ASH 2023 late-breaking abstract rundown

Primary results from the PERSEUS trial

Daratumumab (DARA) is a CD38-directed monoclonal antibody with potential to improve the efficacy of standard of care treatment for transplant-eligible patients with newly diagnosed multiple myeloma (NDMM). Bortezomib, lenalidomide and dexamethasone (VRd) is the current standard for induction therapy in this patient population, followed by autologous stem cell transplantation (autoSCT), consolidation therapy with VRd and lenalidomide maintenance. Initial safety and efficacy of the quadruplet DARA-VRd was observed in the Phase II GRIFFIN study (NCT02874742), which demonstrated that progression-free survival (PFS) significantly improved in patients treated with DARA-VRd versus VRd alone.

At ASH 2023, Pieter Sonneveld, MD, PhD, Erasmus MC, Rotterdam, The Netherlands, presented primary results from the Phase III PERSEUS trial (NCT03710603) further comparing outcomes for transplant-eligible patients with NDMM treated with DARA-VRd induction/consolidation followed by DARA + lenalidomide maintenance versus VRd induction/consolidation followed by lenalidomide maintenance. Patients aged 18-70 were randomized to DARA-VRd (n=355) or VRd (n=354) where they received four 28-day cycles of VRd pre-autoSCT (induction) and two 28-day cycles post-autoSCT (consolidation) followed by lenalidomide maintenance until disease progression. Those in the DARA-VRd arm also received DARA weekly in cycles 1-2, every two weeks in cycles 3-6 and every four weeks during maintenance until disease progression.

After a median follow-up of 47.5 months, the primary endpoint of the trial was met, with the estimated PFS rate in the DARA-VRd arm being 84.3% versus 67.7% in the VRd arm. Improvements in PFS were consistent among subgroups of patients with high-risk cytogenetic abnormalities and in late disease stages.

The benefit of DARA-VRd over VRd was confirmed in secondary endpoint analysis, with improvements in the overall complete response or better (≥CR) rate (87.9% versus 70.1%) and measurable residual disease (MRD) negativity (75.2% versus 47.5%). There were 78 deaths in the study, 34 of which were in the DARA-VRd arm and 44 in the VRd arm. In terms of safety outcomes, serious treatment-emergent adverse events (TEAEs) were more common in DARA-VRd versus VRd treated patients (57.0% versus 49.3%), with neutropenia, thrombocytopenia, diarrhea, and pneumonia being the most frequent. This data builds on the findings from the GRIFFIN trial to support the inclusion of DARA in the treatment of transplant-eligible NDMM.¹

SYMPATICO: ibrutinib + venetoclax combination has promising efficacy in R/R MCL

It is hypothesized that synergistic BTK and BCL2 inhibition with ibrutinib (Ibr) and venetoclax (Ven) enhances efficacy compared to using either agent alone in treating patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL). Results from a Phase II trial (NCT02471391) indicate the safety and efficacy of this combination in MCL, demonstrating a higher complete response (CR) rate compared to the historical CR rate for ibrutinib monotherapy.²

Michael Wang, MD, The University of Texas MD Anderson Center, Houston, TX, reported the primary analysis results from the Phase III SYMPATICO trial (NCT03112174) comparing Ibr+Ven versus Ibr+placebo (Pbo) in patients with R/R MCL at ASH 2023. Patients included in the study were aged ≥18 years with R/R MCL after 1-5 prior lines of therapy. They were randomly assigned to Ibr+Ven (n=134) or Ibr+Pbo (n=133) where they received 560mg of Ibr orally once a day with Ven or Pbo for two years, followed by single-agent Ibr until disease progression or unacceptable toxicity.

After a median follow-up of 51.2 months, Ibr+Ven demonstrated prolonged PFS compared to Ibr+Pbo: 31.9 months versus 22.1 months, with a 24-month PFS rate of 57% versus 45%. Improved PFS was maintained across subgroups of patients with high-risk TP53 mutations or blastoid variant MCL. CR rates were higher in Ibr+Ven treated patients (54% versus 32%), and overall survival (OS) was prolonged (44.9 months versus 38.6 months), although not statistically significant. Grade ≥3 adverse events (AEs) occurred more frequently in the Ibr+Ven group (84% versus 76% in Ibr+Pbo), with neutropenia, pneumonia, thrombocytopenia, and anemia being the most common. This safety profile aligns with known AEs for these agents, indicating no new safety concerns and establishing a positive benefit-risk profile for the Ibr+Ven combination in patients with R/R MCL.³

BMT CTN 1507: haplo-SCT as a potential curative treatment for patients with SCD

Access to curative allogeneic stem cell transplantation (alloSCT) for sickle cell disease (SCD) is limited due to the rarity of myeloablative matched sibling donors (MSD). Haploidentical stem cell transplantation (haplo-SCT) offers a potential solution by allowing a half-match, in which 50% of human leukocyte antigens (HLA) are shared between donor and recipient, thereby expanding the donor pool.⁴ However, this approach may come with an increased risk of graft-versus-host disease (GvHD). Adetola Kassim, MD, Vanderbilt University Medical Center, Nashville, TN, reported outcomes of reduced intensity bone-marrow derived haplo-SCT with post-transplant cyclophosphamide (PTCy) for adults with severe SCD at ASH 2023.

The Blood and Marrow Transplant Clinical Trial Network (BMT CTN) 1507 (NCT03263559) study is a multi-center Phase II trial, including patients aged 15-45 with SCD and co-morbidities such as stroke or pulmonary hypertension.

The primary objective of the study was to assess event-free survival (EFS) two years post haplo-SCT. Patients were preconditioned with hydroxyurea, followed by a multi-agent conditioning regimen, with PTCy for GvHD prophylaxis. Out of 54 patients that enrolled across 19 sites, 38 successfully completed haplo-SCT.

The estimated two-year EFS, defined as survival without primary or secondary graft failure or second infusion of stem cells, was 88% (95% CI: 73.5%, 94.8%). The two-year OS was 93% post-preconditioning and 95% post-transplant. Two participants had primary graft failure and one had secondary graft failure. At day 100, the cumulative incidence of grades II-IV acute GvHD was 26.2% (95% CI: 14.0%, 40.2%), with grades III-IV acute GvHD at 4.8% (95% CI: 0.9%, 14.4%). These results support bone marrow-derived haplo-SCT with cyclophosphamide prophylaxis as an effective and well-tolerated curative treatment option for adults with SCD.⁵

AUGMENT-101: revumenib in patients with R/R KMT2Ar acute leukemia

Prognostic outcomes for patients with acute leukemia harboring rearrangements to the histone-lysine N-methyltransferase 2A gene (KMT2Ar) are poor. Revumenib is a small molecule that inhibits the interaction between KMT2A and menin, hypothesized to be a key driver of leukemogenesis. Following promising Phase I preliminary results, the Phase II AUGMENT-101 trial (NCT04065399) was initiated to further investigate the safety and efficacy of revumenib in patients with relapsed/refractory (R/R) KMT2Ar acute leukemia. An interim analysis of the results from this study were presented at ASH 2023 by Ibrahim Aldoss, MD, City of Hope, Duarte, CA.

The trial included 94 patients, both adult and pediatric, with a diagnosis of KMT2Ar acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL) or mixed-phenotype acute leukemia (MPAL), and a median of two prior lines of therapy. Patients were treated with oral revumenib (163 mg or 95 mg/m² if body weight <40 kg) in 28-day cycles until unacceptable toxicity or lack of treatment effect after four cycles.

Treatment-related adverse events (TRAEs) were reported in 81.9% of patients, with the most common being nausea, differentiation syndrome and QTc prolongation. Grade ≥3 TRAEs, including febrile neutropenia, occurred in 54.3% of patients.

To assess efficacy, a follow-up of 57 patients at a median of 6.1 months demonstrated a CR plus partial hematological recovery (CRh) rate of 22.8% (95 CI: 12.7, 35.8), consistent across pediatric and adult patients. The median duration of CR+CRh was 6.4 months. Most patients with a CR or CRh response achieved MRD negativity, and the overall response rate (ORR) was 63.2% (95% CI: 49.3, 75.6). These findings highlight the clinical activity of revumenib in the treatment of R/R acute leukemia with KMT2Ar.⁶