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Report from the 2023 American Society of Hematology Annual Meeting — Malignant Hematology
Presenters at the 2023 American Society of Hematology (ASH) annual meeting, held December 9–12 in San Diego, reported the latest research in hematology. NEJM Group was on hand to cover the meeting. Here, NEJM Journal Watch Oncology and Hematology reports some of the key findings in hematologic malignancies, and Associate Editor Dr. Michael E. Williams provides clinical perspective. Abstracts can be found on the ASH meeting site.
Patients 60 years and older with advanced-stage Hodgkin lymphoma have poorer outcomes with standard chemotherapy regimens than do younger individuals. Investigators reported a comparison of the immune checkpoint inhibitor nivolumab plus AVD chemotherapy (N-AVD; doxorubicin, vinblastine, dacarbazine) versus brentuximab vedotin plus AVD (Bv-AVD) in a subset of older patients in the industry-supported North American Intergroup phase 3 SWOG S1826 trial.
In the trial, nearly 1000 patients aged 12 years or older with newly diagnosed stage III–IV Hodgkin lymphoma were randomized to six cycles of either N-AVD or Bv-AVD. The researchers previously reported improved progression-free survival (PFS) in the N-AVD arm in the full trial population. The current subset analysis included 97 patients with a median age of 66 years (range, 60–83).
At a median follow-up of 12 months, PFS — the primary endpoint — was 93% in the N-AVD group compared with 64% in the Bv-AVD group (hazard ratio, 0.35). Event-free and overall survival were also improved with N-AVD; nonrelapse mortality was 4% for N-AVD versus 14% for Bv-AVD.
The Bv-AVD group had higher rates of grade ≥3 sepsis (21%, vs. 6% with N-AVD), grade ≥3 infections and infestations (21% vs. 6%, respectively), and any-grade peripheral sensory neuropathy (66% vs. 31%, respectively). Adverse events led to discontinuation of treatment in 33% of patients on Bv-AVD and 10% on N-AVD.
Summary by Cara Adler, Staff Writer
COMMENT — Dr. Michael Williams
The primary data for this practice-changing clinical trial were presented at the American Society of Clinical Oncology 2023 meeting. Now, this important subset analysis shows that benefits in PFS and lower treatment-related toxicity also accrue to older patients. Assuming full reporting of the trial confirms these early findings, the result will support the use of N-AVD for older patients who are candidates to receive AVD chemotherapy.
Another group of researchers reported a subset analysis of the 237 patients aged 12 to 17 years enrolled in the above-mentioned SWOG S1826 trial.
At a median follow-up of 12.1 months, 1-year progression-free survival was 95% in the N-AVD arm versus 88% in the Bv-AVD arm (hazard ratio, 0.48). No deaths were reported. Overall, only two adolescent patients (0.8%) received radiotherapy.
Rates of grade ≥3 hematologic adverse events were 45% with N-AVD and 41% with Bv-AVD. Grade ≥3 febrile neutropenia, sepsis, and immune-related adverse events, including pneumonitis and colitis, were infrequent, occurring in 0% to 3% of patients in the two arms. More patients in the N-AVD arm than the Bv-AVD arm discontinued treatment (8.3% vs. 2.6%).
Summary by Cara Adler, Staff Writer
COMMENT — Dr. Michael Williams
The 1-year follow-up of adolescent patients showed a benefit for N-AVD, with reassuringly low rates of nivolumab-associated immune adverse events. Less than 1% of patients received radiation therapy, which is strikingly lower than with current pediatric Hodgkin regimens. Longer follow-up for efficacy and safety will be awaited with interest and the hope that treatment de-escalation will maintain high cure rates while decreasing late second malignancy and cardiovascular risks.
In patients with newly diagnosed multiple myeloma, adding the anti-CD38 monoclonal antibody isatuximab to carfilzomib-lenalidomide-dexamethasone (IsaKRd) for pre–autologous stem-cell transplant (ASCT) induction and post-ASCT consolidation improves treatment response, compared with KRd alone, according to an industry-supported, multicenter phase 3 trial.
A total of 302 transplant-eligible patients younger than 70 years with newly diagnosed multiple myeloma were randomly assigned either to induction with IsaKRd followed by high-dose melphalan and ASCT, then consolidation with IsaKRd, or to the same regimen without Isa. The primary endpoint was the rate of minimal residual disease (MRD) negativity after post-ASCT consolidation in patients who achieved at least a very good partial response.
The MRD negativity rate after consolidation was 77% in the IsaKRd group versus 67% in the KRd group (odds ratio, 1.67; P=0.049). A key secondary endpoint — MRD negativity rate after induction — also favored IsaKRd, at 45% versus 26% with KRd (OR, 2.34; P<0.001). Another key secondary endpoint — progression-free survival — did not differ between the groups (95% at 1 year). Patients with high-risk myeloma subtypes also benefitted from IsaKRd, consistent with phase 2 trial data for the regimen (J Clin Oncol 2024; 42:26).
Among grade 3–4 hematologic adverse events, neutropenia occurred in 37% of the IsaKRd group versus 22% of the KRd group, while thrombocytopenia occurred in 15% and 17%, respectively.
Summary by Amy Herman, Staff Writer
COMMENT — Dr. Michael Williams
The addition of isatuximab to triplet induction therapy increased rates of MRD negativity following ASCT using highly sensitive next-generation sequencing, although rates of very good partial response and complete response did not differ as yet between the groups at a median 20 months' follow-up.
The combination of azacitidine plus venetoclax has become a standard treatment regimen for subsets of acute myeloid leukemia, especially among older patients. Investigators now report that about one third of patients with newly diagnosed, higher-risk myelodysplastic syndromes (MDS) had a complete response to treatment with venetoclax plus azacitidine in an industry-funded, multicenter, phase 1 trial.
The trial used the recommended phase 2 dose and schedule; 107 treatment-naive patients received venetoclax (400 mg orally) on days 1–14 and azacitidine (75 mg/m2 intravenously or subcutaneously) on days 1–7 or on days 1–5, 8, and 9 of each 28-day cycle. Among the findings, at a median follow-up of 32 months:
- The complete response rate was 30%, and median duration of complete response was approximately 17 months.
- Median duration of overall survival was 26 months; estimated overall survival at 12 months was 71% and at 24 months was 51%.
- Median time to next treatment, including transplantation, was roughly 7 months.
- Nearly 40% of participants underwent transplantation, with a median time to transplantation of 5 months.
- Approximately half of evaluable patients achieved overall hematologic improvement.
With regard to safety, 94% of participants experienced at least one grade 3 or higher adverse event, most commonly neutropenia, thrombocytopenia, febrile neutropenia, and anemia. Infections occurred in 57% of patients.
Summary by Amy Herman, Staff Writer
COMMENT — Dr. Michael Williams
Durable improvement of cytopenias and the delay or prevention of conversion to acute myeloid leukemia remain unmet needs for patients with higher-risk MDS. These promising early results suggest particular value in bridging patients to allogeneic stem-cell transplantation and potential cure.
In patients with relapsed/refractory chronic lymphocytic leukemia or small lymphocytic lymphoma (R/R CLL/SLL), zanubrutinib conferred sustained progression-free survival (PFS) as compared with ibrutinib in the industry-supported, multicenter phase 3 ALPINE trial.
A total of 652 patients with R/R CLL/SLL who had measurable disease following at least one previous line of therapy were randomized to receive zanubrutinib or ibrutinib. Previously, researchers reported that zanubrutinib was associated with better PFS at a median follow-up of 24 months (78% for zanubrutinib vs. 66% for ibrutinib).
Now, at 36 months' follow-up, the zanubrutinib group maintained the PFS benefit (66%, vs. 54% in the ibrutinib group). The difference was significant across major subgroups. At 36 months, the rates of overall survival did not differ for zanubrutinib (83%) versus ibrutinib (80%).
Notably, fewer zanubrutinib recipients experienced cardiac events, including atrial fibrillation or flutter (6% vs. 16% of ibrutinib recipients). In addition, the zanubrutinib group had no grade 5 adverse events related to cardiac disorders, compared with 2% of the ibrutinib group.
Summary by Kelly Young, Staff Writer
COMMENT — Dr. Michael Williams
This extended follow-up of the ALPINE trial confirms ongoing clinical benefit and reduced cardiac toxicity for zanubrutinib, as compared with ibrutinib. Zanubrutinib should thus be considered in the relapsed/refractory setting, in particular among patients with preexisting cardiac disease.
The addition of venetoclax to ibrutinib therapy was associated with extended progression-free survival (PFS) compared with ibrutinib alone among patients with relapsed/refractory mantle cell lymphoma (MCL), according to the industry-funded, multicenter phase 3 SYMPATICO study.
A total of 267 adults who had received 1–5 prior lines of therapy (without prior Bruton's tyrosine kinase [BTK] inhibitor) for MCL were randomized to receive oral ibrutinib (560 mg daily) plus either oral venetoclax (target dose, 400 mg daily) or placebo for 2 years; ibrutinib alone was then continued until disease progression or unacceptable toxicity occurred.
During a median follow-up of 51 months, the median PFS was 32 months with venetoclax and ibrutinib versus 22 months with ibrutinib alone. Combination therapy was also associated with a higher complete response rate and a longer time to next treatment.
No new safety signals were observed. The most common grade 3 or higher adverse events with ibrutinib–venetoclax were neutropenia, pneumonia, thrombocytopenia, and anemia.
Summary by Kelly Young, Staff Writer
COMMENT — Dr. Michael Williams
The efficacy of ibrutinib plus venetoclax in earlier phase 1–2 trials of relapsed/refractory MCL was confirmed in this placebo-controlled study of BTK inhibitor-naive patients. Data regarding response to subsequent therapy in patients progressing on the combination will be of interest, and longer follow-up will be needed to see if an overall survival benefit emerges. Potential use of this regimen in the U.S. is complicated by the withdrawal of the MCL indication for ibrutinib in 2023, and by the trend toward utilization of alternative BTK inhibitors with more-favorable toxicity profiles.
Daratumumab for Newly Diagnosed Multiple Myeloma
Read the meeting abstract here and watch an interview with the lead author.
MRD-Guided Ibrutinib plus Venetoclax in Untreated CLL
Read the meeting abstract here.
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Michael E. Williams, MD, ScM