T-cell-based cellular therapy was first approved in lymphoid malignancies (B-cell acute lymphoblastic leukemia and large B-cell lymphoma) and expanding its investigation and application both in ...hematological and non-hematological malignancies. Two anti-BCMA (B cell maturation antigen) CAR (Chimeric Antigen Receptor) T-cell therapies have been recently approved for relapsed and refractory multiple myeloma with excellent efficacy even in the heavily pre-treated patient population. This new therapeutic approach significantly changes our practice; however, there is still room for further investigation to optimize antigen receptor engineering, cell harvest/selection, treatment sequence, etc. They are also associated with unique adverse events, especially CRS (cytokine release syndrome) and ICANS (immune effector cell-associated neurotoxicity syndrome), which are not seen with other anti-myeloma therapies and require expertise for management and prevention. Other T-cell based therapies such as TCR (T Cell Receptor) engineered T-cells and non-genetically engineered adoptive T-cell transfers (Vγ9 Vδ2 T-cells and Marrow infiltrating lymphocytes) are also actively studied and worth attention. They can potentially overcome therapeutic challenges after the failure of CAR T-cell therapy through different mechanisms of action. This review aims to provide readers clinical data of T-cell-based therapies for multiple myeloma, management of unique toxicities and ongoing investigation in both clinical and pre-clinical settings.
Early precursor T cell-acute lymphoblastic leukemia (ETP-ALL) is a rare entity characterized by chemo-resistance and a paucity of data regarding optimal management. We review here the literature ...regarding the management of ETP-ALL and focus on the recent, emerging data, regarding the potential role of molecularly targeted approaches with a focus on venetoclax.
Abstract
Although several decades have passed since the description of myeloproliferative neoplasms (MPN), many aspects of their pathophysiology have not been elucidated. In this review, we discuss ...the mutational landscape of patients with essential thrombocythemia (ET), prognostic scores and salient pathology, and clinical points. We discuss also the diagnostic challenges of differentiating ET from prefibrotic MF.
We then focus on post-essential thrombocythemia myelofibrosis (post-ET MF), a rare subset of MPN that is usually studied in conjunction with post-polycythemia vera MF. The transition of ET to post-ET MF is not well studied on a molecular level, and we present available data. Patients with secondary MF could benefit from allogenic hematopoietic stem cell transplantation, and we present available data focusing on post-ET MF.
Clinical experience of CAR T cells for multiple myeloma Simmons, Gary L.; Satta, Toshihisa; Castaneda Puglianini, Omar
Best practice & research. Clinical haematology,
September 2021, 2021-09-00, 20210901, Letnik:
34, Številka:
3
Journal Article
Recenzirano
Important advances in the treatment landscape of multiple myeloma (MM) had been seen over the past two decades leading to improved overall survival but despite the progress multiple myeloma is still ...considered incurable and the prognosis of the pentarefractory patients have been poor. The development of immunotherapy and in particular adoptive cell therapy with chimeric antigen receptor (CAR) T cells have dramatically improved the outcomes of heavily pretreated relapsed/refractory MM patients. The bulk of CAR T-cell constructs currently in clinical development target the B-cell maturation antigen (BCMA) and to date only idecabtagene vicleucel (ide-cel) is approved by the Food and Drug Administration (FDA) for commercial use in adult patients with relapsed or refractory MM based on the promising clinical responses and positive safety record shown in the pivotal KarMMa study. This review focus on the development of CAR T-cell therapy for multiple myeloma as well as a brief review of the mechanisms of resistance, toxicity and new approaches under development.
We investigated whether a dendritic cell (DC) vaccine transduced with an adenoviral vector encoded with full-length survivin (Ad-S), with mutations neutralizing its antiapoptotic function, could ...safely generate an immune response and deepen clinical responses when administered before and after autologous stem cell transplant (ASCT) for multiple myeloma.
This phase I first-in-human trial (NCT02851056) evaluated the safety of DC:Ad-S in newly diagnosed multiple myeloma not having achieved complete response with induction, given 7 to 30 days prior to stem cell collection and 20 to 34 days after ASCT. Anti-survivin antibodies and CD4+ and CD8+ specific T cells were quantified.
A total of 14 patients were treated and 13 included in the primary efficacy analysis. No serious adverse events were attributed to DC:Ad-S vaccine. Detectable anti-survivin antibodies increased from baseline in 9 of 13 (69%) patients, and 11 of 13 (85%) mounted either a cellular or humoral immune response to survivin. Seven patients had an improved clinical response at day +90, all of whom had mounted an immune response, and 6 of 7 patients remain event-free at a median follow-up of 4.2 years. Estimated progression-free survival at 4 years is 71% (95% confidence interval, 41-88).
Two doses of DC:Ad-S, one given immediately before and another after ASCT, were feasible and safe. A high frequency of vaccine-specific immune responses was seen in combination with durable clinical outcomes, supporting ongoing investigation into the potential of this approach. See related commentary by Dhodapkar, p. 4524.
While response rates and survival outcomes have been very promising for idecabtagene vicleucel (ide-cel), a proportion of patients do not respond or relapse early after this B-cell maturation antigen ...(BCMA) targeted chimeric antigen receptor (CAR) T-cell therapy. Understanding the characteristics of these patients is important for patient selection and development of novel strategies to improve outcomes. We evaluated factors associated with early progression (progression or death due to myeloma ≤3 months after CAR T-cell infusion) in patients treated with standard of care ide-cel at 11 US academic centers. Among 211 patients that received ide-cel, 43 patients had a progressive event ≤3 months of infusion. Patients with a history of extramedullary disease, prior BCMA targeted therapy, elevated ferritin at lymphodepletion, use of bridging therapy, Hispanic ethnicity, plasma cell leukemia and t(4;14) were more likely to progress ≤3 months of infusion (P<0.05). Of these risk factors for early progression identified in univariate analyses, history of extramedullary disease, prior BCMA targeted therapy, elevated ferritin at lymphodepletion, plasma cell leukemia, and t(4;14) were associated with worse progression-free survival (PFS) in multivariable analysis. Presence of three or more of these factors had a significant negative impact on PFS (P<0.001; median PFS for ≥3 factors, 3.2 months vs. 0 factors, 14.1 months). This study helps identify patients at high risk of early progression after CAR T-cell therapy who may benefit from specific interventions pre and post CAR T-cell therpy to improve outcomes.
•Grade ≥ 3 cytopenias were at their worst at day 7 after ide-cel (94% of patients) but persisted in 40% at day 90, particularly thrombocytopenia.•Infections within 30 days of ide-cel were typically ...bacterial (68%) and severe (50%); moderate viral infections were more prevalent later.
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Idecabtagene vicleucel (ide-cel) was FDA-approved in March 2021 for the treatment of relapsed/refractory multiple myeloma after 4 lines of therapy. On the KarMMa trial, grade ≥ 3 cytopenias and infections were common. We sought to characterize cytopenias and infections within 100 days after ide-cel in the standard-of-care (SOC) setting. This multi-center retrospective study included 52 patients who received SOC ide-cel; 47 reached day-90 follow-up. Data were censored at day 100. Grade ≥ 3 cytopenia was present among 65% of patients at day 30 and 40% of patients at day 90. Granulocyte colony stimulating factor (G-CSF) was administered to 88%, packed red blood cell transfusions to 63%, platelet transfusions to 42%, thrombopoietin (TPO) agonists to 21%, intravenous immunoglobulin to 13%, and CD34+ stem cell boosts to 8%. At day 100, 19% and 13% of patients had ongoing use of TPO agonists and G-CSF, respectively. Infections occurred in 54% of patients and were grade ≥ 3 in 23%. Earlier infections in the first 30 days were typically bacterial (68%) and severe (50%). Later infections between days 31 and 100 were 50% bacterial and 42% viral; only 13% were grade ≥ 3. On univariate analysis, high pre-CAR-T marrow myeloma burden (≥ 50%), circulating plasma cells at pre-lymphodepletion (LD), and grade ≥ 3 anemia at pre-LD were associated with grade ≥ 3 cytopenia at both days 30 and 90. Longer time from last bridging treatment to LD was the only significant risk factor for infection.
Immunotherapy has revolutionized the treatment of cancers. There are several approaches, including naked monoclonal antibodies, antibody–drug conjugates, immune-checkpoint inhibitors and chimeric ...antigen receptor T cell therapies with important success. Bispecific antibodies represent a novel immunotherapeutic approach for the treatment of several malignancies, in particular non-Hodgkin’s lymphoma (NHL) and multiple myeloma (MM). Early-phase studies have shown encouraging clinical activity in poor-risk B cell NHL and MM. Several constructs are currently available and in clinical development for the treatment of these malignancies. Here, we present a narrative review of the most current data on bispecific antibodies in B cell NHL and MM.
•Ide-cel CAR-T for RRMM is associated with a cardiac event profile similar to that of anti-CD19 CAR-T.•Worse baseline functional status and higher-grade CRS and neurotoxicity are associated with ...cardiac events after ide-cel CAR-T.
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Idecabtagene vicleucel (ide-cel) is a type of B-cell maturation antigen (BCMA)–targeting chimeric antigen receptor T-cell (CAR-T) approved for the treatment of relapsed and refractory multiple myeloma (RRMM). Currently, the incidence of cardiac events associated with ide-cel remains unclear. This was a retrospective single-center observational study of patients treated with ide-cel for RRMM. We included all consecutive patients who received standard-of-care ide-cel treatment at least 1-month follow-up. Baseline clinical risk factors, safety profile, and responses were examined based on the development of a cardiac event. A total of 78 patients were treated with ide-cel, and 11 patients (14.1%) developed cardiac events: heart failure (5.1%), atrial fibrillation (10.3%), nonsustained ventricular tachycardia (3.8%), and cardiovascular death (1.3%). Only 11 of the 78 patients had repeat echocardiogram. Baseline risk factors associated with the development of cardiac events included being female sex and having poor performance status, λ light-chain disease, and advanced Revised International Staging System stage. Baseline cardiac characteristics were not associated with cardiac events. During index hospitalization after CAR-T, higher-grade (≥grade 2) cytokine release syndrome (CRS) and immune cell–associated neurologic syndrome were associated with cardiac events. In multivariable analyses, the hazard ratio for the association of the presence of cardiac events with overall survival (OS) was 2.66 and progression-free survival (PFS) was 1.98. Ide-cel CAR-T for RRMM was associated with similar cardiac events as other types of CAR-T. Worse baseline performance status and higher-grade CRS and neurotoxicity were associated with cardiac events after BCMA-directed CAR-T-cell therapy. Our results suggest that the presence of cardiac events may confer worse PFS or OS; although because of the small sample size, the power to detect an association was limited.
Idecabtagene vicleucel (Ide-cel) has demonstrated excellent efficacy and durable responses in patients with relapsed/refractory multiple myeloma (RRMM). However, the outcomes with ide-cel in patients ...with extramedullary disease (EMD) remain incompletely characterized. We included patients with RRMM treated with ide-cel between May 2021 and April 2023 across 11 US academic institutions. Visceral or soft tissue lesions non-contiguous from bone was classified as EMD. Time-to-event analyses were performed from date of ide-cel infusion. Among 351 patients, 84 (24%) had EMD prior to infusion. The median follow-up from ide-cel infusion was 18.2 months (95% CI: 17-19.3). The day 90 overall response rates (ORR) were 52% vs. 82% for the EMD and non-EMD cohorts, respectively (p < 0.001). The median progression-free survival (PFS) was 5.3 months (95% CI: 4.1-6.9) for the EMD cohort vs. 11.1 months (95% CI: 9.2-12.6; p < 0.0001) for the non-EMD cohort. In a multivariable analysis, EMD was an independent predictor of inferior PFS hazard ratio 1.5 (1.1-2.2), p = 0.02. The median overall survival was 14.8 months 95% CI: 9-Not reached (NR) vs. 26.9 months (26.3 vs. NR, p = 0.006) for the EMD and non-EMD cohorts, respectively. Extramedullary disease represents an independent predictor of inferior day 90 ORR and PFS among patients treated with ide-cel. Keywords: BCMA CAR-T, Ide-cel, Relapsed/refractory myeloma, Radiation, Immunotherapy
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