Timing of Toxicities and Non-relapse Mortality Following CAR T Therapy in Myeloma.

BACKGROUND: BCMA-directed chimeric antigen receptor T-cell (CAR T) therapies, including idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel), have transformed the treatment landscape for relapsed-refractory multiple myeloma (RRMM), offering remarkable efficacy with hallmark toxicity risks of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The FDA mandates a 4-week monitoring period at the treatment center as part of a Risk Evaluation and Mitigation Strategy (REMS) to monitor and manage these toxicities, which, while prudent, may add unnecessary challenges related to access and socioeconomic disparities. OBJECTIVE: We sought to assess CRS and ICANS onset and duration, as well as causes of non-relapse mortality (NRM) in real-world BCMA CAR T recipients in order to better inform future changes to the monitoring guidelines for CAR T recipients. STUDY DESIGN: This is a retrospective study across four academic centers that examined 129 ide-cel and cilta-cel recipients that received CAR T cell infusions from May 2021 to June 2023. Infusion and toxicities were managed per institutional guidelines in accordance with previously published guidelines. RESULTS: While differences were noted in the incidence and duration of CRS/ ICANS between ide-cel and cilta-cel, late-onset CRS and ICANS were rare after 2 weeks following infusion (0% and 1.6%, respectively). NRM was driven by hemophagocytic lymphohistiocytosis and infections in the early follow-up period (1.1% until Day 29), then by infections through three months post-infusion (1.2%). Our findings suggest that 25% of patients had to relocate for 4 weeks due to distance from the treatment center. CONCLUSIONS: With the low risk of CRS and ICANS after 2 weeks, a flexible shorter monitoring period may be reasonable, emphasizing collaboration with referring oncologists to improve NRM.

Safety and efficacy of eltrombopag in patients with post-CAR T cytopenias.

BACKGROUND: While chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment outcomes of relapsed/refractory hematological malignancies, this therapy is associated with post-treatment cytopenias, which can pose a challenge to its safe administration. This study describes the management of post-CAR T cytopenias using the thrombopoietin mimetic eltrombopag. METHODS: This retrospective analysis included adult patients with lymphoma or myeloma who received CAR T-cell therapy at two academic medical centers. Eltrombopag was initiated for patients who had persistent high-grade leukopenia and/or thrombocytopenia beyond 21 days post-CAR T infusion. Risk factors and outcomes were assessed and compared for patients who did or did not receive eltrombopag. RESULTS: Among the 185 patients analyzed, a majority (88%) experienced thrombocytopenia or leukopenia at day +30 post-CAR T infusion. A total of 42 patients met the criteria for eltrombopag treatment and initiated therapy. Patients who received eltrombopag were more likely to have pre-existing cytopenias at lymphodepletion, receive bridging therapy, experience an infection, or require intensive care. Recovery from cytopenias occurred within 180 days for a majority (94%) of patients. CONCLUSIONS: The use of eltrombopag for post-CAR T leukopenia and thrombocytopenia was considered safe without any significant toxicities. The use of eltrombopag for post-CAR T cytopenias might be effective in a high-risk patient population but requires further study.

"Waitlist mortality" is high for myeloma patients with limited access to BCMA therapy.

Background: The first-in-class approved BCMA CAR-T therapy was idecabtagene vicleucel (ide-cel), approved in March 2021, for RRMM patients who progressed after 4 or more lines of therapy. Despite the promising outcomes, there were limited apheresis/production slots for ide-cel. We report outcomes of patients at our institution who were on the "waitlist" to receive ide-cel in 2021 and who could not secure a slot. Methods: We conducted a retrospective review of RRMM patients evaluated at the University of Kansas Cancer Center for ide-cel from 3/2021-7/2021. A retrospective chart review was performed to determine patient and disease characteristics. Descriptive statistics were reported using medians for continuous variables. Survival analysis from initial consult was performed using Kaplan-Meier Survival estimator. Results: Forty patients were eligible and were on the "waitlist" for CAR-T. The median follow-up was 14 months (2-25mo). Twenty-four patients (60%) secured a production slot and 16 (40%) did not. The median time from consult to collection was 38 days (8-703). The median time from collection to infusion was 42 days (34-132 days). The median overall survival was higher in the CAR-T group (NR vs 9 mo, p<0.001). Conclusions: Many patients who were eligible for ide-cel were not able to secure a timely slot in 2021. Mortality was higher in this group, due to a lack of comparable alternatives. Increasing alternate options as well as improvement in manufacturing and access is an area of high importance to improve RRMM outcomes.

Efficacy and Safety of CD34+ Stem Cell Boost for Delayed Hematopoietic Recovery After BCMA Directed CAR T-cell Therapy.

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized treatment outcomes for patients with relapsed refractory multiple myeloma (RRMM). Despite supportive care with growth factors and thrombopoietin (TPO) mimetics, nearly half of the patients experience severe and prolonged cytopenias after CAR T infusion, which have become a major therapeutic challenge for patients with RRMM. Given the successful use of CD34+ autologous hematopoietic stem cells for treatment of non- or delayed engraftment after allogeneic and autologous stem cell transplantations, there is a need to explore the role of previously stored autologous stem cells as a boost for post-CAR T cytopenias in RRMM. We performed a multicenter retrospective analysis of adult patients with RRMM who received previously collected and stored CD34+ stem cell boosts after CAR T-cell therapy between 2 July 2020 and 18 January 2023. Indications for boost were determined per physician discretion and primarily included cytopenias and related complications. Overall, a total of 19 patients received stem cell boost, at a median dose of 2.75 × 106 CD34+ cells/kg (range 1.76-7.38), given at a median of 53 days (range 24-126) after CAR T infusion. Eighteen (95%) patients successfully recovered hematopoiesis after stem cell boost with median time for neutrophil, platelet, and hemoglobin engraftment of 14 (range 9-39), 17 (range 12-39), and 23 (range 6-34) days after the boost, respectively. Stem cell boosts were well tolerated, with no patients experiencing infusion reactions. Although infections were common and severe before stem cell boost, only 1 patient experienced a new infection after boost. All patients had experienced independence from use of growth factors, TPO agonists, and transfusions at the last follow-up. Autologous stem cell boosts can be effectively and safely used to promote hematopoietic recovery for post-CAR T cytopenias in patients with RRMM. Stem cell boosts can be a very effective rescue measure for post-CAR T cytopenias and related complications, as well as supportive care needs.

Patient Characteristics and Outcomes of Outpatient Tisagenlecleucel Recipients for B Cell Non-Hodgkin Lymphoma.

Tisagenlecleucel (tisa-cel) is an approved CD19-directed chimeric antigen receptor T cell (CAR-T) therapy for relapsed/refractory B cell malignancies. Given potentially life-threatening toxicities, including cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, inpatient tisa-cel infusion and toxicity monitoring are often considered; however, the toxicity profile of tisa-cel may be conducive to outpatient administration. Here we review the characteristics and outcomes of tisa-cel recipients treated in the outpatient setting. Patients age ≥18 years with B cell non-Hodgkin lymphoma who received tisa-cel between June 25, 2018, and January 22, 2021, at 9 US academic medical centers were included in a retrospective analysis. Six of the 9 representative centers (75%) had an outpatient program in place. A total of 157 patients were evaluable, including 93 (57%) in the outpatient treatment group and 64 (43%) in the inpatient treatment group. Baseline characteristics, toxicity and efficacy, and resource utilization were summarized. The most common lymphodepletion (LD) regimen was bendamustine in the outpatient group (65%) and fludarabine/cyclophosphamide (91%) in the inpatient group. The outpatient group had more patients with a Charlson Comorbidity Index of 0 (51% versus 15%; P < .001), fewer patients with an elevated lactate dehydrogenase (LDH) level above the normal range at the time of LD (32% versus 57%, P = .003) compared to the inpatient group, and a lower Endothelial Activation and Stress Index score (.57 versus 1.4; P < .001). Any-grade CRS and ICANS were lower in the outpatient group (29% versus 56% [P < .001] and 10% versus 16% [P = .051], respectively). Forty-two outpatient tisa-cel recipients (45%) required an unplanned admission, with a median length of stay of 5 days (range, 1 to 27 days), compared to 13 days (range, 4 to 38 days) in the inpatient group. The median number of tocilizumab doses administered was similar in the 2 groups as were the rate of intensive care unit (ICU) transfer (5% versus 8%; P = .5) and median length of ICU stay (6 days versus 5 days; P = .7). There were no toxicity-related deaths in the 30 days post-CAR-T infusion in either group. Progression-free survival and overall survival were similar in the 2 groups. With careful patient selection, outpatient tisa-cel administration is feasible and associated with similar efficacy outcomes as inpatient treatment. Outpatient toxicity monitoring and management may help optimize healthcare resource utilization.

Impact of Cytogenetic Abnormalities, Induction and Maintenance Regimens on Outcomes After High-Dose Chemotherapy and Autologous Stem Cell Transplantation in Patients With Newly Diagnosed Multiple Myeloma: A Decade-Long Real-World Experience.

Background: High-dose chemotherapy and autologous stem cell transplant (HDT-ASCT) has become a standard of care for transplant eligible newly diagnosed multiple myeloma (NDMM) patients. While cytogenetic abnormalities have been shown to affect outcomes after HDT-ASCT in clinical trials, these trials often exclude or underrepresent elderly patients with comorbidities and those belonging to ethnic minorities. We describe our institutional experience highlighting the impact of high-risk cytogenetic abnormalities (HRCAs) on outcomes after HDT-ASCT for NDMM patients. Methods: A total of 449 patients with NDMM who underwent HDT-ASCT between February 2012 and August 2022 were included in this retrospective analysis. HRCAs included the presence of one or more of: deletion 17p, t(14;16), t(4;14), and amplification 1q. Survival analyses, including progression-free survival (PFS) and overall survival (OS), were performed using Kaplan-Meier estimator. Results: With a median follow-up of 29 (1 - 128) months for the entire patient population, the best overall response rate for the patients with HRCAs was lower compared to those with standard risk cytogenetics (90% vs. 96%; P = 0.01). Patients with HRCAs had an inferior PFS compared to patients with standard-risk cytogenetics (29 vs. 58 months; P < 0.001) without a difference in OS (70 months vs. not reached; P = 0.13). Conclusions: In a multivariable analysis adjusting for factors including age, race, and comorbidities, HRCAs, non-lenalidomide-based maintenance, non-proteasome inhibitor-based maintenance, and age greater than 65 were associated with inferior PFS. Amongst these factors, only non-lenalidomide-based maintenance was associated with inferior OS.

Characteristics of clinical trials for haematological malignancies from 2015 to 2020: A systematic review.

BACKGROUND: As the landscape of haematological malignancies dramatically changes due to diagnostic and therapeutic advances, it is important to evaluate trends in clinical trial designs. The objective of our study was to describe the design of clinical trials for five common haematological malignancies with respect to randomisation and end-points. We also aimed to assess trends over time and examine the relationships of funding source and country of origin to proportions of randomisation and utilisation of clinical end-points. METHODS: This systematic review identified haematological malignancy clinical trials starting in 2015-2020 registered at ClinicalTrials.gov as of 20th February 2021. Trial-related variables including randomisation status, type of primary end-point, and both projected and actual enrolment numbers were captured. Clinical end-points were defined as overall survival and quality of life, while surrogate end-points included all other end-points. RESULTS: Of 2609 relevant trials included in this analysis, only one-fifth were randomised (538, 21%), with a significant decrease in the proportion of randomised clinical trials from 26% of trials in 2015 to 19% in 2020 (p < 0.00001). Between the years 2015 and 2020, the proportion of randomised trials for all haematological malignancies using primary surrogate end-points remained relatively consistent, ranging from 84% in 2015 to 78% in 2020 (p = 0.352). Overall, only 15% of trials utilised primary end-points of overall survival or quality of life in a randomised design. CONCLUSIONS: This systematic review of haematological malignancy trials found that the majority of trials are non-randomised and that there has been an increase in the ratio of non-randomised to randomised studies over time. The vast majority of randomised haematological malignancy trials use surrogate primary end-points.