Multiple myeloma (MM)

GSK announces positive result from the DREAMM-8 phase III trial (NCT04484623). This DREAMM-8 phase III open label clinical trial that randomized in a 1:1 ratio, 302 patients with MM previously treated with at least one prior line of therapy, including a lenalidomide-containing regimen, and who had documented disease progression during or after their most recent therapy, to receive either belantamab mafodotin plus PomDex, or bortezomib plus PomDex. The primary endpoint was achieved (progression-free survival, PFS).  Positive findings from DREAMM-7, a phase III head-to-head trial evaluating belantamab mafodotin in combination with bortezomib and dexamethasone (BorDex) versus daratumumab plus BorDex in the same treatment setting, were presented at the American Society of Clinical Oncology (ASCO) Plenary Series on 6 February 2024. We await the full publications of these two clinical trials.

T-prolymphocytic leukemia (T-PLL)

T-PLL is a rare, aggressive T-lymphoid malignancy with a poor prognosis and short durations of response with current therapies, including allogeneic stem cell transplantation (allo-SCT). This open-label, single-arm phase II study (NCT03873493) enrolled 14 patients. Patients received 420 mg oral ibrutinib once daily and oral venetoclax once daily starting with an in-hospital, 5-day, dose-accelerated 20-400 mg ramp-up, then continued treatment at 400 mg as an outpatient (see Supplemental Table 1). Patients could continue ibrutinib plus venetoclax for up to 2 years or until eligibility for SCT after reaching complete remission (CR), until progressive disease (PD), or unacceptable toxicity. The primary end point was overall response rate (ORR). There was 1 partial response (PR), yielding an ORR of 7.1% (95% confidence interval [CI], 0.2-33.9]. Three (21.4%) patients had stable disease; hence, the disease control rate was 28.6%. Nine (64.3%) patients had progressive disease as best response, and 1 patient discontinued the study before the first protocol–defined response assessment. Median PFS was 11.7 weeks (95% CI, 5.2-23.1). The median overall survival (OS) for all patients was 31.8 weeks (95% CI, 28.7-not evaluable). No patients achieved CR or were eligible for consolidation chemotherapy or salvage SCT.

High-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML)

A phase I trial assessing safety and efficacy of prophylactic maintenance therapy with venetoclax and azacitidine (Ven/Aza) for patients with high-risk MDS/acute myeloid leukemia (AML) undergoing reduced intensity allo-SCT after Ven and fludarabine/busulfan conditioning (Ven/FluBu2 allo-SCT) with tacrolimus and methotrexate as graft-versus-host disease (GVHD) prophylaxis. Among 27 patients who underwent Ven/FluBu2 allo-SCT, 22 received maintenance therapy with Aza at 36 mg/m² intravenously on days 1 to 5, and Ven at 400 mg by mouth on days 1 to 14 per assigned dose schedule/level (42-day cycles × 8, or 28-day cycles × 12). During maintenance, the most common grade 3-4 adverse events were leukopenia, neutropenia, and thrombocytopenia, which were transient and manageable. Infections were uncommon (n = 4, all grade 1-2). The 1-year and 2-year moderate/severe chronic GVHD rates were 4% (95% CI, 0.3%-18%) and 22% (95% CI, 9%-40%), respectively. After a median follow-up of 25 months among survivors, the median OS was not reached. Among the 22 patients who received Ven/Aza maintenance, the 2-year rates of OS, PFS, non-relapse mortality, and cumulative incidence of relapse were 67% (95% CI, 43%-83%), 59% (95% CI, 36%-76%), 0%, and 41% (95% CI, 20%-61%), respectively. This study demonstrates that prophylactic Ven/Aza maintenance can be safely administered to patients with high-risk MDS/AML, but a randomized study is required to properly assess any potential benefit.

Aplastic anemia (AA)

SOAR (NCT02998645), was a phase II, single-arm study investigating eltrombopag and cyclosporin (an antithyocyte globulin-free regimen) in 54 adult patients with severe AA who were treatment-naive. 35 (65%) patients completed 6 months of treatment with eltrombopag and cyclosporin and six (11%) completed the cyclosporin tapering period up to month 24. Overall haematological response rate by month 6 of treatment was 46% (25 of 54; 95% CI, 33–60).  Eight patients died on-treatment, but no deaths were considered treatment-related. Eltrombopag and cyclosporin was active as front-line treatment of severe AA, with no unexpected safety concerns. This approach might be beneficial where antithymocyte globulin is not available or not tolerated.

Chimeric antigen receptor (CAR)-T-cell therapy

Rare secondary T-cell lymphomas after CD19- and B-cell maturation antigen (BCMA)-directed CAR-T-cell therapy. Recently the US Food and Drug Administration (FDA) had become aware of 22 cases of T-cell cancers that occurred after treatment with CAR-T products. Such cancers have included: “T-cell lymphoma, T-cell large granular lymphocytosis, peripheral T-cell lymphoma, and cutaneous T-cell lymphoma”. Of the 14 cases for which sufficient data are currently available, the malignancies appeared 2o years (range: 1 to 19 months) following the infusion of CAR-T-cells.  Conclusions on the strength of an association with any product are precluded by the small number of instances and diversity in product use. In three cases for which genetic sequencing has been performed to date, the CAR transgene has been detected in the malignant clone, which indicates that the CAR-T product was most likely involved in the development of the T-cell cancer. Many times, sufficient lymphoma samples have been lost too soon to be tested using genome sequencing or polymerase chain reaction. The FDA plans to provide updates as substantive new information becomes available. It is important for clinicians caring for people who have received CAR-T-cells to report the occurrence of any new cancer. Clinical trial participants who receive treatment with these products must be monitored for new cancers. The overall benefits of CAR-T-cell products continue to outweigh potential risks for approved uses, but patients should be monitored, and events reported (post-marketing reporting can understate the number of these incidents).