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A PET/CT was performed after 8 cycles, and pts in CR were observed without further treatment. B Introduction: b Mosunetuzumab (mosun) is a CD3:CD20 bispecific antibody that has been FDA-approved for relapsed/refractory follicular lymphoma after two prior lines of therapy. Response-adapted mosunetuzumab for untreated follicular and marginal zone lymphomas: significant monotherapy activity seen in results of an interim efficacy analysis. [Extracted from the article]

Background: We previously reported in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) treated with immune checkpoint inhibitors (ICIs), pretreatment higher lactate dehydrogenase (LDH) and absolute (abx) neutrophils as well as lower percent (%) lymphocytes correlated with worse overall survival (OS). In this study we aimed to develop a prognostic signature for HNSCC treated with ICIs using these peripheral blood biomarkers (PBBMs)., Methods: Adults with R/M HNSCC treated with ICIs at our institution from 08/2012 to 03/2021 with pretreatment PBBMs were included. Follow-up continued until 02/15/2022. The cohort (n = 151) was randomly split into training (n = 100) and testing (n = 51) datasets. A prognostic score incorporating LDH, % lymphocytes, and abx neutrophils was developed from the training dataset using Cox proportional hazards regression. In the training dataset, a grid search identified the optimal cutpoints classifying patients into high, medium, and low-risk groups (trichotomized signature) as well as high vs. low-risk groups (dichotomized signature). The prognostic score, dichotomized and trichotomized signatures were then validated in the testing dataset., Results: Training and testing datasets showed no clinically meaningful differences in clinicodemographic characteristics or PBBMs. An OS prognostic model was developed from the training dataset: Risk score = 1.24*log10(LDH) - 1.95*log10(% lymphocytes) + 0.47*log10(abx neutrophils). Optimal risk score cutpoints for the dichotomized and trichotomized signatures were defined in the training dataset, and Kaplan-Meier curves for both dichotomized and trichotomized signatures showed good separation between risk groups. Risk scores were calculated in the testing dataset, where the trichotomized signature demonstrated overlap between low and medium-risk groups but good separation from the high-risk group while the dichotomized signature showed clear separation between low and high-risk groups. Higher risk score correlated with worse OS (HR 2.08, [95%CI 1.17-3.68], p = 0.012). Progression-free survival Kaplan-Meier curves likewise showed excellent separation between dichotomized risk groups in the training and testing datasets., Conclusions: We developed a prognostic signature for OS based on 3 previously identified PBBMs for HNSCC treated with ICIs and identified a high-risk group of patients least likely to have survival benefit from ICIs. This signature may improve ICI patient selection and warrants validation in an independent cohort as well as correlation with CPS., Competing Interests: Declarations Ethics approval and consent to participate This study was reviewed and approved by the Fred Hutchinson Cancer Research Institutional Review Board (IRB ID: STUDY00007717). The requirement to obtain informed consent was waived. Consent for publication Not applicable. Competing interests Conflict of Interest Disclosures: Dr. Futran reported educational consultancy role for Stryker Corporation. Dr. Rodriguez reported receipt of institutional research funding from AstraZeneca, Ayala, Bristol Myers Squibb, Ignyta, and Merck, and reported advisory board membership for Cue Biopharma. The other authors declare no potential conflicts of interest., (© 2024. The Author(s).)

Background: Receipt of chimeric antigen receptor T-cell (CAR-T) therapy at an institution different from the primary oncologist's institution is a complex, multistep process. Referral by oncologists plays an important role in the process but may be susceptible to bias., Methods: Oncologists who previously referred patients for CAR-T therapy at 5 pediatric hospitals were sent surveys by email exploring their CAR-T referral practices. Descriptive statistics were generated, and multivariate analyses examined associations among oncologist characteristics, familiarity with CAR-T therapy, and referral practices. We conducted semistructured interviews with a subset of participants and used thematic analysis to code transcripts., Results: Sixty-eight oncologists completed the survey; 77% expressed being "very familiar" with CAR-T therapy. Hispanic oncologists and oncologists at institutions with 50 or fewer new diagnoses per year were more likely to identify as less familiar with CAR-T therapy (odds ratio [OR] = 64.3, 95% confidence interval [CI] = 2.45 to 10 452.50, P = .04 and OR = 24.5, 95% CI = 3.3 to 317.3, P = .005, respectively). In total, 38% of respondents considered nonclinical features (compliance, social support, resources, insurance, language, education, and race or ethnicity) influential in referral decisions. Oncologists who were Hispanic and oncologists who had been practicing for 20 or more years were more likely to consider these features significantly influential (OR = 14.52, 95% CI = 1.49 to 358.66, P = .04 and OR = 6.76, 95% CI = 1.18 to 50.5, P = .04). Nine oncologists completed in-depth interviews; common themes included barriers and concerns regarding CAR-T therapy referral, the value of an established relationship with a CAR-T therapy center, and poor communication after CAR-T therapy., Conclusions: Nearly 40% of oncologists consider nonclinical features significantly influential when deciding to refer patients for CAR-T therapy, raising concern for bias in the referral process. Establishing formal partnerships with CAR-T therapy centers may help address physician barriers in referral., (© The Author(s) 2024. Published by Oxford University Press.)

Abstract: Although Bruton tyrosine kinase inhibitors (BTKis) are generally well tolerated and less toxic than chemotherapy alternatives used to treat lymphoid malignancies, BTKis like ibrutinib have the potential to cause new or worsening hypertension (HTN). Little is known about the optimal treatment of BTKi-associated HTN. Randomly selected patients with lymphoid malignancies on a BTKi and antihypertensive drug(s) and with at least 3 months of follow-up data were sorted into 2 groups: those diagnosed with HTN before BTKi initiation (prior-HTN), and those diagnosed with HTN after BTKi initiation (de novo HTN). Generalized estimating equations assessed associations between time varying mean arterial pressures (MAPs) and individual anti-HTN drug categories. Of 196 patients included in the study, 118 had prior-HTN, and 78 developed de novo HTN. Statistically significant mean MAP reductions were observed in patients with prior-HTN who took β blockers (BBs) with hydrochlorothiazide (HCTZ), (-5.05 mmHg; 95% confidence interval [CI], 10.0 to -0.0596; P = .047), and patients diagnosed with de novo HTN who took either an angiotensin converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) with HCTZ (-5.47 mmHg; 95% CI, 10.9 to -0.001; P = .05). These regimens also correlated with the greatest percentages of normotensive MAPs. Treatment of HTN in patients taking a BTKi is challenging and may require multiple antihypertensives. Patients with prior-HTN appear to benefit from combination regimens with BBs and HCTZ, whereas patients with de novo HTN appear to benefit from ACEi/ARBs with HCTZ. These results should be confirmed in prospective studies., (© 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.)

Background: While generally ineffective in relapsed diffuse large B cell lymphoma (DLBCL), immune checkpoint inhibitors (ICIs) may hold greater promise in untreated, immunocompetent patients. We previously reported safety and early efficacy of pembrolizumab plus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (PR-CHOP) in a phase I trial of untreated DLBCL, noting responses in 90% of patients (complete response 77%) and a 2-year progression-free survival (PFS) of 83%. We herein report long-term safety and efficacy at 5-year follow up., Patients and Methods: Adult patients with untreated DLBCL or grade 3b follicular lymphoma, intended to receive 6 cycles of R-CHOP were eligible. Patients (N = 30) were treated with pembrolizumab 200 mg IV and R-CHOP in 21-day cycles for 6 cycles., Results: At median follow up of 4.8 years, 5-year PFS was 71% (CI, 54%-94%) and 5-year overall survival was 83% (CI, 71%-98%). Immune-related adverse events (IRAEs) occurred in 7 (23%) patients (10% grade 3/4). Three IRAEs (rash, thyroiditis, rheumatoid arthritis) occurred beyond 3 months of treatment completion. PD-L1 tumor expression was documented in 19 of 23 (83%) tested patients. None of the 19 patients who had any PD-L1 expression have relapsed, whereas 2 out of the 4 patients with no PD-L1 expression have relapsed., Conclusion: PR-CHOP has led to durable responses in most patients, with the best outcomes in PD-L1-expressing disease. Furthermore, the safety profile was manageable, with no consistent pattern of late events. These data support ongoing strategies incorporating ICIs in frontline DLBCL therapy and confirmation of predictive biomarkers including tumor PD-L1 expression., Competing Interests: Disclosure A.K.G. reports consultancy/honoraria from Pfizer, Seagen, Janssen Oncology, Millennium, Gilead Sciences, Nurix, Cellectar, Kite/Gilead, Morphosys/Incyte, I-Mab, TG Therapeutics, Pfizer, ADC therapeutics, Amgen, Actinium Pharmaceuticals, Takeda, Epizyme, and Merck; research funding from Merck, Bristol-Myers Squibb, Gilead Sciences, Seagen, Teva, Pfizer, Janssen Oncology, Millennium, IgM, I-Mab, Takeda, and AstraZeneca. B.G.T. reports consultancy at Mustang Bio and Proteios Technology; patents and royalties at Mustang Bio; and research funding from Mustang Bio and BMS/Celgene/Juno. M.S. reports consultancy from AbbVie, Genentech, AstraZeneca, Sound Biologics, Cellectar, Pharmacyclics, BeiGene, Bristol-Myers Squibb, Morphosys/Incyte, Innate Pharma, Kite Pharma, Adaptive Biotechnologies, Epizyme, Fate Therapeutics, Lilly, Regeneron, Adaptimmune, MustangBio, TG Therapeutics, and MEI Pharma; research funding from Pharmacyclics, Acerta Pharma, Merck, TG Therapeutics, BeiGene, Celgene, Genentech, MustangBio, AbbVie, Sunesis, Bristol-Myers Squibb, Genmab, and Vincerx. A.J.C reports consultancy from Doximity, Sanofi, Cellectar, AbbVie, Secura Bio, Janssen, Bristol-Myers Squibb/Celgene/Juno; research funding from Bristol-Myers Squibb, Janssen, AbbVie, Celgene, Nektar, Adaptive Biotechnologies, and Harpoon Therapeutics; has stock in Doximity. R.C.L. reports consultancy from Foresight Diagnostics and Seagen; research funding from Cyteir, Bayer, TG Therapeutics, Genentech, Seagen, and RAPT Therapeutics. C.S.U. reports consultancy/honoraria from AstraZeneca, Epizyme, Atara Biotherapeutics, Pharmacyclics, AbbVie, Genentech, Janssen, Incyte, BeiGene, and Lilly; research funding from Pharmacyclics, AbbVie, Lilly, AstraZeneca/MedImmune, Adaptive Biotechnologies, and Gilead. R.D.C. reports consultancy/honoraria from Amgen, Kite/Gilead, Jazz Pharmaceuticals, and Pfizer; research funding from Amgen, Pfizer, Vanda Pharmaceuticals, Servier, Kite, and Incyte; has reported membership on the boards or advisory committees for Autolus and PeproMene Bio; and spouse-owned stock in Seagen. S.D.S. reports consultancy from AstraZeneca, Karyopharm Therapeutics, Kite, Incyte, ADC Therapeutics, BeiGene, AbbVie, Coherus Biosciences (immediate family member), Epizyme, and Numab; research funding from Acerta Pharma/AstraZeneca, Ayala Pharmaceuticals (immediate family member), Bristol-Myers Squibb (immediate family member), Bayer, Denovo Biopharma, Genentech, Ignyta (immediate family member), Incyte, Merck, Portola Pharmaceuticals, BeiGene, ADC Therapeutics, Enterome, Kymera, MorphoSys/Incyte, Nanjing, Portola Pharmaceuticals/Alexion Pharmaceuticals, and Viracta Therapeutics. All other authors declare no competing financial interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: γ-Secretase inhibitors (GSIs) increase B cell maturation antigen (BCMA) density on malignant plasma cells and enhance antitumour activity of BCMA chimeric antigen receptor (CAR) T cells in preclinical models. We aimed to evaluate the safety and identify the recommended phase 2 dose of BCMA CAR T cells in combination with crenigacestat (LY3039478) for individuals with relapsed or refractory multiple myeloma., Methods: We conducted a phase 1, first-in-human trial combining crenigacestat with BCMA CAR T-cells at a single cancer centre in Seattle, WA, USA. We included individuals aged 21 years or older with relapsed or refractory multiple myeloma, previous autologous stem-cell transplant or persistent disease after more than four cycles of induction therapy, and Eastern Cooperative Oncology Group performance status of 0-2, regardless of previous BCMA-targeted therapy. To assess the effect of the GSI on BCMA surface density on bone marrow plasma cells, participants received GSI during a pretreatment run-in, consisting of three doses administered 48 h apart. BCMA CAR T cells were infused at doses of 50 × 10 6 CAR T cells, 150 × 10 6 CAR T cells, 300 × 10 6 CAR T cells, and 450 × 10 6 CAR T cells (total cell dose), in combination with the 25 mg crenigacestat dosed three times a week for up to nine doses. The primary endpoints were the safety and recommended phase 2 dose of BCMA CAR T cells in combination with crenigacestat, an oral GSI. This study is registered with ClinicalTrials.gov, NCT03502577, and has met accrual goals., Findings: 19 participants were enrolled between June 1, 2018, and March 1, 2021, and one participant did not proceed with BCMA CAR T-cell infusion. 18 participants (eight [44%] men and ten [56%] women) with multiple myeloma received treatment between July 11, 2018, and April 14, 2021, with a median follow up of 36 months (95% CI 26 to not reached). The most common non-haematological adverse events of grade 3 or higher were hypophosphataemia in 14 (78%) participants, fatigue in 11 (61%), hypocalcaemia in nine (50%), and hypertension in seven (39%). Two deaths reported outside of the 28-day adverse event collection window were related to treatment. Participants were treated at doses up to 450 × 10 6 CAR + cells, and the recommended phase 2 dose was not reached., Interpretations: Combining a GSI with BCMA CAR T cells appears to be well tolerated, and crenigacestat increases target antigen density. Deep responses were observed among heavily pretreated participants with multiple myeloma who had previously received BCMA-targeted therapy and those who were naive to previous BCMA-targeted therapy. Further study of GSIs given with BCMA-targeted therapeutics is warranted in clinical trials., Funding: Juno Therapeutics-a Bristol Myers Squibb company and the National Institutes of Health., Competing Interests: Declaration of interest AJC receives research funding from Juno Therapeutics—a Bristol Myers Squibb company, Nektar, Janssen, Abbvie, Harpoon, Sanofi, Adaptive Biotechologies, and Celgene; is a consultant for Adaptive Biotechnologies, Bristol Myers Squibb, and Abbvie; and receives payment for presentations from Curio Science, DAVA Oncology, and MJH Life Sciences. XS receives research funding from Juno Therapeutics—a Bristol Myers Squibb company. MJP is a consultant for SpringWorks Therapeutics, owns stock or has stock options in Lyell Immunopharma, and is currently employed by CellPoint. CJT receives research funding from Bristol Myers Squibb; has right to receive payments from royalties for inventions licensed to third parties, including Bristol Myers Squibb; is a consultant for Caribou, Myeloid Therapeutics, Precision Biosciences, Arsenal Bio, Century Therapeutics, Allogene, Legend Bio, Nektar, Syncopation Life Sciences, Sobi, Expert Connect, Decheng Capital, Asher Bio, Genentech, and Amgen; has received payment for presentations from St Judes, Malaysian Society for Hematology, Japan Society for Transplantation and Cell Therapy, and Bristol Myers Squibb; and has stock or stock options in Caribou, Myeloid Therapeutics, Precision Biosciences, Arsenal bio, and Eureka Therapeutics. BGT receives research funding from Bristol Myers Squibb; royalties from Mustang Bio; has patents with Mustang Bio; participates on a data safety monitoring board with Mustang Bio and Proteios Technology; and has stock or stock options with Proteios Technology. ENL has research funding from GSK, Celgene, Amgen, Genentech, Beigene, and Seattle Genetics and has received payment for presentations from Curio Science, Janssen, and Pharmacyclics. SAT has stock or stock options in Bristol Myers Squibb and is a current employee of Juno Therapeutics—a Bristol Myers Squibb company. BW has research funding from Amgen, Novartis, Kite, Beam, Wugen, and Biosight and receives payment for lectures from Amgen. MS receives research funding from Mustang Bio, Bristol Myers Squibb, Pharmacyclics, Genentech, Abbvie, TG Therapeutics, BeiGene, AstraZeneca, Genmab, Morphosys, Incyte, and Vincerx; is a consultant for AbbVie, Genentech, AstraZeneca, Pharmacyclices, BeiGene, Bristol Myers Squibb, Morphosys, Incyte, Kite, Eli Lilly, Genmab, Mustang Bio, Regeneron, ADC therapeutics, Fate Therapeutics, Nurix, and MEI Pharma; and receives payment for presentations from AbbVie, Genentech, AstraZeneca, Pharmacyclics, BeiGene, Bristol Myers Squibb, Morphosys, Incyte, Kite, Eli Lilly, Genmab, Mustang Bio, Regeneron, ADC therapeutics, Fate Therapeutics, Nurix, and MEI Pharma. JG receives research funding from Sobi, Juno Therapeutics— a Bristol Myers Squibb company, Celgene—a Bristol Myers Squibb company, and Angiocrine Bioscience; is a consultant for Sobi, Legend Biotech, Janssen, Kite Pharma, and MorphoSys;, and is on an advisory board for Century Therapeutics. DGM receives research funding from Kite Pharma, Juno Therapeutics—a Bristol Myers Squibb company, Celgene, Legend Biotech, and Bristol Myers Squibb; is a consultant for A2 Biotherapeutics, Navan Technologies, Chimeric Therapeutics, Genentech, Bristol Myers Squibb, ImmmPACT Bio, and Gilead Sciences; has rights to royalties for patents licensed to Juno Therapeutics—a Bristol Myers Squibb company; serves as an advisory board member for Bristol Myers Squibb, Caribou Biosciences, Celgene, Genentech, Incyte, Janssen, Juno Therapeutics—a Bristol Myers Squibb company, Mustang Bio, Morphosys, Kite, Lilly, Novartis, and Umoja; and has stocks or stock options in A2 Biotherapeutics and Navan Technologies. SRR has research funding from the National Institutes of Health, Leukemia and Lymphoma Society, Juno Therapeutics—a Bristol Myers Squibb company, Lyelle Immunopharma, and Outpace Biosciences; has rights to royalties from Juno Therapeutics—a Bristol Myers Squibb company, Lyell Immunopharma, Deverra Therapeutics; is a consultant from Lyell Immunopharma and Adaptive Biotechnologies; has patents from Juno Therapeutics—a Bristol Myers Squibb company and Lyell Immunopharma; serves on a board of directors for Ozette Technologies; and has stocks or stock options from Lyell Immunopharma and Adaptive Biotechnologies. DJG held the sponsor-investigator investigational new drug application from the US Food and Drug Administration for this study; has obtained grants or contracts through Fred Hutchinson Cancer Center with Juno Therapeutics—a Bristol Myers Squibb company, Seattle Genetics, Janssen Biotech, SpringWorks Therapeutics, Cellectar Biosciences, The Allen Institute for Immunology, The Leukemia and Lymphoma Society, and the National Institutes of Health; is in consulting agreements with Ensoma; has served on an advisory board for GSK, Janssen Biotech, Legend Biotech, and Celgene; and has two US provisional patent applications (62/582,270 and 62/582,308) through Fred Hutchinson Cancer Center and Juno Therapeutics—a Bristol Myers Squibb company. BDS, DGC, TG, JV, VQW, AGC, and FM declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Concurrent administration of pembrolizumab with chemotherapy in untreated classic Hodgkin lymphoma (CHL) has not been studied previously. To investigate this combination, we conducted a single-arm study of concurrent pembrolizumab with AVD (doxorubicin, vinblastine, and dacarbazine; APVD) for untreated CHL. We enrolled 30 patients and met the primary safety end point with no observed significant treatment delays in the first 2 cycles. Twelve patients experienced grade 3 or 4 nonhematologic adverse events (AEs), most commonly febrile neutropenia and infection/sepsis. Grade 3 or 4 immune-related AEs, including alanine aminotransferase elevation and aspartate aminotransferase elevation were observed in 3 patients. One patient experienced an episode of grade 2 colitis and arthritis. Six patients missed at least 1 dose of pembrolizumab because of AEs, primarily grade 2 or higher transaminitis. Among 29 response-evaluable patients, the best overall response rate was 100% and the complete response rate was 90%. With a median follow-up of 2.1 years, the 2-year progression-free survival (PFS) and overall survival were 97% and 100%, respectively. To date, no patient who has withheld or discontinued pembrolizumab because of toxicity has progressed. Clearance of circulating tumor DNA (ctDNA) was associated with superior PFS when measured after cycle 2 and at the end of treatment (EOT). None of the 4 patients with persistent uptake by fluorodeoxyglucose positron emission tomography (PET) at EOT yet negative ctDNA have relapsed to date. Concurrent APVD shows promising safety and efficacy but may yield spurious PET findings in some patients. This trial was registered at www.clinicaltrials.gov as #NCT03331341.

Background: Little is known regarding associations between peripheral blood biomarkers (PBBMs) and survival, response, and toxicity in recurrent/metastatic head and neck squamous cell carcinomas (R/M HNSCC) treated with immune checkpoint inhibitors (ICIs)., Methods: In this single-institution retrospective cohort study, a dataset of patients with R/M HNSCC treated with ICIs between 08/2012-03/2021 was established, including demographic and clinicopathologic characteristics. Pretreatment PBBMs were collected and evaluated for associations with grade ≥3 adverse events (G ≥ 3AE) by CTCAEv5, objective response (ORR) by RECIST 1.1, overall survival (OS), and progression-free survival (PFS). Multivariable models for each outcome were created using elastic net variable selection., Results: Our study included 186 patients, with 51 (27%) demonstrating complete or partial response to immunotherapy. Multivariable models adjusted for ECOG performance status (PS), p16, and smoking demonstrated that pretreatment higher LDH and absolute neutrophils, as well as lower percent lymphocytes correlated with worse OS and PFS. Higher LDH and lower % lymphocytes also correlated with worse ORR., Conclusions: In the largest study to date examining PBBMs in ICI-treated R/M HNSCCs, our variable selection method revealed PBBMs prognostic for survival and response to immunotherapy. These biomarkers warrant further investigation in a prospective study along with validation with CPS biomarker., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Associations between peripheral blood biomarkers and oncologic outcomes were explored in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HN) and salivary gland cancer (SGC) treated with pembrolizumab and vorinostat on a phase II trial (NCT02538510)., Experimental Design: Twenty-five HN and 25 SGCs were treated with pembrolizumab and vorinostat. Baseline peripheral blood was available in 21 HN and 20 SGCs and evaluated for associations with grade ≥3 adverse events (G ≥ 3AE) by CTCAEv4, objective response rate (ORR), overall survival (OS), and progression-free survival (PFS)., Results: Higher pretreatment neutrophil-to-lymphocyte ratio (NLR) and neutrophils, as well as lower pretreatment lymphocytes and T helper cells correlated with worse OS and PFS. Higher NLR further predicted increased rates of G ≥ 3AEs. No correlations with ORR were observed., Conclusions: In a prospectively evaluated cohort of HN and SGCs treated with pembrolizumab and vorinostat, we observed novel associations between peripheral blood biomarkers and oncologic outcomes and toxicities., (© 2022 Wiley Periodicals LLC.)

Cytopenias are important but less studied adverse events following chimeric antigen receptor-engineered T cell (CAR-T) therapy. In our analysis of patients with large cell lymphoma who received axicabtagene ciloleucel (axi-cel), we sought to determine the rate and risk factors of clinically significant short term cytopenias defined as grade ≥3 neutropenia, anemia, or thrombocytopenia, or treatment with growth factors or blood product transfusions between days 20-30 after axi-cel. Fifty-three pts received axi-cel during the study period and severe cytopenias were observed in 32 (60%) pts. Significant cytopenias were more common in non-responders (stable or progressive disease) vs. responders (partial or complete response) (100% vs. 70%; p = .01). In the multivariable model, platelet transfusion within a month before leukapheresis, number of red blood cell and platelet transfusions between leukapheresis to lymphodepletion, pre-lymphodepletion absolute neurophil count, pre-lymphodepletion lactate dehydrogenase, and number of dexamethasone treatments after CAR-T were significantly associated with severe cytopenias after axi-cel.

Chimeric antigen receptor T-cell (CAR T) therapy has shown promising efficacy in relapsed and refractory diffuse large B cell lymphoma (DLBCL). While most patients undergo CAR T infusion with active disease, the impact of some clinical variables, such as responsiveness to the pre-CAR T chemotherapy on the response to CAR T, is unknown. In this single-institution study, we studied the impact of several pre-CAR T variables on the post-CAR outcomes. Sixty patients underwent apheresis for axicabtagene-ciloleucel (axi-cel) and 42 of them (70.0%) had primary refractory disease. Bridging therapy between apheresis and lymphodepletion was given in 34 patients (56.7%). After axi-cel, the overall response rate was 63.3%. Responsiveness to the immediate pre-CAR T therapy did not show a significant association with response to axi-cel, progression-free (PFS) or overall (OS) survival. Multivariable analysis determined that bulky disease before lymphodepletion was independently associated with inferior outcomes, and patients that presented with high-burden disease unresponsive to immediate pre-CAR T therapy had a dismal outcome. This data supports proceeding with treatment in CAR T candidates regardless of their response to immediate pre-CAR T therapy. Interim therapeutic interventions should be considered in patients who have known risk factors for poor outcomes (bulky disease, high LDH)., (© 2022 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Purpose: Young adult (YA) cancer survivors have high rates of adverse health and psychosocial outcomes. This risk-stratified, multicenter, randomized controlled trial (RCT) compared a self-management survivorship intervention to usual care in YA survivors with symptoms of cancer-related distress, insomnia, fatigue, pain, and/or depression., Methods: Eligibility included age 18-39 at diagnosis with an invasive malignancy in the previous 1-5 years. Baseline assessment determined "high need" participants, with 2-5 elevated targeted symptoms. We randomized high need participants to intervention or usual care and offered intervention participants a survivorship clinic visit, which included mutually decided action plans for symptoms. Follow-up calls at 1 and 3 months after the clinic visit reviewed action plan progress. Outcomes compared rates of improved symptoms for intervention vs usual care at 6 months and 12 months., Results: N = 344 completed baseline assessment, with n = 147 (43%) categorized as high need and randomized. Of n = 73 randomized to the intervention, n = 42 (58%) did not attend their survivorship clinic visit. In intent-to-treat analyses, aggregate symptom scores did not differ between arms, though distress improved for 46% in the intervention arm at 6 months compared to 18% in usual care (p = 0.03) among those with elevated distress at baseline., Conclusions: Distress improved for YAs who received self-management survivorship care. However, the study demonstrates a need for alternative strategies for providing YA survivorship care., Trial Registration: NCT02192333 IMPLICATIONS FOR CANCER SURVIVORS: While YA survivors demonstrate some improved distress when provided survivorship care, to make care accessible and effective, they require options such as remote delivery of care., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Homozygous inheritance of a single-nucleotide polymorphism (1245A > C) in HSD3B1 results in an adrenal permissive phenotype of increased adrenal steroid precursor conversion to potent androgens. This is associated with poor outcomes in prostate cancer. We hypothesized that inheritance of the HSD3B1 adrenal permissive genotype would similarly negatively impact breast cancer outcomes., Patients and Methods: Germline HSD3B1 was sequenced in 644 postmenopausal women diagnosed between 2004 and 2015 with stage I-III estrogen receptor-positive (ER + ), HER2/neu-negative (HER2 - ) breast cancer enrolled in a population-based study in western Washington. Primary endpoint was distant metastatic recurrence according to genotype. Secondary endpoint was breast cancer-specific survival. Hazard ratios (HR) were calculated using cause-specific Cox regression accounting for competing risks., Results: Adrenal restrictive genotype (homozygous wild type) was most prevalent (47%), followed by heterozygous (44%) and adrenal permissive (9%). There were no significant differences comparing demographic, tumor, or treatment characteristics apart from higher frequency of adrenal permissive genotype among non-Hispanic white participants (p = 0.04). After accounting for competing risks, the cumulative incidence of distant metastatic recurrence (15 events) was significantly higher among participants with adrenal permissive compared with the adrenal restrictive genotype (HR 4.9, 95% CI 1.32-18.4, p = 0.02). The adrenal permissive genotype was also predictive of breast cancer-specific mortality (HR 3.5, 95% CI 1.27-9.59, p = 0.02)., Conclusions: Inheritance of the HSD3B1 adrenal permissive genotype is associated with increased incidence of distant metastasis and higher cause-specific mortality in postmenopausal ER + /HER2 - breast cancer. Further research is necessary to understand the effect of excess adrenal androgen metabolism in promoting breast cancer growth and progression., (© 2022. Society of Surgical Oncology.)

Background: A previous International Lymphoma Epidemiology (InterLymph) Consortium evaluation of joint associations between five immune gene variants and autoimmune conditions reported interactions between B-cell response-mediated autoimmune conditions and the rs1800629 genotype on risk of B-cell non-Hodgkin lymphoma (NHL) subtypes. Here, we extend that evaluation using NHL subtype-specific polygenic risk scores (PRS) constructed from loci identified in genome-wide association studies of three common B-cell NHL subtypes., Methods: In a pooled analysis of NHL cases and controls of Caucasian descent from 14 participating InterLymph studies, we evaluated joint associations between B-cell-mediated autoimmune conditions and tertile (T) of PRS for risk of diffuse large B-cell lymphoma (DLBCL; n = 1,914), follicular lymphoma (n = 1,733), and marginal zone lymphoma (MZL; n = 407), using unconditional logistic regression., Results: We demonstrated a positive association of DLBCL PRS with DLBCL risk [T2 vs. T1: OR = 1.24; 95% confidence interval (CI), 1.08-1.43; T3 vs. T1: OR = 1.81; 95% CI, 1.59-2.07; P-trend (Ptrend) < 0.0001]. DLBCL risk also increased with increasing PRS tertile among those with an autoimmune condition, being highest for those with a B-cell-mediated autoimmune condition and a T3 PRS [OR = 6.46 vs. no autoimmune condition and a T1 PRS, Ptrend < 0.0001, P-interaction (Pinteraction) = 0.49]. Follicular lymphoma and MZL risk demonstrated no evidence of joint associations or significant Pinteraction., Conclusions: Our results suggest that PRS constructed from currently known subtype-specific loci may not necessarily capture biological pathways shared with autoimmune conditions., Impact: Targeted genetic (PRS) screening among population subsets with autoimmune conditions may offer opportunities for identifying those at highest risk for (and early detection from) DLBCL., (©2022 The Authors; Published by the American Association for Cancer Research.)

CD19-targeted chimeric antigen receptor (CAR) T-cell therapy has demonstrated remarkable efficacy in patients with relapsed/refractory B-cell malignancies; however, it is associated with toxicities including cytokine release syndrome (CRS), neurotoxicity, and impaired hematopoietic recovery. The latter is associated with high-grade cytopenias requiring extended growth factor or transfusional support, potentially leading to additional complications such as infection or hemorrhage. To date, the factors independently associated with hematologic toxicity have not been well characterized. To address this deficit, we retrospectively analyzed 173 patients who received defined-composition CD19 CAR T-cell therapy in a phase 1/2 clinical trial (https://clinicaltrials.gov; NCT01865617), with primary end points of absolute neutrophil count and platelet count at day-28 after CAR T-cell infusion. We observed cumulative incidences of neutrophil and platelet recovery of 81% and 75%, respectively, at 28 days after infusion. Hematologic toxicity was noted in a significant subset of patients, with persistent neutropenia in 9% and thrombocytopenia in 14% at last follow-up. Using debiased least absolute shrinkage selector and operator regression analysis for high-dimensional modeling and considering patient-, disease-, and treatment-related variables, we identified increased CRS severity as an independent predictor for decreased platelet count and lower prelymphodepletion platelet count as an independent predictor of both decreased neutrophil and platelet counts after CD19 CAR T-cell infusion. Furthermore, multivariable models including CRS-related cytokines identified associations between higher peak serum concentrations of interleukin-6 and lower day-28 cell counts; in contrast, higher serum concentrations of transforming growth factor-β1 were associated with higher counts. Our findings suggest that patient selection and improved CRS management may improve hematopoietic recovery after CD19 CAR T-cell therapy., (© 2022 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: Graft-versus-host disease (GVHD) causes morbidity and mortality following allogeneic hematopoietic cell transplantation. Naive T cells (T N ) cause severe GVHD in murine models. We evaluated chronic GVHD (cGVHD) and other outcomes in three phase II clinical trials of T N -depletion of peripheral blood stem-cell (PBSC) grafts., Methods: One hundred thirty-eight patients with acute leukemia received T N -depleted PBSC from HLA-matched related or unrelated donors following conditioning with high- or intermediate-dose total-body irradiation and chemotherapy. GVHD prophylaxis was with tacrolimus, with or without methotrexate or mycophenolate mofetil. Subjects received CD34-selected PBSC and a defined dose of memory T cells depleted of T N . Median follow-up was 4 years. The primary outcome of the analysis of cumulative data from the three trials was cGVHD., Results: cGVHD was very infrequent and mild (3-year cumulative incidence total, 7% [95% CI, 2 to 11]; moderate, 1% [95% CI, 0 to 2]; severe, 0%). Grade III and IV acute GVHD (aGVHD) occurred in 4% (95% CI, 1 to 8) and 0%, respectively. The cumulative incidence of grade II aGVHD, which was mostly stage 1 upper gastrointestinal GVHD, was 71% (95% CI, 64 to 79). Recipients of matched related donor and matched unrelated donor grafts had similar rates of grade III aGVHD (5% [95% CI, 0 to 9] and 4% [95% CI, 0 to 9]) and cGVHD (7% [95% CI, 2 to 13] and 6% [95% CI, 0 to 12]). Overall survival, cGVHD-free, relapse-free survival, relapse, and nonrelapse mortality were, respectively, 77% (95% CI, 71 to 85), 68% (95% CI, 61 to 76), 23% (95% CI, 16 to 30), and 8% (95% CI, 3 to 13) at 3 years., Conclusion: Depletion of T N from PBSC allografts results in very low incidences of severe acute and any cGVHD, without apparent excess risks of relapse or nonrelapse mortality, distinguishing this novel graft engineering strategy from other hematopoietic cell transplantation approaches., Competing Interests: Marie BleakleyStock and Other Ownership Interests: HighPass BioConsulting or Advisory Role: HighPass Bio, Orca BioResearch Funding: HighPass BioPatents, Royalties, Other Intellectual Property: TCRs specific for minor histocompatibility antigen HA-1 and uses thereof US20190211076A1 and international. Patent issued January 21, 2020. US10,538,574. Inventor on patent. Held by Fred Hutchinson Cancer Research CenterOther Relationship: Miltenyi Biotec Alison SehgalSpeakers' Bureau: OncLiveResearch Funding: Kite/Gilead, Juno Therapeutics Melinda A. BiernackiEmployment: Outpace Bio (I), Lyell Immunopharma (I)Stock and Other Ownership Interests: Lyell Immunopharma (I), Outpace Bio (I)Patents, Royalties, Other Intellectual Property: My partner receives royalties from a patent held by the Fred Hutchinson Cancer Research Center pertaining to nanomaterials for mRNA delivery. There is no relationship between the research in the current publication and the technology in the patent (I) Elizabeth F. KrakowResearch Funding: HighPass Bio (Inst) Ann DahlbergResearch Funding: Jazz Pharmaceuticals, Atara Biotherapeutics Paul J. MartinStock and Other Ownership Interests: Procter & GambleHonoraria: Janssen/Pharmacyclics, TherakosConsulting or Advisory Role: Pfizer, Mesoblast, Rigel, Talaris, MalinckrodtResearch Funding: AltruBio (Inst) Paul A. CarpenterHonoraria: Johnson and Johnson CorporationConsulting or Advisory Role: Janssen Scientific AffairsResearch Funding: Pharmacyclics, Janssen, Incyte Mary E. FlowersHonoraria: Astellas Pharma, MallinckrodtResearch Funding: Pharmacyclics, Incyte Theodore A. GooleyConsulting or Advisory Role: Kiadis Pharma, Pharmacyclics, Regimmune Brent L. WoodHonoraria: Amgen, Seattle Genetics, AbbVie, Janssen, Amgen, Astellas Pharma, Roche Diagnostics, Beckman CoulterConsulting or Advisory Role: SysmexResearch Funding: Amgen (Inst), Seattle Genetics (Inst), Pfizer (Inst), Juno Therapeutics (Inst), BiolineRx (Inst), Biosight (Inst), Stemline Therapeutics (Inst), Janssen Oncology (Inst), Novartis, Kite, a Gilead Company (Inst), Macrogenics (Inst)Travel, Accommodations, Expenses: Amgen Stanley R. RiddellEmployment: Lyell ImmunopharmaLeadership: Lyell ImmunopharmaStock and Other Ownership Interests: Lyell Immunopharma (Inst), Adaptive BiotechnologiesConsulting or Advisory Role: Lyell ImmunopharmaResearch Funding: Lyell ImmunopharmaPatents, Royalties, Other Intellectual Property: Patents, licensing fees, and royalties from Bristol Myers Squibb, Lyell, and Deverra. Patents, licensing fees, and royalties from Bristol Myers Squibb, Lyell, and Deverra (Inst) Warren D. ShlomchikEmployment: Bluesphere BioStock and Other Ownership Interests: Bluesphere BioConsulting or Advisory Role: Bluesphere BioResearch Funding: Bluesphere BioPatents, Royalties, Other Intellectual Property: T-cell receptorsNo other potential conflicts of interest were reported.

Consolidative hematopoietic cell transplantation (HCT) after CD19 chimeric antigen receptor (CAR) T cell therapy is frequently performed for patients with refractory/ relapsed B cell acute lymphoblastic leukemia (B-ALL). However, there is controversy regarding the role of HCT following remission attainment. We evaluated the effect of consolidative HCT on leukemia-free survival (LFS) in pediatric and young adult subjects following CD19 CAR T cell induced remission. We evaluated the effect of consolidative HCT on LFS in pediatric and young adult subjects treated with a 41BB-CD19 CAR T cell product on a phase 1/2 trial, Pediatric and Young Adult Leukemia Adoptive Therapy (PLAT)-02 (ClinicalTrials.gov identifier NCT02028455), using a time-dependent Cox proportional hazards statistical model. Fifty of 64 subjects enrolled in PLAT-02 phase 1 and early phase 2 were evaluated, excluding 14 subjects who did not achieve remission, relapsed, or died before day 63 post-CAR T cell therapy. An improved LFS (P = .01) was observed in subjects who underwent consolidative HCT after CAR T cell therapy versus watchful waiting. Consolidative HCT improved LFS specifically in subjects who had no prior history of HCT, with a trend toward significance (P = .09). This benefit was not evident when restricted to the cohort of 34 subjects with a history of prior HCT (P = .45). However, for subjects who had CAR T cell functional persistence of 63 days or less, inclusive of those with a history of prior HCT, HCT significantly improved LFS outcomes (P = .01). These data support the use of consolidative HCT following CD19 CAR T cell-induced remission for patients with no prior history of HCT and those with short functional CAR T cell persistence., (Copyright © 2021 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Objectives: Timely administration of postoperative radiation therapy (PORT) impacts oncologic outcomes in resected squamous cell carcinomas of the head and neck. Salivary gland cancers (SGCs) are uncommon, and timing of PORT has not been extensively explored. We aimed to determine if the interval between surgery and PORT impacts outcomes in SGCs., Materials and Methods: This is a retrospective study of patients with SGCs who underwent curative intent surgical resection followed by adjuvant PORT. Locoregional recurrence free survival (LRFS), disease free survival (DFS), and overall survival (OS) were estimated using the Kaplan Meier method. A multivariate analysis explored the association between demographics, tumor characteristics, and PORT timing with oncologic outcomes using a stepwise Cox proportional hazards model., Results: 180 eligible patients were identified. The median time to PORT start was 61 (range 8-121) days. 169 (93.5%) of patients received neutron radiation. With a median follow up of 8.2 years in surviving patients, the 10-year OS and LRFS estimates were 61% and 53%. In a multivariate analysis, nodal involvement, histologic grade, and age at diagnosis were associated with OS, while nodal involvement, tumor size, and age at diagnosis were associated with LRFS and DFS. Time to PORT start or completion was not statistically associated with survival outcomes., Conclusion: SGC patients who underwent surgery in our tertiary institution received PORT within a median of 61 days after surgery. With long term follow up, PORT timing in this retrospective series was not associated with worse oncologic outcomes, and support timely administration of PORT., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Relapsed or refractory classical Hodgkin lymphoma could be treated with multiagent salvage chemotherapy followed by autologous haematopoietic stem-cell transplantation. The aim of this study is to establish the safety and activity of dose-dense brentuximab vedotin combined with ifosfamide, carboplatin, and etoposide (BV-ICE) chemotherapy in second-line treatment of classical Hodgkin lymphoma., Methods: We conducted a single-arm, open-label, phase 1/2 study of dose-dense BV-ICE at the Seattle Cancer Care Alliance, University of Washington (Seattle, WA, USA). Eligibility criteria were age 18 years or older; diagnosis of first relapse, primary refractory classical Hodgkin lymphoma after one previous line of therapy; measurable disease of at least 1 cm in the longest axis, CT of chest, abdomen, and pelvis with PET within the past 28 days; Eastern Cooperative Oncology Group performance status of 0-1; and adequate organ function. A 3 + 3 dose escalation study was done for the phase 1 part of the trial to establish the maximum tolerated dose to be used for the phase 2 study. Brentuximab vedotin was delivered on days 1 and 8 at either 1·2 mg/kg (dose level 1) or 1·5 mg/kg (dose level 2) intravenously (capped at 150 mg) with standard dosing of ICE on days 1-3 (ifosfamide 5 g/m 2 plus mesna 5 g/m 2 intravenously over 24 h on day 2, carboplatin area under the curve 5 on day 2 in one intravenous injection, and etoposide 100 mg/m 2 on days 1-3 in one intravenous injection per day) for two 21-day cycles. The primary endpoint was to establish the recommended phase 2 dose (phase 1 part) and complete response rate after two cycles, with a prespecified target of 78% (phase 2 part). Safety analysis was done in all enrolled participants and the primary activity analysis was done in all patients with evaluable response data. This study is registered with ClinicalTrials.gov (NCT02227199); enrolment and study treatment are complete., Findings: Between Oct 16, 2014, and Feb 10, 2020, we enrolled 45 patients with a median age of 31 years (IQR 28-45). The recommended phase 2 dose of brentuximab vedotin was established to be 1·5 mg/kg. After a median follow-up of 3·1 years (IQR 1·7-4·1), 32 (74%; 95% CI 58·8-86·5) of 43 evaluable patients had complete responses after two cycles of treatment. Grade 3-4 haematological toxic effects were common, including neutropenia (33 [73%]), anaemia (six [13%]), and thrombocytopenia (36 [80%]). The most common grade 3-4 non-haematological toxic effects were febrile neutropenia (four [9%]), sepsis (six [13%]), increased alanine aminotransferase (five [11%]), hyperglycaemia (three [7%]), pulmonary embolism (two [4%]), and increased aspartate aminotransferase (two [4%]). There was one (2%) on-treatment death due to multisystem organ failure that was considered treatment related. Serious adverse events occurred in 13 (29%) patients., Interpretation: Our data suggest that dose-dense BV-ICE is a rapidly administered and active salvage regimen for patients with relapsed or refractory classical Hodgkin lymphoma despite a complete response in this trial lower than the prespecified phase 2 target. Although cross-trial comparisons should be made with caution, activity results seem to be similar to previously presented brentuximab vedotin chemotherapy salvage combinations delivered over much longer durations and can be considered in young (<60 years), transplantation-eligible patients for second-line therapy., Funding: Seagen, Lymphoma Research Foundation, National Institutes of Health/National Cancer Institute, and generous philanthropic donations to the University of Washington from numerous individuals and families in support of lymphoma research., Competing Interests: Declaration of interests SDS has received research funding from Acerta Pharma, AstraZeneca, Bayer, Beigene, De Novo Biopharma, Genentech, Incyte, Merck, and Portola Pharmaceuticals; and consulting fees from AstraZeneca and Millenium/Takeda. RCL has received research funding from Seagen. RDC has received research funding from Amgen, Merck, Pfizer, and Vanda Pharmaceuticals; has received honoraria and travel payment from Pfizer for an educational lecture; and is on a Data Safety Monitoring Board for a prospective clinical trial by Pepromene Bio. RDC's spouse is an employee of Seagen and has stock or stock options in Seagen. MSS has research funding from Mustang Bio, Celgene, Bristol Myers Squibb, Pharmacyclics, Gilean, Genentech, AbbVie, TG Therapeutics, Beigne, AstraZeneca, Sunesis, Atara Bioptherapeutics, and GenMab; and consulting fees from AbbVie, Genentech, AstraZeneca, Sound Biologics, Pharmacyclics, Beigene, Bristol Myers Squibb, Morphosys, TG Therapeutics, Innate Pharma, Kite Pharma, Adaptive Biotechnologies, Epizyme, Eli Lilly, and Atara Bioptherapeutics. AKG has received research funding from the National Institutes of Health National Cancer Institute (NIH/NCI), Seagen, Bristol Myers Squibb, Pharmacyclics, Gilean, Genentech, AstraZeneca, Pfizer, Teva, Takeda, Acrotec, IgM, I-Mab, Agios, and Merck; has received consulting fees from AbbVie, Genentech, Janssen, AstraZeneca, Pharmacyclics, Bristol Myers Squibb, Amgen, Morphosys, TG Therapeutics, Kite Pharma, Adaptive, Seagen, Icn, Epizyme, Kite, Gilead, ADC Therapeutics, Incyte, Karyopharm, Actinium, Asana Bio, Nurix, and Apteva; and has participated on a Data Safety Monitoring Board for ADC Therapeutics and Janssen. AJC has received research funding from Janssen, AbbVie, Harpoon, Nektar, Bristol Myers Squibb, and Sanofi; has received consulting fees from Janssen, EUSA Pharma, GSK, AbbVie, Sanofi, and Cellectar; and has stock or stock options in Doximity. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Patients with core-binding factor (CBF) acute myeloid leukemia (AML), caused by either t(8;21)(q22;q22) or inv(16)(p13q22)/t(16;16)(p13;q22), have higher complete remission rates and longer survival than patients with other subtypes of AML. However, ∼40% of patients relapse, and the literature suggests that patients with inv(16) fare differently from those with t(8;21). We retrospectively analyzed 537 patients with CBF-AML, focusing on additional cytogenetic aberrations to examine their impact on clinical outcomes. Trisomies of chromosomes 8, 21, or 22 were significantly more common in patients with inv(16)/t(16;16): 16% vs 7%, 6% vs 0%, and 17% vs 0%, respectively. In contrast, del(9q) and loss of a sex chromosome were more frequent in patients with t(8;21): 15% vs 0.4% for del(9q), 37% vs 0% for loss of X in females, and 44% vs 5% for loss of Y in males. Hyperdiploidy was more frequent in patients with inv(16) (25% vs 9%, whereas hypodiploidy was more frequent in patients with t(8;21) (37% vs 3%. In multivariable analyses (adjusted for age, white blood counts at diagnosis, and KIT mutation status), trisomy 8 was associated with improved overall survival (OS) in inv(16), whereas the presence of other chromosomal abnormalities (not trisomy 8) was associated with decreased OS. In patients with t(8;21), hypodiploidy was associated with improved disease-free survival; hyperdiploidy and del(9q) were associated with improved OS. KIT mutation (either positive or not tested, compared with negative) conferred poor prognoses in univariate analysis only in patients with t(8;21)., (© 2021 by The American Society of Hematology.)

Tumor programmed death-ligand 1 (PD-L1) expression in diffuse large B-cell lymphoma (DLBCL) is associated with inferior outcomes. The first-line immunologically-replete setting may be an opportune time for PD-1 inhibition. We evaluated pembrolizumab in combination with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in untreated patients with DLBCL. Eligible patients were age 18 or older, had adequate organ function, and had DLBCL requiring full-course therapy. Patients received pembrolizumab 200 mg/cycle with R-CHOP, primarily to assess toxicity. Response assessment utilized standard criteria, and PD-L1 staining was performed at a validated central laboratory. Among 30 patients, toxicity was comparable to standard R-CHOP but with two grade ≥3 immune related adverse events (rash, pneumonitis). The overall and complete response rate was 90% and 77%. With 25·5 months of median follow-up, 2-year progression-free survival (PFS) is 83%. PD-L1 expression was associated with non-GCB subtype, and improved PFS and survival. Pembrolizumab can safely be added to R-CHOP, and is associated with a high CR rate and 2-year PFS. Improved PFS with PR-CHOP in PD-L1 expressing tumors contradicts historical data in R-CHOP treated patients, supporting evaluation of PD-L1 as a biomarker to identify DLBCL patients who may benefit from this first-line strategy., (© 2020 British Society for Haematology and John Wiley & Sons Ltd.)

Purpose: This clinical trial combined pembrolizumab and vorinostat in recurrent/metastatic squamous cell carcinomas of the head and neck (HN), and salivary gland cancer (SGC)., Patients and Methods: Patients with progressing incurable HN and SGC, Eastern Cooperative Oncology Group (ECOG) ≤1, no prior immunotherapy, RECIST1.1 measurable disease, and normal organ function were eligible. Pembrolizumab 200 mg was given intravenous every 21 days, and vorinostat 400 mg given orally 5 days on and 2 days off during each 21-day cycle. Primary endpoints were safety and objective response rates., Results: From November 2015 to August 2017, 25 patients with HN and 25 SGC were enrolled. Median age was 61 (range, 33-86) years, 39 (78%) were male, 21 (62%) were never smokers, and 27 (54%) had ECOG 0. In HN, 13 (52%) were p16+ oropharynx. Most common SGC histologies were adenoid cystic 12 (48%), acinic cell 3 (12%), and mucoepidermoid 3 (12%). Adverse events (AEs) in all patients were: 27 (54%) with grade ≥ 1 and 18 (36%) with grade ≥ 3. The most common AEs in all patients were renal insufficiency in seven, (14%), fatigue in six, (12%), and nausea in three (6%). There were three (12%) deaths on study. Responses in HN were complete response (CR) 0, partial response (PR) eight (32%), and stable disease (SD) five (20%). Efficacy in SGCs was CR 0, PR four (16%) in one lymphoepithelioma-like carcinoma, two acinic cell, one adenoid cystic, and SD 14 (56%). In the HN group, median follow-up (mFUP) was 12.6 months, median overall survival (mOS) was 12.6 months, and median progression-free survival (mPFS) was 4.5 months. In SGC, mFUP was 13.1 months, mOS was 14.0 months, and mPFS was 6.9 months., Conclusions: This combination demonstrated activity in HN, with fewer responses in SGC. Toxicities were higher than reported with pembrolizumab alone., (©2019 American Association for Cancer Research.)

CD19-targeted chimeric antigen receptor-modified T cell (CAR-T cell) therapy has shown excellent antitumor activity in patients with relapsed/refractory B cell malignancies, with very encouraging response rates and outcomes. However, the late effects following this therapy remain unknown. Here we report late adverse events-defined as starting or persisting beyond 90 days after CAR-T cell infusion-in patients who survived at least 1 year after therapy. The median duration of follow-up was 28.1 months (range, 12.5 to 62.6 months). At last follow-up, 73% of patients were still alive and 24% were in ongoing complete remission (CR). The most common late adverse event was hypogammaglobulinemia (IgG <400 mg/dL or i.v immunoglobulinm (IVIG) replacement, observed in 67% of the patients with available data. Infection density was .55 infection/100 days at risk (2.08 per patient-year). The majority (80%) of the infections were treated in the outpatient setting, and 5% necessitated admission to the intensive care unit (ICU). Subsequent malignancies occurred in 15% of patients, including 5% with myelodysplastic syndrome (MDS). Among patients with ongoing CR and with no MDS, 16% experienced prolonged cytopenia requiring transfusions or growth factor support. Graft-versus-host disease occurred in 3 of 15 patients (20%) who had undergone previous allogeneic hematopoietic cell transplantation. Most of the late events observed in this cohort were not severe, and many could be related to previous or subsequent therapies, suggesting a safe long-term profile of CD19-targeted CAR-T cell immunotherapy., (Copyright © 2019 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Background: Postmenopausal hormone therapy (HT) increases the risk of stroke. Here we evaluate whether leisure time physical activity (LTPA) can change stroke risk in women using HT, leveraging data from the California Teachers Study., Methods: Female California educators without a prior history of stroke (n = 118,294) were followed from 1995 through 2015 for stroke end points. Based on statewide hospitalization data, 4,437 women had ischemic (n = 3,162; International Classification of Diseases [ICD]-9 433, 434, 436) or hemorrhagic (n = 1,275; ICD-9 430-432, excluding 432.1) stroke. LTPA and HT use were evaluated at 2 time points (baseline [1995-1996] and 10-year follow-up [2005-2006]). LTPA was assessed using American Heart Association (AHA) recommendations (>150 min/week moderate or >75 min/week strenuous physical activity). Using multivariable Cox proportional hazards models, we estimated the hazard ratios (HRs) and 95% CIs for the associations between HT use and concurrent LTPA with incident stroke., Results: Compared to women who never used HT, stroke risk was highest among women who were current HT users and did not meet AHA recommendations for LTPA at the time of their HT use: HRbaseline 1.28 (95% CI 1.13-1.44); HR10-year follow-up 1.17 (95% CI 0.91-1.50). Based on the baseline questionnaire, current HT users who met AHA recommendations for LTPA in 1995-1996 still had elevated stroke risk in the 20-year follow-up (HR 1.22, 95% CI 1.08-1.37). However, among current HT users who met AHA recommendations for LTPA at the 2005-2006 follow-up questionnaire, stroke risk was not elevated (HR 1.01, 95% CI 0.80-1.29). Evaluation of the 2 time points in concert further demonstrated that meeting AHA recommendations for LTPA at the most recent follow-up time point was required to reduce HT-related stroke risk., Conclusion: Concurrent physical activity may attenuate the short-term increase in risk of stroke risk associated with HT use., (© 2020 S. Karger AG, Basel.)

CD19-targeted chimeric antigen receptor (CAR) modified T cell immunotherapy is a novel treatment with promising results in patients with relapsed/refractory lymphoid malignancies. CAR T cell therapy has known early toxicities of cytokine release syndrome and neurotoxicity, but little is known about long-term neuropsychiatric adverse effects. We have used patient-reported outcomes, including Patient-Reported Outcomes Measurement Information System (PROMIS) measures, to assess neuropsychiatric and other patient-reported outcomes of 40 patients with relapse/refractory chronic lymphocytic leukemia, non-Hodgkin lymphoma, and acute lymphoblastic leukemia 1 to 5 years after treatment with CD19-targeted CAR T cells. Mean T scores of PROMIS domains of global mental health, global physical health, social function, anxiety, depression, fatigue, pain, and sleep disturbance were not clinically meaningfully different from the mean in the general US population. However, 19 patients (47.5%) reported at least 1 cognitive difficulty and/or clinically meaningful depression and/or anxiety, and 7 patients (17.5%) scored ≤40 in global mental health, indicating at least 1 standard deviation worse than the general population mean. Younger age was associated with worse long-term global mental health (P = .02), anxiety (P = .001), and depression (P= .01). Anxiety before CAR T cell therapy was associated with increased likelihood of anxiety after CAR T cell therapy (P = .001). Fifteen patients (37.5%) reported cognitive difficulties after CAR T cell therapy. Depression before CAR T cell therapy was statistically significantly associated with higher likelihood of self-reported post-CAR T cognitive difficulties (P = .02), and there was a trend for an association between acute neurotoxicity and self-reported post-CAR T cognitive difficulties (P = .08). Having more post-CAR T cognitive difficulties was associated with worse global mental health and global physical health. Our study demonstrates overall good neuropsychiatric outcomes in 40 long-term survivors after CAR T cell therapy. However, nearly 50% of patients in the cohort reported at least 1 clinically meaningful negative neuropsychiatric outcome (anxiety, depression, or cognitive difficulty), indicating that a significant number of patients would likely benefit from mental health services following CAR T cell therapy. Younger age, pre-CAR T anxiety or depression, and acute neurotoxicity may be risk factors for long-term neuropsychiatric problems in this patient population. Larger studies are needed to confirm these findings., (Copyright © 2019 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Purpose: The outgrowth of antigen-negative variants is a significant challenge for adoptive therapy with T cells that target a single specificity. Chimeric antigen receptors (CAR) are typically designed with one or two scFvs that impart antigen specificity fused to activation and costimulation domains of T-cell signaling molecules. We designed and evaluated the function of CARs with up to three specificities for overcoming tumor escape using Designed Ankyrin Repeat Proteins (DARPins) rather than scFvs for tumor recognition., Experimental Design: A monospecific CAR was designed with a DARPin binder (E01) specific for EGFR and compared with a CAR designed using an anti-EGFR scFv. CAR constructs in which DARPins specific for EGFR, EpCAM, and HER2 were linked together in a single CAR were then designed and optimized to achieve multispecific tumor recognition. The efficacy of CAR-T cells bearing a multispecific DARPin CAR for treating tumors with heterogeneous antigen expression was evaluated in vivo ., Results: The monospecific anti-EGFR E01 DARPin conferred potent tumor regression against EGFR + targets that was comparable with an anti-EGFR scFv CAR. Linking three separate DARPins in tandem was feasible and in an optimized format generated a single tumor recognition domain that targeted a mixture of heterogeneous tumor cells, each expressing a single antigen, and displayed synergistic activity when tumor cells expressed more than one target antigen., Conclusions: DARPins can serve as high-affinity recognition motifs for CAR design, and their robust architecture enables linking of multiple binders against different antigens to achieve functional synergy and reduce antigen escape., (©2019 American Association for Cancer Research.)

Understanding the socioeconomic impact of chronic graft-versus-host disease (GVHD) on affected patients is essential to help improve their overall well-being. Using data from the Chronic GVHD Consortium, we describe the insurance, employment, and financial challenges faced by these patients and the factors associated with the ability to work/attend school and associated financial burdens. A 15-item cross-sectional questionnaire designed to measure financial concerns, income, employment, and insurance was completed by 190 patients (response rate, 68%; 10 centers) enrolled on a multicenter Chronic GVHD Consortium Response Measures Validation Study. Multivariable logistic regression models examined the factors associated with financial burden and ability to work/attend school. The median age of respondents was 56years, and 87% of the patients were white. A higher proportion of nonrespondents had lower income before hematopoietic cell transplantation and less than a college degree. All but 1 patient had insurance, 34% had faced delayed/denied insurance coverage for chronic GVHD treatments, and 66% reported a financial burden. Patients with a financial burden had greater depression/anxiety and difficulty sleeping. Nonwhite race, lower mental functioning, and lower activity score were associated with a greater likelihood of financial burden. Younger age, early risk disease, and higher mental functioning were associated with a greater likelihood of being able to work/attend school. In this multicenter cohort of patients with chronic GVHD, significant negative effects on finances were observed even with health insurance coverage. Future research should investigate potential interventions to provide optimal and affordable care to at-risk patients and prevent long-term adverse financial outcomes in this vulnerable group., (Copyright © 2018 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

A growing number of loci within the human leukocyte antigen (HLA) region have been implicated in non-Hodgkin lymphoma (NHL) etiology. Here, we test a complementary hypothesis of "heterozygote advantage" regarding the role of HLA and NHL, whereby HLA diversity is beneficial and homozygous HLA loci are associated with increased disease risk. HLA alleles at class I and II loci were imputed from genome-wide association studies (GWAS) using SNP2HLA for 3,617 diffuse large B-cell lymphomas (DLBCL), 2,686 follicular lymphomas (FL), 2,878 chronic lymphocytic leukemia/small lymphocytic lymphomas (CLL/SLL), 741 marginal zone lymphomas (MZL), and 8,753 controls of European descent. Both DLBCL and MZL risk were elevated with homozygosity at class I HLA-B and -C loci (OR DLBCL = 1.31, 95% CI = 1.06-1.60; OR MZL = 1.45, 95% CI = 1.12-1.89) and class II HLA-DRB1 locus (OR DLBCL = 2.10, 95% CI = 1.24-3.55; OR MZL = 2.10, 95% CI = 0.99-4.45). Increased FL risk was observed with the overall increase in number of homozygous HLA class II loci ( P trend < 0.0001, FDR = 0.0005). These results support a role for HLA zygosity in NHL etiology and suggests that distinct immune pathways may underly the etiology of the different NHL subtypes. Significance: HLA gene diversity reduces risk for non-Hodgkin lymphoma. Cancer Res; 78(14); 4086-96. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Background and Purpose: Whether changes in leisure-time physical activity (LTPA) over time are associated with lower risk of stroke is not well established. We examined the association between changes in self-reported LTPA 10 years apart, with risk of incident stroke in the CTS (California Teachers Study). We hypothesized that the risk of stroke would be lowest among those who remained active., Methods: Sixty-one thousand two hundred and fifty-six CTS participants reported LTPA at 2 intensity levels (moderate and strenuous activity) at 2 time points (baseline 1995-96; 10-year follow-up 2005-2006). LTPA at each intensity level was categorized based on American Heart Association (AHA) recommendations (moderate, >150 minutes/week; strenuous, >75 minutes/week). Changes in LTPA were summarized as follows: (1) not meeting recommendations at both time points; (2) meeting recommendations only at follow-up; (3) meeting recommendations only at baseline; and (4) meeting recommendations at both time points. Incident strokes were identified through California state hospitalization records. Using multivariable Cox models, we examined the associations between changes in LTPA with incident stroke., Results: Nine hundred and eighty-seven women were diagnosed with stroke who completed both questionnaires. Meeting AHA recommendations at both the time points was associated with a lower risk of all stroke (adjusted hazard ratio, 0.84; 95% confidence interval, 0.72-0.98). The protective effects for stroke were driven by meeting AHA recommendations for moderate activity and largely observed for ischemic strokes (adjusted hazard ratio, 0.70; 95% confidence interval, 0.55-0.88)., Conclusions: Meeting AHA recommendations for moderate activity had a protective effect for reducing ischemic stroke risk. Participants who met AHA recommendations at baseline but not at follow-up, however, were not afforded reduced stroke risk., (© 2017 American Heart Association, Inc.)

Background: Traditional methodologies for identifying and recruiting controls in epidemiologic case-control studies, such as random digit dialing or neighborhood walk, suffer from declining response rates. Here, we revisit the feasibility and comparability of using alternative sources of controls, specifically friend and family controls., Methods: We recruited from a recently completed case-control study of non-Hodgkin lymphoma (NHL) among women in Los Angeles County where controls from the parent study were ascertained by neighborhood walk. We calculated participation rates and compared questionnaire responses between the friend/family controls and the original matched controls from the parent study., Results: Of the 182 NHL case patients contacted, 111 (61%) agreed to participate in our feasibility study. 70 (63%) provided contact information for potential friend and/or family member controls. We were able to successfully contact and recruit a friend/family member for 92% of the case patients. This represented 46 friend controls and 54 family controls. Family controls significantly differed from original matched controls by sex and household income. Other characteristics were similar between friend controls and the original study's neighborhood controls., Conclusion: The apparent comparability of neighborhood controls to friend and family controls among respondents in this study suggests that these alternative methods of control identification can serve as a complementary source of eligible controls in epidemiologic case-control studies., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Autoimmune conditions and immune system-related genetic variations are associated with risk of non-Hodgkin lymphoma (NHL). In a pooled analysis of 8,692 NHL cases and 9,260 controls from 14 studies (1988-2007) within the International Lymphoma Epidemiology Consortium, we evaluated the interaction between immune system genetic variants and autoimmune conditions in NHL risk. We evaluated the immunity-related single nucleotide polymorphisms rs1800629 (tumor necrosis factor gene (TNF) G308A), rs1800890 (interleukin-10 gene (IL10) T3575A), rs6457327 (human leukocyte antigen gene (HLA) class I), rs10484561 (HLA class II), and rs2647012 (HLA class II)) and categorized autoimmune conditions as primarily mediated by B-cell or T-cell responses. We constructed unconditional logistic regression models to measure associations between autoimmune conditions and NHL with stratification by genotype. Autoimmune conditions mediated by B-cell responses were associated with increased NHL risk, specifically diffuse large B-cell lymphoma (odds ratio (OR) = 3.11, 95% confidence interval (CI): 2.25, 4.30) and marginal zone lymphoma (OR = 5.80, 95% CI: 3.82, 8.80); those mediated by T-cell responses were associated with peripheral T-cell lymphoma (OR = 2.14, 95% CI: 1.35, 3.38). In the presence of the rs1800629 AG/AA genotype, B-cell-mediated autoimmune conditions increased NHL risk (OR = 3.27, 95% CI: 2.07, 5.16; P-interaction = 0.03) in comparison with the GG genotype (OR = 1.82, 95% CI: 1.31, 2.53). This interaction was consistent across major B-cell NHL subtypes, including marginal zone lymphoma (P-interaction = 0.02) and follicular lymphoma (P-interaction = 0.04)., (© The Author 2015. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The role of medication use in multiple myeloma (MM) risk remains unclear., Methods: The Los Angeles County Multiple Myeloma Case-Control Study, comprising 278 MM cases and individually matched neighborhood controls, provided data to assess associations between medication use and MM risk. Odds ratios (OR) and 95 % confidence intervals (CI) were estimated using conditional logistic regression., Results: Erythromycin (ever) use was associated with increased MM risk (OR 1.85, 95 % CI 1.13-3.03). This association was restricted to men (OR 3.77, 95 % CI 1.72-8.29) and was especially apparent among men who took two or more courses of erythromycin (OR 4.68, 95 % CI 1.70-12.87)., Conclusions: Compared to females, males have lower levels of cytochrome P450 3A4 (CYP3A4), for which erythromycin is both a substrate and inhibitor. Use of CYP3A4-inhibiting drugs such as erythromycin in men may thus result in even lower levels of CYP3A4 and, consequently, higher levels of CYP3A4-metabolized substances. These results could potentially provide clues to explain discrepancies in MM incidence by sex. Consortial efforts to confirm these associations are warranted.

Background: Risk of developing multiple myeloma (MM) rises with age and is greater among men and blacks than among women and whites, respectively, and possibly increased among obese persons. Other risk factors remain poorly understood. By pooling data from two complementary epidemiologic studies, we assessed whether obesity, smoking, or alcohol consumption alters MM risk and whether female reproductive history might explain the lower occurrence of MM in females than in males., Methods: The Los Angeles County MM Case-Control Study (1985-1992) included 278 incident cases and 278 controls, matched on age, sex, race, and neighborhood of residence at case's diagnosis. We estimated MM risk using conditional logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs). In the prospective California Teachers Study (CTS), 152 women were diagnosed with incident MM between 1995 and 2009; we calculated hazard ratios using Cox proportional hazards analysis. Data from the two studies were pooled using a stratified, nested case-control sampling scheme (10:1 match) for the CTS; conditional logistic regression among 430 cases and 1,798 matched controls was conducted., Results: Obesity and smoking were not associated with MM risk in the individual or combined studies. Alcohol consumption was associated with decreased MM risk among whites only (pooled OR = 0.66, 95% CI = 0.49-0.90) for ever versus never drinking. Higher gravidity and parity were associated with increased MM risk, with pooled ORs of 1.38 (95 % CI = 1.01-1.90) for ≥3 versus 1-2 pregnancies and 1.50 (95% CI = 1.09-2.06) for ≥3 versus 1-2 live births., Conclusions: Female reproductive history may modestly alter MM risk, but appears unlikely to explain the sex disparity in incidence. Further investigation in consortial efforts is warranted.

Objective: Heterocyclic amines (HAA) are animal carcinogens that are present in meat cooked at high temperature and in tobacco smoke. These compounds require activation by cytochrome P450 1A2 (CYP1A2) and N-acetyltransferase-2 (NAT2) before they can damage DNA. This study tested the hypotheses that well-done meat and cigarette smoking increase the risk of adenoma, the precursor to most colorectal cancers, especially in individuals with rapid CYP1A2 and rapid NAT2 activities., Design: An endoscopy-based case-control study of adenoma was conducted among Caucasians, Japanese and native Hawaiians to test this hypothesis. The overall diet and consumption of well-done meat cooked by various high-temperature methods were assessed by interview in 1016 patients with a first adenoma and 1355 controls with a normal endoscopy. A caffeine test was used to assess CYP1A2 and NAT2 activities in 635 cases and 845 controls. Logistic regression was used to account for matching factors and potential confounders., Results: Smoking was associated with an increased risk of adenoma. Weak non-significant elevated OR were observed for the main effects of HAA intakes or NAT2 activity. However, the combined effects of HAA intakes and NAT2 activity were statistically significant. Subjects in both the upper tertiles of NAT2 activity and HAA intake were at increased risk of adenoma compared with subjects in the lower tertiles of NAT2 activity and exposure (2-amino-3,4,8-dimethylimidazo[4,5-f]quinoxaline intake OR 1.70, 95% CI I 1.06 to 2.75; 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline intake OR 1.91, 95% CI 1.16 to 3.16; and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine intake OR 2.14, 95% CI 1.31 to 3.49)., Conclusion: The data suggest that rapid N-acetylators with high HAA intake may be at increased risk of adenoma.