Isatuximab, Bortezomib, Lenalidomide, and Dexamethasone for Multiple Myeloma [Clinical trial]

Highlights(s): Isatuximab plus bortezomib, lenalidomide, and dexamethasone (VRd) was more effective than VRd as initial therapy in patients with newly diagnosed multiple myeloma (NDMM) who were ineligible to undergo transplantation.

This study (IMROZ, NCT03319667) was presented at the 2024 meeting of the European Hematology Association (Madrid, Spain; 13 to 16 June).  The original study was published this week in the New England Journal of Medicine.  

This is an international, open-label, phase 3 trial in which 446 patients aged 18 to 80 years with NDMM who were ineligible for transplantation were randomly assigned in a 3:2 ratio to receive either isatuximab-VRd or VRd alone. The primary efficacy endpoint was progression-free survival (PFS).

At a median follow-up of 59.7 months, the estimated PFS at 60 months was 63.2% in the isatuximab-VRd group, as compared with 45.2% in the VRd group (hazard ratio [HR] for disease progression or death, 0.60; 98.5% confidence interval, 0.41 to 0.88; p<0.001). The percentage of patients with a complete response (CR) or better was significantly higher in the isatuximab-VRd group than in the VRd group (74.7% vs. 64.1%, p= 0.01), as was the percentage of patients with minimal residual disease negative status and a CR (55.5% vs. 40.9%, p=0.003). No new safety signals were observed with the isatuximab-VRd regimen. The incidence of serious adverse events during treatment and the incidence of adverse events leading to discontinuation were similar in the two groups.

Proposals for revised International Working Group–European LeukemiaNet criteria for anemia response in myelofibrosis [Consensus]

An international panel of 38 experts and clinical trialists in myelofibrosis (MF) participated in preparing this document. The initial draft of the 2024 International Working Group–European LeukemiaNet (IWG-ELN) proposed criteria were subsequently circulated to a broader group of international experts, and their feedback was incorporated. The proposed articles include new definitions for transfusion-dependent anemia (TDA [≥ three units in the 12 weeks before study enrollment]) and hemoglobin thresholds for eligibility criteria (<10 g/dL for women and <11 g/dL for men). The revised document also provides separate (TDA vs. non-TDA) and graded (major vs. minor response) response criteria while preserving the requirement for 12 weeks of screening and observation on treatment (See Table 3 in the original article). Here is a summary: 

- Anemia response criteria:

- Major response for TDA: No transfusions x 12wk and rolling 12-wk average. Hemoglobin (HB) increase of ≥1.5 g/dL from pretreatment baseline.

- Major response for non-TDA: Rolling 12-week average Hb increase of ≥1.5 g/dL from pretreatment baseline (also requires no transfusions).

- Minor response for TDA: a  ≥ 50% reduction in transfusions.

- Minor response for non-TDA: Rolling 12-week average Hb increase of  ≥ 1.0g/dL from pretreatment baseline.

- Progressive anemia: TDA, ≥ 50% increase in transfusion requirement. Non-TDA, Hb decrease of >1.5g/dL from baseline, or meeting criteria for TDA.

Valemetostat for patients with relapsed or refractory peripheral T-cell lymphoma (VALENTINE-PTCL01): a multicentre, open-label, single-arm, phase 2 study  [Clinical trial]

Highlights(s): These data show that treatment with valemetostat leads to durable responses in patients with relapsed or refractory peripheral T-cell lymphoma (R/R PTCL) and has a manageable safety profile. This study provides a rationale for further exploring valemetostat in a confirmatory randomized trial.

VALENTINE-PTCL01 (NCT04703192) was a multicenter, open-label, single-arm, phase 2 trial in 12 countries across Asia, Europe, North America, and Oceania. Patients (n=155) with either PTCL (n=133) or adult T-cell leukemia/lymphoma (ATLL, n=22), aged ≥18 years with an Eastern Cooperative Oncology Group performance status of 0–2 received oral valemetostat (a potent, novel, dual inhibitor of EZH2 and EZH1) at 200 mg per day in continuous 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint for patients with PTCL  was the computed tomography-based objective response rate by blinded independent central review using 2014 Lugano response criteria. The primary endpoint for patients with ATLL was the safety and tolerability of valemetostat.

133 patients with R/R PTCL (median age 69·0 years, interquartile range [IQR] 58.0–74.0) and 22 patients with ATLL (66.5 years, IQR 54.0–73.0) were enrolled. The median follow-up time was 12.3 months (95% confidence interval [CI] 11.8–13.8). 52 (44%; 95% CI 35–53) of 119 efficacy-evaluable patients with R/R PTCL had an objective response. The most common grade 3−4 adverse events were thrombocytopenia (31 [23%] of 133 patients in the PTCL group and 11 [50%] of 22 patients in the ATLL group), anemia (25 [19%] and ten [46%]), and neutropenia (23 [17%] and four [18%]). Serious treatment-emergent adverse events were reported in 53 (40%) patients with PTCL and 15 (68%) patients with ATLL; nine (7%) patients and one (5%) patient had a serious treatment-emergent adverse event considered to be treatment-related, respectively. Treatment-emergent adverse events were generally manageable and infrequently required treatment discontinuation (10% of patients with PTCL and 9% of those with ATLL). No treatment-related deaths were reported.

Zanubrutinib, Obinutuzumab, and Venetoclax for First-Line Treatment of Mantle Cell Lymphoma with a TP53 Mutation [Clinical trial]

Highlight(s): Zanubrutinib, obinutuzumab, and venetoclax were safe and effective for the frontline treatment of TP53-mutant mantle cell lymphoma (MCL). The 2-year progression-free survival (PFS) of 72% compares favorably with previously reported outcomes with chemoimmunotherapy in TP53-mutant MCL.

This was a multicenter phase 2 study (NCT03824483) of zanubrutinib (Bruton tyrosine kinase inhibitor), obinutuzumab (anti-CD20), and venetoclax (anti-BCL-2) (BOVen) in untreated MCL patients with TP53 mutation. Patients initially received zanubrutinib 160mg twice daily and obinutuzumab (1000mg on cycle 1, days 1, 8, 15, and day 1 of cycles 2-8). After two cycles, venetoclax was added with weekly dose-ramp up to 400mg daily. Treatment consisted of at least 24 cycles. After 24 cycles, for patients achieving a complete response (CR) with undetectable minimal residual disease (MRD) by immuno-sequencing, at a sensitivity level of 1x10^-6 (uMRD6) in peripheral blood and bone marrow, treatment was discontinued. The primary endpoint was met if 311 patients were progression-free at 2 years. The study included 25 patients with untreated MCL with TP53 mutation. The best overall response rate was 96% (24/25), and the CR rate was 88% (22/25). Frequency of uMRD6 at cycle 13 was 84% (16/19). With a median follow-up of 28.2 months, the primary endpoint was met with a 2-year PFS of 72%, and the 2-year disease-specific and overall survival were 91% and 76%, respectively. Common side effects were generally low-grade and included diarrhea (64%), neutropenia (32%), and infusion-related reactions (24%). BOVen was well tolerated and met its primary efficacy endpoint in TP53-mutant MCL.

Molecular mechanisms promoting long-term cytopenia after BCMA CAR-T therapy in multiple myeloma [Retrospective and basic research study]

Highlights(s): Long-lasting cytopenia after B-cell maturation antigen (BCMA)  chimeric antigen receptor (CAR)-T-cell therapy correlates with baseline cytopenia and peak inflammatory markers. Ex vivo findings indicate that activated CAR-T cells secrete proinflammatory substances that impair hematopoietic differentiation and reshape transcriptional programs, which could help to explain the persistence of the hematopoietic toxicity observed because damage seems to happen early in the hematopoietic hierarchy.

This study aimed to characterize 48 patients with relapsed/refractory (R/R) multiple myeloma (MM) treated with BCMA CAR-T cells to gain insight into the kinetics of cytopenia, identify predictive factors, and determine potential mechanisms underlying these toxicities. Overall, 95.7% of patients experienced cytopenia and grade >3 thrombocytopenia and neutropenia, one month after infusion, was observed in 57% and 53% of patients, respectively. These toxicities persisted in four and three patients, respectively, one year after infusion. Baseline cytopenia and elevated peak inflammatory markers were found to be significantly correlated with the persistence of cytopenia for up to three months.

These results are consistent with previous observations in patients with MM who were treated with CAR-T cells and with the CAR-HEMATOTOX model for predicting hematologic toxicity in patients with R/R large B-cell lymphoma in that baseline cytopenia and inflammatory markers were correlated with the duration of cytopenia.

To ascertain the potential mechanisms underlying cytopenias, the researchers evaluated the paracrine effect of BCMA CAR-T cells on hematopoietic stem and progenitor cell (HSPC) differentiation using an ex vivo myeloid differentiation model. Phenotypic analysis demonstrated that supernatants from activated CAR-T cells (spCAR) impeded the differentiation of HSPCs, promoting more immature phenotypes. This effect could be prevented with a combination of interferon γ, tumor necrosis factor α/β, transforming growth factor β, interleukin-6 (IL-6), and IL-17 inhibitors. Single-cell RNA sequencing revealed an increase in the expression of transcription factors linked to the early stages of hematopoietic differentiation in the presence of spCAR (GATA2, RUNX1, CEBPA) and a reduction in the activity of critical regulons involved in neutrophil and monocytic maturation (ID2 and MAFB).

Intensive chemotherapy after hypomethylating agent and venetoclax in adult acute myeloid leukemia [Retrospective study]

Highlight(s): After hypomethylating agent plus venetoclax (HMA/VEN) treatment, patients with acute myeloid leukemia (AML) treated with intensive chemotherapy (IC) had a complete remission/complete remission with incomplete count recovery (CR/CRi) rate of 28% and median overall survival (mOS) of 7.2 months. 

This retrospective single-institution study identified 46 patients who received IC after HMA/VEN, including 24 patients who received HMA/VEN as the first treatment for AML. This population had a CR/CRi/morphologic leukemia-free state rate of 37%, a CR/CRi rate of 28%, and a mOS of 7.2 months (95% confidence interval, 5.0-10.3). Patients who relapsed after an initial response to HMA/VEN and subsequently received IC were more likely to achieve a CR/CRi than those refractory to HMA/VEN (50% vs. 19%; respectively, p= 0.04), although there was no statistically significant difference in survival (mOS, 8.8 vs. 5.4 months; p= 0.64). Age >≥65 years predicted poorer survival (mOS, 4.3 vs. 10.6 months; p< 0.001).

The most common mutations in this cohort, notably RUNX1, TP53, TET2, and ASXL1, were all associated with CR/CRi rates of ≤20%. A small signal of favorable response was noted for NRAS mutations (50% CR after failure of 1L HMA/VEN). Complex cytogenetics were also common and associated with a 13% CR/CRi and 13% ORR after 1L HMA/VEN. No patients with chromosome 17 abnormalities responded.