Consensus recommendations on the management of toxicity associated with CD3×CD20 bispecific antibody therapy.

ABSTRACT: Bispecific antibodies (BsAb) that target CD3 and CD20 represent a new milestone in the treatment of patients with B-cell non-Hodgkin lymphoma. These drugs have demonstrated remarkable single-agent activity in patients with heavily pretreated disease, and 3 drugs have so far received regulatory approvals in various countries. However, BsAbs can potentially lead to severe toxicity associated with T-cell activation, particularly cytokine release syndrome (CRS). The anticipated widespread use of these off-the-shelf products poses challenges for implementation and highlights the need for guidance in anticipating, mitigating, and managing adverse events. In clinical trials, guidance for the evaluation and treatment of CRS and neurotoxicity associated with BsAb therapy has been modeled after algorithms originally created for chimeric antigen receptor (CAR) T-cell therapies and other immune effector therapies, yet notable differences in timing, quality, and severity exist between the toxicities of BsAbs and CAR T-cell therapies. We therefore convened an international panel of academic and community practice physicians, advanced practitioners, registered nurses, and pharmacists with experience using CD3×CD20 BsAbs in clinical trial and off-trial settings to provide comprehensive, consensus-based recommendations specific to the assessment and management of CD3×CD20 BsAb-related toxicities.

Real-world evidence of the safety and survival with CD19 CAR-T cell therapy for relapsed/refractory solid organ transplant-related PTLD.

The use of CD19 chimeric antigen receptor T-cell (CAR-T) therapy for relapsed/refractory solid organ transplantation (SOT)-related post-transplant lymphoproliferative disorder (PTLD) is not well studied. We conducted a multicentre, retrospective analysis of adults with relapsed/refractory SOT-associated PTLD. Among 22 relapsed/refractory SOT-PTLD patients, the pathology was monomorphic B cell. Prior SOTs included 14 kidney (64%), three liver (14%), two heart (9%), one intestinal (5%), one lung (5%), and one pancreas after kidney transplant (5%). The median time from SOT to PTLD diagnosis was 107 months. Pre-CAR-T bridging therapy was used in 55% of patients, and immunosuppression was stopped completely before CAR-T infusion in 64%. Eighteen (82%) patients experienced cytokine release syndrome: one (5%) each grade (G) 3 and G4. The immune effector cell-associated neurotoxicity syndrome was observed in 16 (73%) patients: six (27%) G3 and two (9%) G4. The overall response rate was 64% (55% complete response). Three patients (14%) experienced allograft rejection after CAR-T. The two-year progression-free survival and overall survival rates were 35% and 58%, respectively. Additionally, the achievement of CR post-CAR-T was strongly associated with survival. Collectively, the safety and efficacy of CD19 CAR-T therapy in relapsed/refractory SOT-related PTLD appeared similar to pivotal CAR-T data, including approximately one-third of patients achieving sustained remission.

The Management of older patients with Hodgkin lymphoma: implications of S1826.

Classical Hodgkin lymphoma (cHL) is diagnosed in patients ages 60 and older in approximately 20%-25% of cases in Western populations. Outcomes in this subset of patients have historically been poor, with 5-year progression free survival (PFS) and overall survival rates significantly lower than those seen in younger patients. Challenges to overcome include age-related co-morbidities, and prominent and potentially lethal treatment-related toxicity. There have been increased efforts to study the older cHL patient population, including analysis of geriatric assessments and the integration of newer targeted therapies such as brentuximab vedotin (BV) and nivolumab (N) into treatment paradigms. A recent phase 3 clinical trial (S1826, NCT03907488) led by the North American oncology cooperative groups compared brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (BV-AVD) with nivolumab, doxorubicin, vinblastine, and dacarbazine (N-AVD). At a median follow-up of 1-year, N-AVD improved PFS vs BV-AVD in patients and few immune adverse events were observed. Moreover, in a pre-planned subset analyses of cHL patients ages ≥60 years, the 1-year PFS for N-AVD was 93% (95% CI, 79%-98%) versus 64% (95% CI, 45%-77%) for BV-AVD. In addition, N-AVD was largely better tolerated particularly in older patients, which included markedly less neuropathy, lower treatment discontinuation, and less nonrelapse mortality. As a result, N-AVD is poised to become a standard of care for older, advanced-stage cHL patients who are fit for full-dose anthracycline-based combination therapy. More studies are needed to continue to improve outcomes for older cHL patients, especially unfit and frail populations.

A phase I study of CPX-351 in combination with busulfan and fludarabine conditioning and allogeneic stem cell transplantation in adult patients with refractory acute leukemia.

This phase I study evaluated the maximal tolerated dose of CPX-351 when administered sequentially with allogeneic hematopoietic stem cell transplantation (HSCT) in patients with refractory acute leukemia. CPX-351 is a novel liposomal formulation that combines cytosine arabinoside (ara-c) and daunorubicin in a fixed molar ratio of 5:1. Patients in cohorts of 3 were treated with CPX-351 followed by fludarabine and busulfan (Bu/Flu) conditioning at 4-week (schedule A) or 3-week (schedule B) intervals. CPX-351 doses were escalated in 20-U/m(2) increments starting at 60 U/m(2) for 3 doses. Of the 36 patients enrolled, 29 were able to undergo HSCT, and the other 7 (the majority on schedule A) did not proceed to HSCT because of rapid disease progression. The maximal tolerated dose of CPX-351 was not reached at the 120 U/m(2) × 3 dose level. All 29 patients who proceeded to HSCT demonstrated adequate neutrophil and platelet engraftment. The median follow-up on the study for all 36 patients was 205 days (range, 20 to 996 days). The 1-year cumulative incidence of relapse for the 36 patients was 60.1% (95% confidence interval [CI], 43.4% to 77.3%), and that of nonrelapse mortality was 23.8% (95% CI, 10.9% to 47.4%). The 1-year overall survival and leukemia-free survival were 37% (95% CI, 21% to 53%) and 27% (95% CI, 13% to 43%), respectively. Our data suggest that a phase II trial should incorporate CPX-351 120 U/m(2) × 3 dosing on schedule B. Patients with good performance status and those who achieve effective cytoreduction from CPX-351 derived the greatest benefit.

Hodgkin lymphoma treatment for older persons in the modern era.

There has been a renewed effort globally in the study of older Hodgkin lymphoma (HL) patients, generating a multitude of new data. For prognostication, advancing age, comorbidities, altered functional status, Hispanic ethnicity, and lack of dose intensity (especially without anthracycline) portend inferior survival. Geriatric assessments (GA), including activities of daily living (ADL) and comorbidities, should be objectively measured in all patients. In addition, proactive multidisciplinary medical management is recommended (eg, geriatrics, cardiology, primary care), and pre-phase therapy should be considered for most patients. Treatment for fit older HL patients should be given with curative intent, including anthracyclines, and bleomycin should be minimized (or avoided). Brentuximab vedotin given sequentially before and after doxorubicin, vinblastine, dacarbazine (AVD) chemotherapy for untreated patients is tolerable and effective, and frontline checkpoint inhibitor/AVD platforms are rapidly emerging. Therapy for patients who are unfit or frail, whether due to comorbidities and/or ADL loss, is less clear and should be individualized with consideration of attenuated anthracycline-based therapy versus lower-intensity regimens with inclusion of brentuximab vedotin +/- checkpoint inhibitors. For all patients, there should be clinical vigilance with close monitoring for treatment-related toxicities, including neurotoxicity, cardiopulmonary, and infectious complications. Finally, active surveillance for "postacute" complications 1 to 10 years post therapy, especially cardiac disease, is needed for cured patients. Altogether, therapy for older HL patients should include anthracycline-based therapy in most cases, and novel targeted agents should continue to be integrated into treatment paradigms, with more research needed on how best to utilize GAs for treatment decisions.

Matched Cohort Study of Convalescent COVID-19 Plasma Treatment in Severely or Life Threateningly Ill COVID-19 Patients.

BACKGROUND: The utility of convalescent coronavirus disease 2019 (COVID-19) plasma (CCP) in the current pandemic is not well defined. We sought to evaluate the safety and efficacy of CCP in severely or life threateningly ill COVID-19 patients when matched with a contemporaneous cohort. METHODS: Patients with severe or life-threatening COVID-19 were treated with CCP according to Food and Drug Administration criteria, prioritization by an interdisciplinary team, and based on CCP availability. Individual-level matched controls (1:1) were identified from patients admitted during the prior month when no CCP was available. The safety outcome was freedom from adverse transfusion reaction, and the efficacy outcome was a composite of death or worsening O2 support. Demographic, clinical, and laboratory data were analyzed by univariate and multivariable regression analyses accounting for matched design. RESULTS: Study patients (n = 94, 47 matched pairs) were 62% male with a mean age of 58, and 98% (90/94) were minorities (53% Hispanic, 45% Black, non-Hispanic) in our inner-city population. Seven-day composite and mortality outcomes suggested a nonsignificant benefit in CCP-treated patients (adjusted hazard ratio [aHR], 0.70; 95% CI, 0.23-2.12; P = .52; aHR, 0.23; 95% CI, 0.04-1.51; P = .13, respectively). Stratification by pretransfusion mechanical ventilation status showed no differences between groups. No serious transfusion reactions occurred. CONCLUSIONS: In this short-term matched cohort study, transfusion with CCP was safe and showed a nonsignificant association with study outcomes. Randomized and larger trials to identify appropriate timing and dosing of CCP in COVID-19 are warranted. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04420988.