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.

Efficacy and safety of daratumumab, pomalidomide, and dexamethasone versus daratumumab, carfilzomib, and dexamethasone in daratumumab-naïve relapsed multiple myeloma.

OBJECTIVES AND METHODS: We conducted a multicenter retrospective study to analyze the safety and efficacy of DPd versus DKd in daratumumab naïve RRMM patients treated in real-world practice. RESULTS: A total of 187 patients with RRMM were included in the analysis; 128 patients received DPd, and 59 patients received DKd. A vast majority (80%) of patients had lenalidomide refractory disease and nearly 50% had bortezomib refractory disease. The overall response and complete response rates were 76% and 34% in the DPd group versus 80% and 51% in the DKd group, respectively. With a median follow up of 36 months for the entire patient population, median PFS and OS in the DPd versus DKd groups were 12, 12, 37, and 35 months, respectively. The most common grade 3+ adverse events in the DPd versus DKd groups were neutropenia (32% vs. 7%), anemia (14% vs. 10%), thrombocytopenia (13% vs. 15%), and cardiovascular events (4% vs. 15%), respectively. Both DPd and DKd appeared to be a safe and effective treatment options for RRMM. CONCLUSIONS: While there were more cytopenias associated with DPd and more cardiovascular side effects with DKd, there were no significant differences in the survival outcomes with these two regimens.

TACTUM: Trends in Access to Cellular Therapies in Multiple Myeloma, Perspectives of Treating Versus Referring Physicians.

Chimeric antigen receptor T cell therapy (CAR-T) and bispecific T cell engagers (TCE) for multiple myeloma (MM) are readily available at many large US medical centers. However, many potentially eligible patients may not be referred to the specialized centers administering these therapies. Perspectives regarding potential barriers for MM cellular therapy from referring-center oncologists (ROs) versus treating-center oncologists (TOs) have not been reported previously. We conducted TACTUM-23, a survey of US oncologists who treat MM, to identify perceived barriers to these cellular therapies. This 24-question survey, which focused on demographics and perceived barriers to CAR-T and TCE, was conducted between June and August 2023. Of 247 oncologists, 37 (15%) completed the survey including 26 (70%) TOs who prescribed both CAR-T and TCEs, 4 (11%) TOs who only prescribed TCEs, and 7 (19%) ROs who referred patients. The top RO-stated barrier to CAR-T was financial toxicity, while the top TO-stated barrier to CAR-T was leukapheresis/ manufacturing slot availability. The top RO-stated barrier to TCE was financial toxicity, while the top TO-stated barrier to TCE was the hospitalization requirement. In conclusion, financial concerns are perceived by ROs to be the top barrier to both CAR-T and TCEs in myeloma. In contrast, TOs perceive logistical concerns to be the top barrier. Interventions to lower financial toxicity during these therapies, and outreach to raise awareness of such interventions among ROs, are needed alongside strategies to streamline manufacturing (for CAR-T) and monitoring.

The Glass Wall: Gendered Authorship Disparities in CD 19 and BCMA CAR-T Clinical Trials for Lymphoma and Myeloma.

INTRODUCTION: Existing literature suggests that women are significantly underrepresented in the field of hematology-oncology. Women make up 35.6% of hematologists and data on females as site investigators for pivotal trials and authors in publications of pivotal trials in hematologic malignancies, specifically in the novel niche of Chimeric antigen receptor T cell (CAR-T), is sparse. METHODS: We examined the proportion of women in pivotal trials, screening a total of 2180 studies from PubMed using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. 2180 initially searched records were filtered by date (2017-2023) and clinical trial status, yielding 149 records. Following a manual review, we included 15 studies that led to the approval of or anticipated approval of CD19 and BCMA CAR-T therapies in lymphoid and plasma cell malignancies. We examined overall number of female authors, number of lead female authors, and ratio of all authors to female authors in the 15 trials, which were all high impact, cited on average 1314 times. RESULTS: Of the 436 authors assessed, 132 were female, correlating to 29.5% female authorship. The only study with female authorship >50% was ELIANA, a 2017 pediatric study. 7 of the 15 studies had female lead authors; notably, 6 out of 7 of these studies were published in 2021 or later. CONCLUSION: In conclusion, our data suggests gender iniquities for female investigators exist in the field of immune effector cell therapy. We suggest further investigation and strategies to decrease gendered authorship disparities.

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

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. 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. 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. 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. 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.

Chemical synthesis of human syndecan-4 glycopeptide bearing O-, N-sulfation and multiple aspartic acids for probing impacts of the glycan chain and the core peptide on biological functions.

Proteoglycans are a family of complex glycoproteins with glycosaminoglycan chains such as heparan sulfate (HS) attached to the core protein backbone. Due to the high structural heterogeneity of HS in nature, it is challenging to decipher the respective roles of the HS chain and the core protein on proteoglycan functions. While the sulfation patterns of HS dictate many activities, the core protein can potentially impact HS functions. In order to decipher this, homogeneous proteoglycan glycopeptides are needed. Herein, we report the first successful synthesis of proteoglycan glycopeptides bearing multiple aspartic acids in the core peptide and O- and N-sulfations in the glycan chain, as exemplified by the syndecan-4 glycopeptides. To overcome the high acid sensitivities of sulfates and base sensitivities of the glycopeptide during synthesis, a new synthetic approach has been developed to produce a sulfated glycan chain on a peptide sequence prone to the formation of aspartimide side products. The availability of the structurally well-defined synthetic glycopeptide enabled the investigation of their biological functions including cytokine, growth factor binding and heparanase inhibition. Interestingly, the glycopeptide exhibited context dependent enhancement or decrease of biological activities compared to the peptide or the glycan alone. The results presented herein suggest that besides varying the sulfation patterns of HS, linking the HS chain to core proteins as in proteoglycans may be an additional approach to modulate biological functions of HS in nature.