = 48) and FL (n = 11) consecutively treated with axi-cel at the University of Pennsylvania. We also analyzed serum samples for cytokine levels and metabolomic changes before and after LD. Flu/Cy and Benda demonstrated similar efficacy, with complete remission rates of 51.4% and 50.0% (P = .981), respectively, and similar progression-free and overall survivals. Any-grade cytokine-release syndrome occurred in 91.9% of patients receiving Flu/Cy vs 72.7% of patients receiving Benda (P = .048); any-grade neurotoxicity after Flu/Cy occurred in 45.9% of patients and after Benda in 18.2% of patients (P = .031). In addition, Flu/Cy was associated with a higher incidence of grade ≥3 neutropenia (100% vs 54.5%; P < .001), infections (78.4% vs 27.3%; P < .001), and neutropenic fever (78.4% vs 13.6%; P < .001). These results were confirmed both in patients with LBCL and those with FL. Mechanistically, patients with Flu/Cy had a greater increase in inflammatory cytokines associated with neurotoxicity and reduced levels of metabolites critical for redox balance and biosynthesis. This study suggests that Benda LD may be a safe alternative to Flu/Cy for CD28-based CART CD19-directed immunotherapy with similar efficacy and reduced toxicities. Benda is associated with reduced levels of inflammatory cytokines and increased anabolic metabolites., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma; data indicate that blastoid and pleomorphic variants have a poor prognosis. We report characteristics and outcomes of patients with blastoid/pleomorphic variants of MCL. We retrospectively studied adults with newly diagnosed MCL treated from 2000 to 2015. Primary objectives were to describe progression-free survival (PFS) and overall survival (OS). Secondary objectives included characterization of patient characteristics and treatments. Of the 1029 patients with MCL studied, a total of 207 neoplasms were blastoid or pleomorphic variants. Median follow-up period was 82 months (range, 0.1-174 months); median PFS was 38 months (95% confidence interval [CI], 28-66) and OS was 68 months (95% CI, 45-96). Factors associated with PFS were receipt of consolidative autologous hematopoietic transplantation (auto-HCT; hazard ratio [HR], 0.52; 95% CI, 0.31-0.80; P < .05), MCL International Prognostic Index (MIPI) intermediate (HR, 2.3; 95% CI, 1.2-4.3; P < .02) and high (HR, 3.8; 95% CI, 2.0-7.4; P < .01) scores, and complete response to induction (HR, 0.29 (95% CI, 0.17-0.51). Receipt of auto-HCT was not associated with OS (HR, 0.69; 95% CI, 0.41-1.16; P = .16) but was associated with MIPI intermediate (HR, 5.7; 95% CI, 2.5-13.2; P < .01) and high (HR, 10.8; 95% CI, 4.7-24.9; P < .01) scores. We report outcomes in a large cohort of patients with blastoid/pleomorphic variant MCL. For eligible patients, receipt of auto-HCT after induction was associated with improved PFS but not OS. Higher MIPI score and auto-HCT ineligibility were associated with worse survival., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Genetic subgroups of diffuse large B-cell lymphoma (DLBCL) have been identified through comprehensive genomic analysis; however, it is unclear whether this can be applied in clinical practice. We assessed whether mutations detected by clinical laboratory mutation analysis (CLMA) were predictive of outcomes in patients with newly diagnosed DLBCL/high-grade B-cell lymphoma (HGBL). Patients diagnosed from 2018 to 2022 whose biopsy samples were subjected to CLMA and who received rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone or rituximab plus etoposide, prednisolone, vincristine, cyclophosphamide, and doxorubicin were analyzed for overall/complete response rate (ORR/CRR) and estimated progression-free/overall survival (PFS/OS). CLMA was successfully performed in 117 of 122 patient samples (96%), with a median turnaround time of 17 days. Median duration of follow-up was 31.3 months. Of the mutations detected in ≥10% of the samples, only TP53 was associated with both progression and death at 2 years. TP53 mutations were detected in 36% of tumors, and patients with TP53 mutations experienced significantly lower ORR (71% vs 90%; P = .009), CRR (55% vs 77%; P = .01), 2-year PFS (57% vs 77%; P = .006), 2-year OS (70% vs 91%; P = .001), and median OS after relapse (6.1 months vs not yet reached; P = .001) as than those without TP53 mutations. Furthermore, patients with TP53 loss-of-function (LOF) mutations experienced lower rates of 2-year PFS/OS than those with non-LOF mutations and inferior or near-inferior 2-year PFS if harboring high-risk clinicopathologic features. TP53 mutations identified through CLMA can predict for inferior outcomes in patients with newly diagnosed DLBCL/HGBL. Results of CLMA can be used in real time to inform prognosis and/or identify candidates for clinical trials., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Brentuximab vedotin (BV) in combination with doxorubicin, vinblastine, and dacarbazine (AVD) is increasingly used for frontline treatment of stage III/IV classical Hodgkin lymphoma (cHL). Peripheral neuropathy (PN) was the most common and treatment-limiting side effect seen in clinical trials but has not been studied in a nontrial setting, in which clinicians may have different strategies for managing it. We conducted a multisite retrospective study to characterize PN in patients who received BV + AVD for newly diagnosed cHL. One hundred fifty-three patients from 10 US institutions were eligible. Thirty-four patients (22%) had at least 1 ineligibility criteria for ECHELON-1, including stage, performance status, and comorbidities. PN was reported by 80% of patients during treatment; 39% experienced grade (G) 1, 31% G2, and 10% G3. In total, BV was modified in 44% of patients because of PN leading to BV discontinuation in 23%, dose reduction in 17%, and temporary hold in 4%. With a median follow-up of 24 months, PN resolution was documented in 36% and improvement in 33% at the last follow-up. Two-year progression-free survival (PFS) for the advanced-stage patients was 82.7% (95% confidence interval [CI], 0.76-0.90) and overall survival was 97.4% (95% CI, 0.94-1.00). Patients who discontinued BV because of PN did not have inferior PFS. In the nontrial setting, BV + AVD was associated with a high incidence of PN. In our cohort, which includes patients who would not have been eligible for the pivotal ECHELON-1 trial, BV discontinuation rates were higher than previously reported, but 2-year outcomes remain comparable., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

In this multi-institutional retrospective study, we examined the characteristics and outcomes of 160 patients with high-grade B-cell lymphoma, not otherwise specified (HGBL-NOS)-a rare category defined by high-grade morphologic features and lack of MYC rearrangements with BCL2 and/or BCL6 rearrangements ("double hit"). Our results show that HGBL-NOS tumors are heterogeneous: 83% of patients had a germinal center B-cell immunophenotype, 37% a dual-expressor immunophenotype (MYC and BCL2 expression), 28% MYC rearrangement, 13% BCL2 rearrangement, and 11% BCL6 rearrangement. Most patients presented with stage IV disease, a high serum lactate dehydrogenase, and other high-risk clinical factors. Most frequent first-line regimens included dose-adjusted cyclophosphamide, doxorubicin, vincristine, and etoposide, with rituximab and prednisone (DA-EPOCH-R; 43%); rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP; 33%); or other intensive chemotherapy programs. We found no significant differences in the rates of complete response (CR), progression-free survival (PFS), or overall survival (OS) between these chemotherapy regimens. CR was attained by 69% of patients. PFS at 2 years was 55.2% and OS was 68.1%. In a multivariable model, the main prognostic factors for PFS and OS were poor performance status, lactate dehydrogenase >3 × upper limit of normal, and a dual-expressor immunophenotype. Age >60 years or presence of MYC rearrangement were not prognostic, but patients with TP53 alterations had a dismal PFS. Presence of MYC rearrangement was not predictive of better PFS in patients treated with DA-EPOCH-R vs R-CHOP. Improvements in the diagnostic criteria and therapeutic approaches beyond dose-intense chemotherapy are needed to overcome the unfavorable prognosis of patients with HGBL-NOS., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Purpose: Parenteral nutrition (PN) has been shown to be a safe method of feeding in the intensive care unit with modern infection prevention practices, but similar analysis in the hematology-oncology setting is lacking., Methods: A retrospective analysis of 1,617 patients with hematologic malignancies admitted and discharged from the Hospital of the University of Pennsylvania during 3,629 encounters from 2017 to 2019 was undertaken to evaluate the association of PN administration with risk of central line-associated bloodstream infection (CLABSI). Proportions of mucosal barrier injury (MBI)-CLABSI and non-MBI-CLABSI were also compared between groups., Results: Risk of CLABSI was associated with cancer type and duration of neutropenia but not with PN administration (odds ratio, 1.015; 95% CI, 0.986 to 1.045; P = .305) in a multivariable analysis. MBI-CLABSI comprised 73% of CLABSI in patients exposed to and 70% in patients not exposed to PN, and there was no significant difference between groups (χ 2 = 0.06, P = .800)., Conclusion: PN was not associated with increased risk of CLABSI in a sample of patients with hematologic malignancy with central venous catheters when adjusting for cancer type, duration of neutropenia, and catheter days. The high proportion of MBI-CLABSI highlights the effect of gut permeability within this population.

Patients diagnosed with relapsed/refractory (R/R) diffuse large B cell lymphoma (DLBCL) or high-grade B cell lymphoma (HGBL) may achieve prolonged survival following receipt of high-dose chemotherapy/autologous stem cell transplantation (HDC/ASCT) or CD19-directed chimeric antigen receptor modified T cell therapy (CART19). Although early results from randomized clinical trials suggest that assignment to CART19 versus salvage immunochemotherapy as second-line therapy results in improved survival, analysis of a large series of patients who actually received HDC/ASCT or CART19 has yet to be performed. Such an analysis may inform future research efforts to optimize the risk stratification of R/R DLBCL/HGBL patients who are candidates for either therapy. The aim of this study was to evaluate clinicopathologic factors predictive of freedom from treatment failure (FFTF) for R/R DLBCL/HGBL patients following receipt of HDC/ASCT or CART19, and to compare patterns of treatment failure (TF) in R/R DLBCL/HGBL patients receiving HDC/ASCT and those receiving CART19. THE STUDY GROUP COMPRISED: patients age ≤75 years with R/R DLBCL/HGBL who received HDC/ASCT demonstrating partial or complete metabolic response to salvage immunochemotherapy and/or CART19 in the standard of care setting at the University of Pennsylvania between 2013 and 2021. Survival analyses were performed from the time of infusion of either HDC/ASCT or CART19, as well as at landmark time points postinfusion for patients who achieved FFTF. For 100 HDC/ASCT patients with a median follow-up of 62.7 months, the estimated 36-month FFTF and overall survival (OS) rates were 59% and 81%, respectively. For 109 CART19 patients with a median follow-up of 37.6 months, the estimated 36-month FFTF and OS rates were 24% and 48%, respectively. HDC/ASCT patients had significantly higher rates of estimated 36-month FFTF when they achieved actual FFTF at 3, 6, 12 and 24 months. Additionally, the rates of baseline characteristics predictive of TF at 36 months for either HDC/ASCT or CART19 patients were either similar to or significantly lower for CART19 patients compared to HDC/ASCT patients who achieved actual FFTF at 3, 6, 12, and 24 months. Patients with R/R DLBCL/HGBL achieving response to salvage immunochemotherapy who received HDC/ASCT had a high rate of estimated FFTF regardless of whether they harbored features predictive of resistance to salvage immunochemotherapy, which may be more durable than that of R/R DLBCL/HGBL patients receiving CART19. These findings support further investigation of disease characteristics, such as molecular features, that may predict response to salvage immunochemotherapy in patients fit for HDC/ASCT., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Plasmablastic lymphoma (PBL) is a rare entity, commonly associated with immunosuppressed states such as human immunodeficiency virus (HIV) infection or solid organ transplant. The clinical course is characterized by high relapse rates and a poor prognosis, leading some clinicians to recommend aggressive frontline therapy. However, a specific review of limited stage (LS) PBL patients is not available to evaluate outcomes and justify treatment recommendations. We performed a retrospective review of LS PBL cases to provide insight into this rare disease. Our cohort consisted of 80 stage I or II PBL patients from 13 US academic centers. With a median follow up of 34 months (1-196), the 3-year progression-free survival (PFS) and overall survival (OS) of the entire cohort were 72% (95% CI 62, 83) and 79% (95% CI 70, 89), respectively. The 3-year PFS and OS of patients treated with frontline chemotherapy alone was 65% (95% CI 50, 84) and 71% (95% CI 56, 89), respectively, compared to 85% (95% CI 72, 100) and 96% (95% CI 89, 100), respectively, in patients treated with combined frontline chemotherapy with radiation consolidation. Our data demonstrate favorable outcomes in LS PBL with no improvements in outcome from aggressive frontline treatment including Hyper-CVAD or auto-SCT consolidation. Multivariate regression analysis (MRA) demonstrated improved PFS for patients receiving EPOCH based frontline therapy versus CHOP (HR: 0.23; p = 0.029). Frontline chemotherapy followed by radiation consolidation versus chemotherapy alone appeared to be associated with improved relapse and survival outcomes but did not show statistical significance in MRA., (© 2023 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

Background and Purpose: CD19-targeting chimeric antigen receptor T-cell (CART) therapy is a promising treatment for relapsed/refractory non-Hodgkin lymphoma, but most patients experience post-CART progression. We describe our institutional experience of salvage radiotherapy (SRT) in this setting., Materials and Methods: Of 94 patients who received CART therapy from 2018 to 2020, 21 received SRT for post-CART progression. Patients were divided into two groups: locoregional disease (n = 9 [43 %], all disease encompassable within an RT field) and advanced disease (n = 12 [57 %]). Patterns of failure, progression-free survival (PFS), overall survival (OS), and toxicity were assessed., Results: Median time from CART infusion to SRT was 4.0 months (range, 0.6-11.5 months). In the locoregional disease group, 8/9 patients (89 %) were treated with comprehensive SRT to a median dose of 37.5 Gy in a median of 15 fractions. In the advanced disease group, all patients (n = 12) were treated with focal SRT to a median dose of 20.8 Gy in a median of 5 fractions. Median follow-up post-SRT was 15.2 months. In-field response was observed in 8/9 (89 %) in the locoregional disease and 8/9 (89 %) evaluable patients in the advanced disease groups. 17/18 evaluable patients (94 %) patients experienced post-SRT progression, all with a distant component. Median OS was 7.4 months; 21 months for locoregional disease versus 2.4 months for advanced disease (p = 0.0002). Median PFS was 1.1 month, and similarly poor regardless of group. No grade ≥ 3 toxicities occurred., Conclusions: SRT post-CART therapy appears safe with encouraging in-field response but high rates of out-of-field progression, even for those presenting with locoregional disease, highlighting the need for integration of novel systemic agents., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 Published by Elsevier B.V. on behalf of European Society for Radiotherapy and Oncology.)

Patients with double- and triple-hit lymphomas (DHL/THL) have inferior outcomes with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), and higher-intensity regimens such as dose-adjusted (DA)-EPOCH-R are standard. Dose-intensification of DA-EPOCH-R is guided by hematologic toxicity, without conclusive benefit for DHL/THL patients. To determine if cumulative doses of DA-EPOCH-R or compliance with dose adjustment impacts survival, we retrospectively evaluated detailed clinical data from 109 adult (age ≥18 years) patients with DHL/THL treated with ≥4 cycles of induction DA-EPOCH-R from 2014 to 2019 at six centers. A comprehensive multivariate analysis was performed. Survival outcomes for the entire cohort were comparable to historical estimates for DHL/THL treated with this regimen (median follow-up 27.9 months). Overall survival (OS) and progression-free survival (PFS) were not significantly associated with cumulative chemotherapy dose, dose escalation, or compliance with dose adjustment. Heterogeneous dosing practices were observed. Prospective investigation is warranted to evaluate the practice of dose adjustment of R-EPOCH for patients with DHL/THL.

Comprehensive genomic analyses of tumor biopsies from patients with newly-diagnosed germinal center B cell (GCB) diffuse large B cell/high grade B cell lymphoma (DLBCL/HGBL) have identified molecular subtypes predictive of inferior survival, which are characterized by somatic mutations that can be detected through clinical laboratory mutation analysis (CLMA). To determine the frequency and predictive value of individual genetic mutations associated with these experimentally-defined poor-risk subgroups, we reviewed the findings from CLMA performed on tumors from patients with newly-diagnosed GCB DLBCL/HGBL who were previously treated at our institution. CLMA was successfully performed on 58/59 patient tumor biopsies with a median turnaround time of 16 days, and 51 on which CLMA was routinely performed with adequate clinical follow-up were analyzed. Patients whose tumors demonstrated CREBBP mutation experienced a lower estimated rate of 2-year disease free survival (DFS) as compared to those whose tumors did not (45% [95% CI 18-68%] vs. 67% [95% CI 44-83%], P = 0.045). CREBBP mutations may be frequent and predict for inferior DFS in patients with newly-diagnosed GCB DLBCL/HGBL. Furthermore, CLMA may be practically-applied to translate experimental findings into those with more direct application to risk stratification and clinical trial design in subsets of patients with DLBCL/HGBL.

Introduction: Chimeric antigen receptor T-cell therapy (CAR T) is a revolutionary adoptive immunotherapy approach in lymphoma; however, substantial resources are necessary for administration and care of these patients. Our institution has administered tisagenlecleucel primarily in an outpatient setting, and here we report our clinical outcomes., Patients and Methods: We conducted a single institution, retrospective study investigating outcomes of adult lymphoma patients treated with commercial tisagenlecleucel between 10/2017 and 12/2020. We analyzed patient characteristics and outcomes of efficacy and safety including overall response rate, progression-free survival, overall survival and cytokine-release syndrome, neurotoxicity, and hospitalizations., Results: Seventy-two patients with relapsed or refractory non-Hodgkin lymphoma (NHL) who received commercial tisagenlecleucel were identified; 68 (94.4%) patients received outpatient tisagenlecleucel. The overall response rate was 43% with a complete response observed in 25 patients (34.7%). At a median follow-up of 9.1 months, the median progression-free survival was 3.3 months. Grade 3-4 cytokine release syndrome was not observed in the study group and two patients had grade 3-4 neurotoxicity. Twenty-six patients (36.1%) were admitted within 30 days after infusion with a median length of stay of 5 days. Fourteen patients (19.4%) were admitted within 72 hours of infusion. No patient died of CAR T cell-related toxicity., Conclusion: Our experience affirms treatment with tisagenlecleucel in the outpatient setting is safe and feasible with close supervision and adequate institutional experience. After infusion, adverse events were manageable and the majority of patients did not require hospitalization., (Copyright © 2022. Published by Elsevier Inc.)

CD19-directed chimeric antigen receptor-modified (CAR T) T cells achieve durable remissions in about 30% to 40% of relapsed/refractory large B-cell lymphomas. T-cell exhaustion and/or an immunosuppressive tumor microenvironment may contribute to CAR T-cell failure. Pembrolizumab, an anti-PD1 immune checkpoint inhibitor, may reverse T-cell exhaustion after CAR T-cell therapy. We treated 12 patients with B-cell lymphomas who were either refractory to (n = 9) or relapsed after (n = 3) CD19-directed CAR T-cell (4-1BB-costimulated) therapy with pembrolizumab 200 mg IV every 3 weeks. Median time from CAR T-cell infusion to first pembrolizumab dose was 3.3 months (range, 0.4-42.8 months). Pembrolizumab was well tolerated, and the only grade ≥3 adverse events related to pembrolizumab were neutropenia (n = 3; 25%). Best overall response rate after pembrolizumab was 25% (3 of 12 patients; 1 complete response; 2 partial responses). One (8%) patient had stable disease; thus, 4 of 12 (33%) patients had clinical benefit. After pembrolizumab, 4 patients with clinical benefit had an increase in percentage of CAR T cells by mass cytometry by time of flight (CyTOF); 3 of 4 of these patients also had increases in CAR19 transgene levels by quantitative polymerase chain reaction. Deep immune profiling using CyTOF revealed increased CAR T-cell activation and proliferation and less T-cell exhaustion in clinical responders. Together, PD1 blockade with pembrolizumab after CD19-directed CAR T-cell therapy appears safe and may achieve clinical responses in some patients with B-cell lymphomas refractory to or relapsed after CAR T-cell therapy. This trial was registered at www.clinicaltrials.gove as #NCT02650999., (© 2022 by The American Society of Hematology.)

Prophylaxis is commonly used to prevent central nervous sy stem (CNS) relapse in diffuse large B-cell lymphoma (DLBCL), with no clear standard of care. We retrospectively evaluated 1162 adult patients across 21 US academic centers with DLBCL or similar histologies who received single-route CNS prophylaxis as part of frontline therapy between 2013 and 2019. Prophylaxis was administered intrathecally(IT) in 894 (77%) and using systemic high-dose methotrexate (HD-MTX) in 236 (20%); 32 patients (3%) switched route due to toxicity and were assessed separately. By CNS-International Prognostic Index (IPI), 18% were considered low-risk, 51% moderate, and 30% high. Double-hit lymphoma (DHL) was confirmed in 243 of 866 evaluable patients (21%). Sixty-four patients (5.7%) had CNS relapse after median 7.1 months from diagnosis, including 15 of 64 (23%) within the first 6 months. There was no significant difference in CNS relapse between IT and HD-MTX recipients (5.4% vs 6.8%, P = .4), including after propensity score matching to account for differences between respective recipient groups. Weighting by CNS-IPI, expected vs observed CNS relapse rates were nearly identical (5.8% vs 5.7%). Testicular involvement was associated with high risk of CNS relapse (11.3%) despite most having lower CNS-IPI scores. DHL did not significantly predict for CNS relapse after single-route prophylaxis, including with adjustment for treatment regimen and other factors. This large study of CNS prophylaxis recipients with DLBCL found no significant difference in CNS relapse rates between routes of administration. Relapse rates among high-risk subgroups remain elevated, and reconsideration of prophylaxis strategies in DLBCL is of critical need., (© 2022 by The American Society of Hematology.)

Purpose: Patients weigh competing priorities when deciding whether to travel to a cellular therapy center for treatment. We conducted a choice-based conjoint analysis to determine the relative value they place on clinical factors, oncologist continuity, and travel time under different post-treatment follow-up arrangements. We also evaluated for differences in preferences by sociodemographic factors., Methods: We administered a survey in which patients with diffuse large B-cell lymphoma selected treatment plans between pairs of hypothetical options that varied in travel time, follow-up arrangement, oncologist continuity, 2-year overall survival, and intensive care unit admission rate. We determined importance weights (which represent attributes' value to participants) using generalized estimating equations., Results: Three hundred and two patients (62%) responded. When all follow-up care was at the center providing treatment, plans requiring longer travel times were less attractive ( v 30 minutes, importance weights [95% CI] of -0.54 [-0.80 to -0.27], -0.57 [-0.84 to -0.29], and -0.17 [-0.49 to 0.14] for 60, 90, and 120 minutes). However, the negative impact of travel on treatment plan choice was mitigated by offering shared follow-up (importance weights [95% CI] of 0.63 [0.33 to 0.93], 0.32 [0.08 to 0.57], and 0.26 [0.04 to 0.47] at 60, 90, and 120 minutes). Black participants were less likely to choose plans requiring longer travel, regardless of follow-up arrangement, as indicated by lower value importance weights for longer travel times., Conclusion: Reducing travel burden through shared follow-up may increase patients' willingness to travel to receive cellular therapies, but additional measures are required to facilitate equitable access., Competing Interests: Daniel J. LandsburgConsulting or Advisory Role: Celgene, MorphoSys, Karyopharm TherapeuticsResearch Funding: Takeda, Triphase Accelerator Group, CurisSpeakers' Bureau: Seattle Genetics Sunita D. NastaConsulting or Advisory Role: Merck, MorphoSysResearch Funding: Millenium, Incyte, Aileron Therapeutics, Debiopharm Group, Roche/Genentech, Atara Biotherapeutics, Rafael Pharmaceuticals Forty Seven, Pharmacyclics/Janssen Justin E. BekelmanConsulting or Advisory Role: UnitedHealthcareHonoraria: National Comprehensive Cancer Network, CVS Health, Optum, American Journal of Managed Care, PfizerResearch Funding: United Health Group, Blue Cross Blue Shield North Carolina, Embedded Healthcare Carmen E. GuerraLeadership: Freenome, Guardant Health, GenentechStock and Other Ownership Interests: Crispr Therapeutics, BEAM Therapeutics, Intellia Therapeutics, Editas MedicineConsulting or Advisory Role: Bristol Myers Squibb (I)Research Funding: Bristol Myers SquibbSpeakers' Bureau: Janssen (I), Pfizer (I)Travel, Accommodations, Expenses: Janssen (I), Lundbeck (I)Honoraria: Lundbeck (I)Uncompensated Relationships: Tapestry NetworksNo other potential conflicts of interest were reported.

Fimepinostat (CUDC-907), a first-in-class oral small-molecule inhibitor of histone deacetylase and phosphatidylinositol 3-kinase, demonstrated efficacy in a phase 1 study of patients with relapsed/refractory (R/R) diffuse large and high-grade B-cell lymphomas (DLBCL/HGBL), particularly those with increased MYC protein expression and/or MYC gene rearrangement/copy number gain (MYC-altered disease). Therefore, a phase 2 study of fimepinostat was conducted in this patient population with 66 eligible patients treated. The primary end-point of overall response (OR) rate for patients with MYC-IHC ≥40% (n = 46) was 15%. Subsequently, exploratory pooled analyses were performed including patients treated on both the phase 1 and 2 studies based upon the presence of MYC-altered disease as well as a biomarker identified by Virtual Inference of Protein activity by Enriched Regulon analysis (VIPER). For these patients with MYC-altered disease (n = 63), the overall response (OR) rate was 22% with seven responding patients remaining on treatment for approximately two years or longer, and VIPER yielded a three-protein biomarker classification with positive and negative predictive values of ≥85%. Prolonged durations of response were achieved by patients with MYC-altered R/R DLBCL/HGBL treated with single-agent fimepinostat. Combination therapies and/or biomarker-based patient selection strategies may lead to higher response rates in future clinical trials., (© 2021 British Society for Haematology and John Wiley & Sons Ltd.)

We conducted a phase I/II multicenter trial using 6 cycles of brentuximab vedotin (BV) in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) for treatment of patients with CD30-positive (+) B-cell lymphomas. Thirty-one patients were evaluable for toxicity and 29 for efficacy including 22 with primary mediastinal B-cell lymphoma (PMBCL), 5 with diffuse large B-cell lymphoma (DLBCL), and 2 with gray zone lymphoma (GZL). There were no treatment-related deaths; 32% of patients had non-hematological grade 3/4 toxicities. The overall response rate was 100% (95% CI: 88-100) with 86% (95% CI: 68-96) of patients achieving complete response at the end of systemic treatment. Consolidative radiation following end of treatment response assessment was permissible and used in 52% of all patients including 59% of patients with PMBCL. With a median follow-up of 30 months, the 2-year progression-free survival (PFS) and overall survival (OS) were 85% (95% CI: 66-94) and 100%, respectively. In the PMBCL cohort, 2-year PFS was 86% (95% CI: 62-95). In summary, BV-R-CHP with or without consolidative radiation is a feasible and active frontline regimen for CD30+ B-cell lymphomas (NCT01994850).

Importance: Treatment options for Sézary syndrome (SS) are limited and associated with low response rates. Brentuximab vedotin is a CD30-directed antibody-drug conjugate approved for refractory CD30-positive cutaneous T-cell lymphoma. However, limited data exist on its efficacy in SS, including in the pivotal phase 3 ALCANZA (A Phase 3 Trial of Brentuximab Vedotin (SGN-35) Versus Physician's Choice [Methotrexate or Bexarotene] in Participants With CD30-Positive Cutaneous T-Cell Lymphoma) trial., Objective: To assess the preliminary efficacy and tolerability of brentuximab vedotin for SS., Design, Setting, and Participants: From January 1, 2017, to July 31, 2020, a total of 13 patients with SS received brentuximab vedotin and were analyzed as part of a retrospective case series. Median follow-up was 10.4 months (range, 1.4-34.6 months). All patients were 18 years or older with a diagnosis of SS and with B2 blood involvement at the time brentuximab vedotin therapy was initiated. This single-center study was conducted at a major academic referral center., Interventions: Intravenous brentuximab vedotin administration approximately every 3 weeks., Main Outcomes and Measures: The primary end point was the global response rate. Outcomes were assessed in the skin and lymph nodes per the 2011 European Organization for Research and Treatment of Cancer-International Society of Cutaneous Lymphoma response criteria and in the blood per the 2018 Prospective Cutaneous Lymphoma International Prognostic Index revised blood response criteria., Results: The study included 13 patients (8 [62%] male; mean [SD] age, 68.2 [8.6] years). Of these 13 patients, 5 (38%) achieved a global response after a median of 6 cycles, including 1 complete response. Response rates by disease compartment were 38% in the skin, 63% in the blood, and 50% in the lymph nodes. Three of 11 patients (27%) with pruritus reported improvement. Skin CD30 positivity (>10%) was detected in 9 patients but was not associated with responses. Among responders, the median time to response was 6 weeks (range, 6-9 weeks), and the median duration of response was 5.5 months (range, 2.5-28.9 months). The median time to next treatment was 3.2 months (range, 1.5-36.7 months). Peripheral neuropathy occurred in 4 patients but resolved in 2 patients. Grade 2 adverse events were neuropathy (n = 2), constipation (n = 1), and hand-foot syndrome (n = 1)., Conclusions and Relevance: In this case series, brentuximab vedotin use was associated with some efficacy in SS across multiple disease compartments and in the setting of refractory disease or low CD30 skin expression. Brentuximab vedotin may offer a manageable treatment schedule and low incidence of significant toxic effects.

Given the poor prognosis of MYC-overexpressing diffuse large B cell lymphoma (DLBCL) and B cell lymphoma unclassifiable with features intermediate between DLBCL and Burkitt lymphoma/high grade B cell lymphoma (BCLU/HGBL), and preclinical data suggesting that MYC may regulate the antitumor immune response, we sought to characterize expression of immune checkpoint proteins on tumor tissue from patients diagnosed with these lymphomas. Immunohistochemical staining for immune checkpoint protein expression was applied to 56 cases of MYC-overexpressing DLBCL and BCLU/HGBL, 35 of which also harbored MYC rearrangement (MYC-R). Analysis revealed both frequent overexpression of immune checkpoint proteins as well as differences in overexpression patterns based upon MYC-R status, with MYC-R cases more likely to overexpress PD-L1 and PD-1 in the tumor microenvironment (50 vs. 15%, p = 0.02 and 32 vs. 5%, p = 0.02, respectively) but less likely to overexpress CTLA-4 and CD80 on tumor cells (34 vs. 71%, p = 0.01 and 34 vs. 81%, p = 0.001, respectively), as compared to cases without MYC-R. These data may suggest a biologic rationale for investigation of the effect of checkpoint inhibitor therapies in these subgroups of MYC-overexpressing DLBCL and BCLU/HGBL.

Purpose: Poor nutrition status in patients receiving high-dose chemotherapy and autologous stem cell transplant (ASCT) has been associated with inferior clinical outcomes. We aim to determine whether a malnutrition-driven nutritional support protocol can improve these outcomes., Methods: In this prospective cohort study, we assessed adults for malnutrition who were consecutively admitted for ASCT between October 2017 and March 2019 (n = 251), and provided enteral or parenteral nutrition (EN/PN) to patients who were malnourished early in the transplantation admission. We compared their clinical outcomes with those of a historical cohort admitted between May 2016 and October 2017 (n = 257) for whom nutrition assessment and initiation of EN/PN were not protocol-driven., Results: Patients receiving ASCT during the intervention period experienced decreased odds of prolonged hospital stay (p = 0.023), central line-associated bloodstream infection (p = 0.015), mucosal barrier injury (p = 0.037), and high weight loss (p = 0.002), in a multivariate analysis as compared with those receiving ASCT during the control period. Outcomes for ICU transfer, deconditioning on discharge, time to platelet engraftment, and unplanned 30-day hospital readmission did not differ significantly between groups., Conclusion: A malnutrition-driven nutritional support protocol may improve outcomes for ASCT patients.

Background: Outcomes in patients with relapsed/refractory (R/R) diffuse large b-cell lymphoma (DLBCL) who are ineligible for and/or fail high-dose chemotherapy and autologous stem cell transplantation in the second line are poor. There is no preferred palliative-intent treatment for patients in this setting., Patients and Methods: A retrospective cohort study was performed using the nationwide de-identified electronic health record-derived Flatiron Health database. Event-free survival (EFS) and overall survival (OS) was evaluated for patients with R/R DLBCL who were ineligible for and/or failed autologous stem cell transplantation in the second line and received bendamustine, gemcitabine, or lenalidomide., Results: Three hundred eighty-three patients were included. Therapy received was bendamustine in 158 patients, gemcitabine in 142 patients, and lenalidomide in 83 patients. The median EFS and OS for all patients was 4.1 months and 8.7 months, respectively. Compared with patients receiving bendamustine or gemcitabine, those receiving lenalidomide demonstrated significantly longer median EFS (6.8 vs. 3.8 months; P = .006) and median OS (15.4 vs. 7.7 months; P = .045). Survival outcomes were also improved for lenalidomide-treated patients specifically in the second- as well as third- or fourth-line settings., Conclusion: Use of lenalidomide resulted in prolonged EFS and OS as compared with bendamustine or gemcitabine in this cohort of patients with R/R DLBCL receiving palliative therapy. This first large-scale analysis of real-world outcomes for this patient population may guide current clinical management as well as serve as a benchmark for survival outcomes in the standard-of-care setting, which may aid in the design of future clinical trials., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: To describe long-term outcomes of anti-CD19 chimeric antigen receptor T (CART) cells in patients with relapsed or refractory chronic lymphocytic leukemia (CLL)., Methods: Between January 2013 and June 2016, 42 patients with relapsed or refractory CLL were enrolled in this study and 38 were infused with anti-CD19 CART cells (CART-19). Of these, 28 patients were initially randomly assigned to receive a low (5 × 10 7 ) or high (5 × 10 8 ) dose of CART-19, and 24 were evaluable for response assessment. After an interim analysis, 10 additional patients received the selected (high) dose and of these, eight were evaluable for response. Patients were followed for a median 31.5 months (range, 2 to 75 months)., Results: At 4 weeks, the complete and overall responses for the 32 evaluable patients were 28% (90% CI, 16% to 44%) and 44% (90% CI, 29% to 60%), respectively. The median overall survival (OS) for all patients was 64 months; there was no statistically significant difference between low- and high-dose groups ( P = .84). Regardless of dose, prolonged survival was observed in patients who achieved a CR versus those who did not ( P = .035), with median OS not reached in patients with CR versus 64 months in those without CR. The median progression-free survival was 40.2 months in patients with CR and 1 month in those without a CR ( P < .0001). Toxicity was comparable in both dose groups., Conclusion: In patients with advanced CLL, a 5 × 10 8 dose of CART-19 may be more effective than 5 × 10 7 CART-19 at inducing CR without excessive toxicity. Attainment of a CR after CART-19 infusion, regardless of cell dose, is associated with longer OS and progression-free survival in patients with relapsed CLL.

Purpose: CD19-targeting chimeric antigen receptor T-cell (CART) therapy has emerged as a promising treatment for relapsed/refractory aggressive B-cell lymphoma (r/rABL), culminating in 2 US Food and Drug Administration-approved therapies: tisagenlecleucel (tisa-cel) and axicabtagene ciloleucel (axi-cel). Following leukapheresis and in preparation for CART infusion, contemporary bridging and lymphodepletion regimens rely mostly on cytotoxic chemotherapy. Here, in a cohort of patients treated with commercial tisa-cel and axi-cel, we show that bridging-RT may offer a supplemental approach., Methods and Materials: Thirty-one patients receiving commercial tisa-cel (n = 13) or axi-cel (n = 18) between August 2018 and February 2019 for r/rABL were retrospectively reviewed. Patients were categorized into 2 groups: (1) bridging-RT within 30 days of CART infusion or (2) nonbridging-RT (NBRT), in which patients received either remote RT greater than 30 days before CART infusion or no prior RT., Results: Five patients received bridging-RT within 30 days of CART infusion. Median bridging-RT dose was 37.5 Gy and was completed a median of 13 days before infusion. No grade 3 (G3) or higher RT-toxicities occurred. No patients in the bridging-RT group experienced G3 or higher CART-related toxicities (CRS or neurotoxicity), and 23% (n = 6) and 15% (n = 4) experienced G3-5 CRS and G3-5 neurotoxicity in the NBRT group, respectively. Overall treatment response in the bridging-RT and NBRT groups was 80% and 64%, respectively. The axi-cel CART product was associated with CRS (odds ratio [OR] = 26.67, P = .001) and CRS correlated with neurotoxicity (OR = 12.22, P = .028). There was a trend toward an association for CRS with metabolic tumor volume (OR = 1.06/mL, P = .141) and TLG (OR = 1.01/mL x standard uptake value, P = .099)., Conclusions: Bridging-RT before commercial CART does not appear to increase the risk for CART-related toxicities or negatively affect outcomes in r/rABL patients. No G3 or higher RT-toxicities occurred in this series. Pretreatment metabolic tumor burden may be associated with CART-associated CRS; however, larger patient numbers are required to elucidate significant associations. Future work to prospectively assess the value of bridging-RT is warranted., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib has transformed the treatment of chronic lymphocytic leukemia (CLL), leading to unprecedented improvements in progression-free and overall survival for all patients, including those with poor prognostic features. The side effect profile of ibrutinib is unique compared with chemoimmunotherapy and includes atrial fibrillation, increased bleeding risk, and arthralgias/myalgias. Although common, arthralgias/myalgias and their management are poorly described., Patients and Methods: We identified 214 patients with CLL treated with ibrutinib (as a single agent or in combination) from 2011 to 2018 at the University of Pennsylvania., Results: In this cohort, 36% (76/214) of patients developed arthralgias/myalgias during follow-up with a median onset of 34.5 months. Most (79%) events were grade 1 or 2. Risk factors for developing arthralgias/myalgias included younger age at start of ibrutinib, female gender, and ibrutinib use as first treatment. Twenty-eight percent of patients with grade 1 or 2 toxicity continued ibrutinib and had resolution of symptoms. Dose holds were frequently used to manage this toxicity, and this strategy was more successful than dose reduction. Sixty-two percent of patients with grade 3 toxicity ultimately discontinued ibrutinib. Supportive care measures such as discontinuing statins or use of non-steroidal anti-inflammatory drugs, acetaminophen, or corticosteroids were not used frequently enough in this cohort to evaluate their efficacy., Conclusions: Additional studies to determine the mechanism of ibrutinib-related arthralgias/myalgias are needed to develop optimal management strategies., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Sinus histiocytosis with massive lymphadenopathy (Rosai Dorfman Disease [RDD]), is a rare, benign but clinically heterogeneous histiocytic disorder. Our aims were to analyze the clinical characteristics of the disease and explore the outcomes of patients with RDD followed at our institution. Between January 2000 and February 2019, there were 15 patients with a pathologically confirmed diagnosis of RDD. Median age at diagnosis was 48 years old (range 26-78). The majority (87%, n  = 13) of the patients had extranodal disease. Frontline approaches included surgical intervention/complete excision ( n  = 5, 33%), rituximab monotherapy ( n  = 5, 33%), observation ( n  = 3, 20%), and radiation ( n  = 2, 13%). Two of the five patients underwent surgical excision and were subsequently treated with rituximab. Of the 7 patients who were given rituximab, 64% remained progression free 24 months after the initial rituximab administration. Our review parallels previous reports and highlights rituximab as a favorable option for therapy if ineligible for surgery or radiation.

While patients with double-hit lymphoma (DHL) are now frequently treated with intensive front-line immunochemotherapy, outcomes for those who fail these regimens and subsequently receive curative-intent second-line immunochemotherapy are unknown. We identified 55 such patients who achieved an overall/complete response rate of 29%/11%, median progression-free/overall survival (PFS/OS) of 2/5·1 months and one-year PFS/OS of 10/19% following the start of second-line therapy. These outcomes may serve as a standard against which future second-line treatment strategies for relapsed/refractory DHL can be measured and justify investigation of non-cytotoxic therapies in the second-line setting for these patients., (© 2019 British Society for Haematology and John Wiley & Sons Ltd.)

The genetic and molecular abnormalities underlying histological transformation (HT) of nodal marginal zone lymphoma (NMZL) to diffuse large B-cell lymphoma (DLBCL) are not well known. While del(20q12) is commonly deleted in myelodysplastic syndrome it has not previously been associated with DLBCL. We recently described a case of DLBCL harboring del(20q12) in a patient with a history of MZL involving lymph nodes and skin. Here we report eight matched cases of transformed MZL(tMZL): six from nodal MZL (tNMZL) and two from splenic MZL (tSMZL). We found >20% del(20q12) in 4/6 tNMZL, but not in tSMZL, nor in unmatched DLBCL, MZL with increased large cells (MZL-ILC), or MZL cases. To examine whether transformation is associated with a specific gene signature, the matched cases were analyzed for multiplexed gene expression using the Nanostring PanCancer Pathways panel. The differential gene expression signature revealed enrichment of inflammatory markers, as previously observed in MZL. Also, tMZL and de novo DLBCL were enriched for extracellular matrix proteins such as collagen and fibronectin, vascular development protein PDGFRβ, DNA repair protein RAD51, and oncogenic secrete protein Wnt11. A subset of genes is expressed differentially in del(20q12) tMZL cases vs non-del(20q12) tMZL cases. These results suggest a specific pathway is involved in the histological transformation of NMZL, which could serve as an indicator of aggressive clinical course in this otherwise indolent neoplasm., (© 2019 Wiley Periodicals, Inc.)

There is a paucity of data regarding outcomes and response to standard therapy in patients with limited-stage (LS) agressive B-cell lymphoma (LS-ABCL) who harbor MYC rearrangement (MYC-R) with or without BCL2 and/or BCL6 rearrangements. We conducted a multicenter retrospective study of MYC-R LS-ABCL patients who received either rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), or more intensive immunochemotherapy (IIC) plus or minus consolidative involved-field radiation therapy (IFRT). One hundred four patients from 15 academic centers were included. Forty four patients (42%) received R-CHOP, of whom 52% had IFRT. Sixty patients (58%) received IIC, of whom 40% had IFRT. Overall response rate was 91% (84% complete response [CR]; 7% partial response). Patients with double-hit lymphoma (DHL; n = 40) had a lower CR rate compared with patients with MYC-R only (75% vs 98%; P = .003). CR rate was higher in the IFRT vs no-IFRT group (98% vs 72%; P < .001). Median follow-up was 3.2 years; 2-year progression-free survival (PFS) and overal survival (OS) were 78% and 86% for the entire cohort, and 74% and 81% for the DHL patients, respectively. PFS and OS were similar across treatment groups (IFRT vs no IFRT, R-CHOP vs IIC) in the entire cohort and in DHL patients. Our data provide a historical benchmark for MYC-R LS-ABCL and LS-DHL patients and show that outcomes for this population may be better than previously recognized. There was no benefit of using IIC over R-CHOP in patients with MYC-R LS-ABCL and LS-DHL., (© 2020 by The American Society of Hematology.)

Background: Salvage immunochemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation is the standard-of-care second-line treatment for patients with relapsed/refractory diffuse large B-cell lymphoma after first-line R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). Outcomes after receipt of second-line immunochemotherapy in patients with aggressive B-cell lymphomas who relapse or are refractory to intensive first-line immunochemotherapy regimens (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab [R-EPOCH], rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and cytarabine [R-HyperCVAD], rituximab, cyclophosphamide, vincristine, doxorubicin, and high-dose methotrexate alternating with ifosfamide, etoposide, and cytarabine [R-CODOX-M/IVAC]) remain unknown., Methods: Outcomes of patients with non-Burkitt, aggressive B-cell lymphomas and relapsed/refractory disease after first-line treatment with intensive immunochemotherapy regimens who received platinum-based second-line immunochemotherapy were reviewed retrospectively. Analyses were performed to determine progression-free survival (PFS) and overall survival (OS) from the time of receipt of second-line immunochemotherapy., Results: In total, 195 patients from 19 academic centers were included in the study. The overall response rate to second-line immunochemotherapy was 44%, with a median PFS of 3 months and a median OS of 8 months. Patients with early treatment failure (primary refractory or relapse <12 months from completion of first-line therapy) experienced inferior median PFS (2.8 vs 23 months; P < .001) and OS (6 months vs not reached; P < .001) compared with patients with late treatment failure. Although the 17% of patients with early failure who achieved a complete response to second-line immunochemotherapy experienced prolonged survival, this outcome could not be predicted by clinicopathologic features at the start of second-line immunochemotherapy., Conclusions: Patients with early treatment failure after intensive first-line immunochemotherapy experience poor outcomes after receiving standard second-line immunochemotherapy. The use of standard-of-care or experimental therapies currently available in the third-line setting and beyond should be investigated in the second-line setting for these patients., (© 2019 American Cancer Society.)

Diffuse large B-cell lymphoma (DLBCL) transformed from follicular lymphoma (FL) (tDLBCL) has been traditionally associated with an aggressive course, but more recent studies have shown longer survivals. The clinical significance of concurrent FL at the time of diagnosis of DLBCL (cDLBCL/FL) is less clear. We compared outcomes of tDLBCL, cDLBCL/FL, and de novo DLBCL (dDLBCL) and then evaluated the impact of double hit (DH) rearrangements (MYC with BCL2 and/or BCL6) in these subgroups' outcomes. The progression free survival (PFS) and overall survival (OS) were not significantly different among the three groups (dDLBCL, tDLBCL, and cDLBCL/FL). The effect of DH on survival was then analyzed in two subgroups: (1) dDLBCL and (2) tDLBCL + cDLBCL/FL. PFS and OS were significantly shorter in lymphomas with DH in each of these two subgroups. We conclude that DH status drives outcomes in all DLBCLs, regardless of their transformation status.

Introduction: Venetoclax is a highly effective agent in chronic lymphocytic leukemia and acute myeloid leukemia. Phase I/II clinical trials have shown it to be safe and effective in non-Hodgkin lymphoma (NHL). Adverse events were consistent with package labeling despite escalation to high doses. To the best of our knowledge, venetoclax use outside the setting of a clinical trial of NHL has not been reported., Patients and Methods: We conducted a single-center, retrospective study of 34 adult patients who had been treated off-label with venetoclax-containing regimens from 2016 to 2018., Results: Of the 34 patients with NHL treated with venetoclax therapy, 13 had had high-grade B-cell lymphoma/diffuse large B-cell lymphoma, 10 mantle cell lymphoma, 5 transformed follicular lymphoma, 2 Richter transformation, 2 marginal zone lymphoma, 1 follicular lymphoma, and 1 post-transplant lymphoproliferative disorder. The patients had received a median of 4 previous therapies. The overall response rate was 26% (3% with a complete response and 35% with stable disease). The median venetoclax dose achieved was 400 mg. Of those receiving combination therapy, 18% had undergone radiation and 62% had received other systemic antineoplastic therapy. The median progression-free and overall survival for the cohort was 2 and 4.5 months, respectively. Adverse events occurred in 76% of the patients during venetoclax therapy. The adverse events included neutropenia, thrombocytopenia, tumor lysis syndrome, infection, neutropenic fever, diarrhea, and 1 opportunistic infection., Conclusion: Venetoclax therapy in a real-world cohort offered modest benefits in heavily pretreated patients. Adverse events were observed at a greater incidence than in the clinical trials. A wide heterogeneity of venetoclax dose escalation, multiagent combinations, and timing of initiation were identified and require investigation in subsequent clinical trials., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Although classical Hodgkin lymphoma (cHL) is highly curable, 20%-30% of patients will not be cured with conventional treatments. The programmed death-1 (PD-1) inhibitors (PD-1i) nivolumab and pembrolizumab have been Food and Drug Administration-approved for relapsed/refractory (R/R) cHL. There is limited data on the real-world experience with PD-1i in cHL and it is unknown whether fewer selected patients treated with PD-1i derive benefits similar to those observed in published trials., Materials and Methods: We performed a multicenter, retrospective analysis of R/R cHL patients treated with PD-1i in the nontrial setting. The primary objective was to describe progression-free survival (PFS) and overall survival (OS) in this population. Secondary objectives were to characterize response rates, toxicities, discontinuation patterns, and post-PD-1i therapies., Results: The study included 53 patients from nine U.S. centers. Overall response rate (ORR), complete response (CR), and partial response (PR) to PD-1i were 68%, 45%, and 23%, respectively. Twelve-month OS and PFS were 89% and 75%, respectively; median PFS was 29 months. Ninety-six percent of patients with CR continue to respond at a median follow-up of 20 months. Toxicities were similar to those previously described. Seventy percent of patients treated with systemic therapy after PD-1i demonstrated objective responses., Conclusion: To our knowledge, this analysis is the first describing real-world experience with PD-1i in cHL patients in the U.S. Here, we demonstrate similar response rates compared to prior studies. The toxicity profile of PD-1i was similar to that seen in previous studies; we further describe toxicity patterns in those with prior autoimmune disease or allogeneic transplant. Post-PD-1i systemic therapies appear active. These results support the effectiveness and tolerability of PD-1i therapy in R/R cHL in a real-world setting., Implications for Practice: Two PD-1 inhibitors have recently been approved for patients with relapsed/refractory classical Hodgkin lymphoma based on results from nonrandomized clinical trials. However, to date, there have been no studies evaluating the effectiveness and toxicity profile of these drugs in the real-world setting in the U.S. The present study demonstrates that patients treated in a real-world context experience similar rates of overall effectiveness compared with published clinical trials. Patients who discontinue PD-1 inhibitors may experience clinical responses to subsequent treatment with systemic chemotherapy or targeted therapy. This study provides clinicians with further insight into the effectiveness and tolerability of PD-1 inhibitors and suggests that when patients progress while on these drugs, conventional systemic chemotherapy may be an effective treatment option., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2018.)

Introduction: Autologous stem cell transplantation (ASCT) patients are at risk for malnutrition before transplantation admission as well as malnutrition acquired during their transplantation admission., Patients and Methods: In this retrospective, observational study we examined data related to consecutive adults (n = 330) admitted for ASCT between 2014 and 2016 at the Hospital of the University of Pennsylvania. Malnutrition risk on admission (identified by the Malnutrition Screening Tool) and transplantation-associated weight loss were analyzed for independent associations with hospital length of stay, nosocomial infection, intensive care unit transfer, deconditioning, time to platelet and neutrophil engraftment, 30-day readmission, and 1-year mortality., Results: Adults with high malnutrition risk (n = 60) had a longer median hospital stay (P = .004), longer median time to platelet engraftment (P = .022), increased nosocomial infections (P = .047), and increased 1-year mortality (P = .036). Adults with high transplantation-associated weight loss (n = 100) experienced longer hospital stays (P < .001) and more intensive care unit transfers (P = .001). Outcomes for deconditioning, time to neutrophil engraftment, and 30-day readmission did not differ significantly on the basis of nutrition risk or weight loss., Conclusion: Further research is needed to determine whether early nutrition intervention would improve these outcomes., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Idiopathic acquired aplastic anemia (AA) is a rare lymphocyte-mediated bone marrow aplasia. No specific mechanisms or triggers of AA have been identified. We recently observed several patients who developed AA after Hodgkin lymphoma (HL). We hypothesized that the co-occurrence of HL and AA is not random and may be etiologically significant. To test this hypothesis, we determined the incidence of AA in HL patients at our institution. We identified four patients with co-occurring HL and AA, with the incidence of AA in HL patients >20-fold higher compared to the general population. We identified 12 additional patients with AA and HL through a systematic literature review. Of the 16 total patients,15 (93.8%) developed AA after or concurrent with a HL diagnosis. None of the patients had marrow involvement by HL. Five of 15 patients were in complete remission from HL at the time of AA diagnosis, and six had a concurrent presentation with no prior cytotoxic therapy, with diagnostic timeframe information unavailable for four patients. The median interval between HL diagnosis and AA onset was 16 months, ranging from concurrent to 14 years after a HL diagnosis. The median survival after AA diagnosis was 14 months (range: 1 month to 20 years). Our results show that patients with HL have a higher incidence of AA compared to the general population and suggest that HL-related immune dysregulation may be a risk factor for AA. Better recognition and management of AA in HL patients is needed to improve outcomes in this population., Competing Interests: The authors have declared that no competing interests exist.

Purpose: Mantle cell lymphoma (MCL) is a B-cell lymphoma characterized by cyclin D1 expression. Autologous hematopoietic cell transplantation (AHCT) consolidation after induction chemotherapy is often used for eligible patients; however, the benefit remains uncertain in the rituximab era. Herein we retrospectively assessed the impact of AHCT consolidation on survival in a large cohort of transplantation-eligible patients age 65 years or younger., Patients and Methods: We retrospectively studied transplantation-eligible adults age 65 years or younger with newly diagnosed MCL treated between 2000 and 2015. The primary objective was to assess for improved progression-free survival (PFS) with AHCT consolidation and secondarily to assess for improved overall survival (OS). Cox multivariable regression analysis and propensity score-weighted (PSW) analysis were performed., Results: Data were collected from 25 medical centers for 1,254 patients; 1,029 met inclusion criteria. Median follow-up for the cohort was 76 months. Median PFS and OS were 62 and 139 months, respectively. On unadjusted analysis, AHCT was associated with improved PFS (75 v 44 months with v without AHCT, respectively; P < .01) and OS (147 v 115 months with v without AHCT, respectively; P < .05). On multivariable regression analysis, AHCT was associated with improved PFS (hazard ratio [HR], 0.54; 95% CI, 0.44 to 0.66; P < .01) and a trend toward improved OS (HR, 0.77; 95% CI, 0.59 to 1.01; P = .06). After PSW analysis, AHCT remained associated with improved PFS (HR, 0.70; 95% CI, 0.59 to 0.84; P < .05) but not improved OS (HR, 0.87; 95% CI, 0.69 to 1.1; P = .2)., Conclusion: In this large cohort of younger, transplantation-eligible patients with MCL, AHCT consolidation after induction was associated with significantly improved PFS but not OS after PSW analysis. Within the limitations of a retrospective analysis, our findings suggest that in younger, fit patients, AHCT consolidation may improve PFS.

Purpose of Review: Diffuse large B cell lymphoma (DLBCL) remains the most common non-Hodgkin lymphoma (NHL) in developed countries. Up to 30-40% of patients experience either refractory or relapsed disease following receipt of front-line chemoimmunotherapy, and the majority of these patients will not be cured following receipt of subsequent therapy., Recent Findings: Small-molecule inhibitors (SMIs) are an attractive class of therapeutics for patients with chemorefractory DLBCL, and early-phase studies with these agents have typically demonstrated prolonged periods of disease control in responding patients without significant toxicity. Later-phase studies have investigated the combination of SMIs with cytotoxic agents in hopes that exposure to SMIs in the treatment course may improve outcomes for patients who would otherwise develop chemorefractory disease. SMIs appear to be effective in the treatment of DLBCL. A greater understanding of the molecular features of cases of DLBCL will allow for the more rational and presumably successful utilization of these targeted agents.

Background: Patients with a diagnosis of MYC-rearranged non-Burkitt aggressive B-cell lymphoma (MYC-R), including those with double hit lymphoma, are at high risk of developing relapsed/refractory disease, even if treated with intensive front-line immunochemotherapy. It is common in clinical practice and clinical trials to perform an interim positron emission tomography (PET)/computed tomography (CT) scan (iPET) during front-line therapy for diffuse large B-cell lymphoma. However, the utility of the iPET result for MYC-R patients for predicting outcomes is unclear., Patients and Methods: We performed a single-center retrospective study with centralized pathologic review and PET/CT image acquisition and interpretation for 28 MYC-R patients. The patients received front-line therapy with R-CHOP (rituximab, cyclophosphamide, hydroxydaunorubicin [doxorubicin], Oncovin [vincristine], prednisone) or intensive immunochemotherapy., Results: Eight patients had iPET-positive (iPET + ) and 20 patients had iPET-negative (iPET - ) results using the Deauville visual assessment criteria. At a median follow-up length of 30.4 months, progression-free survival was 65% and overall survival was 76%, neither of which differed significantly between the iPET - and iPET + patients. The positive predictive value of iPET for progression at 30 months was 25%, and the negative predictive value was 65%., Conclusion: Although patients with MYC-R lymphoma have been reported to be at high risk of primary treatment failure, this was not predicted by iPET + results. Thus, the iPET result should not be used to guide changes in front-line or consolidative therapy for these patients., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Chimeric antigen receptor (CAR)-modified T cells are being investigated in many settings, including classical Hodgkin lymphoma (cHL). The unique biology of cHL, characterized by scant Hodgkin and Reed-Sternberg (HRS) cells within an immunosuppressive tumor microenvironment (TME), may pose challenges for cellular therapies directly targeting antigens expressed on HRS cells. We hypothesized that eradicating CD19 + B cells within the TME and the putative circulating CD19 + HRS clonotypic cells using anti-CD19-directed CAR-modified T cells (CART19) may indirectly affect HRS cells, which do not express CD19. Here we describe our pilot trial using CART19 in patients with relapsed or refractory cHL. To limit potential toxicities, we used nonviral RNA CART19 cells, which are expected to express CAR protein for only a few days, as opposed to CART19 generated by viral vector transduction, which expand in vivo and retain CAR expression. All 5 enrolled patients underwent successful manufacturing of nonviral RNA CART19, and 4 were infused with protocol-specified cell dose. There were no severe toxicities. Responses were seen, but these were transient. To our knowledge, this is the first CART19 clinical trial to use nonviral RNA gene delivery. This trial was registered at www.clinicaltrials.gov as #NCT02277522 (adult) and #NCT02624258 (pediatric)., (© 2018 by The American Society of Hematology.)