The 2022 American Society of Hematology (ASH) Annual Meeting and Exposition took place in the vibrant city of New Orleans. The meeting brought together tens of thousands of participants from across the world to present and discuss the results of studies that ranged from hypothesis-generating to practice-changing. Below are short summaries of some of the data we thought were most compelling this year.
GUEST EDITORS
Vijaya Raj Bhatt, MBBS, MS
R. Gregory Bociek, MD, MSc
Dr. Bhatt is Associate Professor and Section Leader of the Malignant Hematology Program in the Division of Hematology and Oncology at the University of Nebraska Medical Center. Dr. Bociek is Professor in the Division of Hematology and Oncology at the University of Nebraska Medical Center.
Upfront Integration of Blinatumomab in ALL
Blinatumomab is approved by the U.S. Food and Drug Administration (FDA) to treat patients with B-cell acute lymphocytic leukemia (ALL) with measurable residual disease (MRD)-positive disease. If blinatumomab works for MRD-positive disease, can it work for MRD-negative disease? Mark R. Litzow, MD, presented the results of the practice-changing phase III ECOG-ACRIN E1910 trial to answer this question.1 The study added blinatumomab to consolidation chemotherapy in patients with Philadelphia chromosome (Ph)-negative B-cell ALL who have achieved MRD-negative status following chemotherapy. The result was an impressive 18% absolute improvement in overall survival at 3.6 years. Although some patients underwent stem cell transplantation in this study, the study raises the question of whether upfront integration of novel drugs such as blinatumomab can
decrease the need for upfront
transplantation.
The results of another study raised the same question but in Philadelphia–positive B-cell ALL. In a single-center phase II trial of newly diagnosed Ph-positive ALL, Nicholas Short, MD, and colleagues demonstrated high rates of complete remission and complete molecular response with the upfront combination of ponatinib and blinatumomab.2 With only one patient receiving transplant, event-free survival and overall survival rates were 92% and 95%, respectively, at 2 years. The study result is supported by a previously published phase II trial using dasatinib and blinatumomab, where survival results were similarly high.3 Although larger multicenter randomized trials are necessary to validate these findings, the chemotherapy-free combination of tyrosine kinase inhibitors and blinatumomab represents a new promising treatment strategy for Ph-positive ALL.
Triplet Combination Regimens in AML
If a two-drug regimen consisting of azacitidine and venetoclax is superior to monotherapy with azacitidine alone, will a three-drug combination be better than two? Naval Daver, MD, presented results of two early-phase trials adding either magrolimab (an investigational anti-CD47 monoclonal antibody) or pivekimab sunirine (antibody-drug conjugate targeting CD123) to the combination of venetoclax plus azacitidine.4,5 Early results demonstrated the safety of these approaches. The triplet combination using magrolimab in high-risk older adults with newly diagnosed acute myeloid leukemia (AML) resulted in a promising rate of complete response with or without incomplete hematologic recovery of 72% and an MRD negativity rate of 67%. As one would expect, the relapsed/refractory AML turned out not to be as responsive, particularly if patients had prior exposure to venetoclax. The triplet combination using pivekimab sunirine resulted in promising rates of remission and MRD negativity in venetoclax-naive patients with relapsed or refractory disease, and 25% of patients were able to proceed to allogeneic stem cell transplantation. Future randomized trials will have to demonstrate whether the promising early results can change practice in the future.
Bispecific Antibodies in Multiple Myeloma
Two new bispecific antibodies, elranatamab (anti-CD3/B-cell maturation antigen [BCMA]) and talquetamab (anti-CD3/ GPRC5D), showed strong activity in patients with heavily pretreated multiple myeloma in early-phase trials. Nizar Jacques Bahlis, MD, presented the results of a phase II trial that demonstrated a high overall response rate of 61% with elranatamab including a high response rate in a subset of patients who had received prior BCMA-targeting treatment.6Ajai Chari, MD, presented the results of a phase I/II trial, where talquetamab resulted in responses in more than 70% of patients; response rates were high even among those who had received prior chimeric antigen receptor T-cell therapy and bispecific antibody therapy.7
Ibrutinib Challenges ASCT as the Standard of Care in MCL
Induction chemotherapy followed by autologous stem cell transplantation (ASCT) and up to 3 years of maintenance rituximab has been an accepted current standard of care for transplant-eligible individuals with mantle cell lymphoma. The TRIANGLE trial was presented on behalf of the European Mantle Cell Network by Martin Dreyling, MD.8 Patients (n = 870) were randomly assigned to induction therapy with three cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone/dexamethasone, cytarabine, and cisplatin (R-CHOP/R-DHAP) followed by ASCT (standard-of-care regimen, A); ibrutinib added to the same regimen followed by 2 years of ibrutinib (A+I); or to the ibrutinib-containing regimen without proceeding to ASCT (I). Rituximab maintenance was allowed in all arms based on national guidelines. With a median follow-up of 31 months, progression-free survival was superior to induction/ASCT alone in both ibrutinib-containing arms, with no clear advantage to the addition of ASCT in the ibrutinib arms. There was more reported toxicity with the combination of ASCT plus ibrutinib. Although follow-up is short, the addition of ibrutinib to cytarabine-containing induction chemotherapy did not add significant toxicity, and this study will certainly challenge the notion that ASCT is required as part of initial therapy for MCL.
Superiority of Zanubrutinib Demonstrated in Relapsed or Refractory CLL
The treatment landscape of chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) has changed dramatically over the past 10 years with the availability of Bruton’s tyrosine kinase (BTK) inhibitors and venetoclax. Ibrutinib was first approved by the FDA for relapsed CLL in 2014 and has been a valuable part of the treatment armamentarium for CLL as well as a number of other B-cell malignancies including mantle cell lymphoma, Waldenström’s macroglobulinemia, and marginal zone lymphomas. Second-generation BTK inhibitors (acalabrutinib, zanubrutinib) have less off-target activity, offering the possibility of reduced toxicity.
The ALPINE trial was a direct head-to-head comparison between ibrutinib and zanubrutinib for patients with relapsed or refractory CLL/SLL.9 At 2 years, progression-free survival was superior for patients randomly assigned to zanubrutinib (79.5% vs 67.3%; P = .0024). Progression-free survival outcomes were superior for all major subgroups, including specifically those subjects with TP53/del(17)p mutation (77.6% vs 55.7%; P = .0134). The cardiac safety profile was more favorable among patients treated with zanubrutinib, with fewer observed cardiac adverse events, serious cardiac events, and cardiac events leading to treatment discontinuation compared with ibrutinib. With an earlier randomized trial comparing acalabrutinib to ibrutinib in the relapsed setting demonstrating noninferiority of acalabrutinib with a lower incidence of atrial fibrillation/flutter,10 second-generation BTK inhibitors are poised to be the preferred therapies for relapsed or refractory CLL/SLL along with venetoclax in 2023.
CAR T-Cell Therapy vs ASCT as Second-Line Therapy for DLBCL
The primary analysis of the TRANSFORM trial was presented by Jeremy Abrams, MD.11 In this study, patients with primary refractory or early relapsing diffuse large B-cell lymphoma were randomly assigned to standard-of-care, platinum-based salvage followed by ASCT in responders vs CD19-targeted CAR T-cell therapy with lisocabtagene maraleucel. Leukapheresis was performed on all subjects at study entry to allow patients who had failed to respond to the standard of care to cross over rapidly to receive lisocabtagene maraleucel. One cycle of bridging therapy was discretionarily allowed for patients who received lisocabtagene maraleucel. This analysis confirmed the results of the previous prespecified interim analysis.12 With a median follow-up of 17.5 months, the hazard ratio (HR) for event-free survival was 0.356 (0.243–0.522) in favor of lisocabtagene maraleucel. The 18-month event-free survival rate was 52.6% for lisocabtagene maraleucel vs 20.8% for the standard of care and favored lisocabtagene maraleucel in all prespecified subgroups. Overall survival at 18 months is trending in favor of lisocabtagene maraleucel at 73.1% vs 60.6% (HR = 0.74, P = .0987). These results have led to a change in the standard of care for this group of patients, and the FDA has now also approved lisocabtagene maraleucel as second-line therapy for patients who have relapsed beyond 12 months of therapy and who are deemed unfit for ASCT.
DISCLOSURE: Dr. Bhatt has served as a consultant or advisor for AbbVie, Genentech, Incyte, Protagonist Therapeutics, and Servier; has received research funding from AbbVie, Incyte, Jazz Pharmaceuticals, National Marrow Donor Program, Pfizer, and Tolero Pharmaceuticals; and reported other relationships with Chimerix, Novartis, and Pfizer. Dr. Bociek has served as a consultant or advisor for Innate Pharma; and has served on a data safety monitoring committee for Innate Pharma.
REFERENCES
1. Litzow MR, Sun Z, Paletta E, et al: Consolidation therapy with blinatumomab improves overall survival in newly diagnosed adult patients with B-lineage acute lymphoblastic leukemia in measurable residual disease negative remission: Results from the ECOG-ACRIN E1910 randomized phase III National Cooperative Clinical Trials Network trial. 2022 ASH Annual Meeting and Exposition. Abstract LBA1. Presented December 13, 2022.
2. Short N, Kantarjian H, Jain N, et al: Ponatinib and blinatumomab for patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia: A subgroup analysis from a phase II study. 2022 ASH Annual Meeting and Exposition. Presented December 10, 2022.
3. Foa, R, Bassan R, Vitale, A et al: Dasatinib-blinatumomab for Ph-positive acute lymphoblastic leukemia in adults. N Engl J Med 383:1613-1623, 2020.
4. Daver N, Senapati J, Maiti A, et al: Phase I/II study of azacitidine with venetoclax and magrolimab in patients with newly diagnosed older/unfit or high-risk acute myeloid leukemia (AML) and relapsed/refractory AML. 2022 ASH Annual Meeting and Exposition. Abstract 61. Presented December 10, 2022.
5. Daver NG, Montesinos P, Arbi A, et al: Broad activity for the pivekimab sunirine (PVEK, IMGN632), azacitidine, and venetoclax triplet in high-risk patients with relapsed/refractory and frontline acute myeloid leukemia. 2022 ASH Annual Meeting and Exposition. Abstract 62. Presented December 10, 2022.
6. Bahlis NJ, Tomasson MH, Mohty M, et al: Efficacy and safety of elranatamab in patients with relapsed/refractory multiple myeloma naive to B-cell maturation antigen (BCMA)-directed therapies: Results from Cohort A of the MagnetisMM-3 study. 2022 ASH Annual Meeting and Exposition. Abstract 159. Presented December 10, 2022.
7. Chari A, Touzeau C, Schinke C, et al: Talquetamab, a G protein-coupled receptor family C group 5 member D x CD3 bispecific antibody, in patients with relapsed/refractory multiple myeloma: Phase 1/2 results from MonumenTAL-1. 2022 ASH Annual Meeting and Exposition. Abstract 157. Presented December 10, 2022.
8. Dreyling M, Doorduijn JK, Gine E, et al: Efficacy and safety of ibrutinib combined with standard first-line treatment or as substitute for autologous stem cell transplantation in younger patients with mantle cell lymphoma: Results from the randomized Triangle trial by the European MCL Network. 2022 ASH Annual Meeting and Exposition. Abstract 1. Presented December 11, 2022.
9. Brown JR, Eichhorst B, Hillmen P, et al: Zanubrutinib demonstrates superior progression-free survival compared with ibrutinib for treatment of relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma: Results from final analysis of ALPINE randomized phase 3 study. 2022 ASH Annual Meeting and Exposition. Abstract LBA-6. Presented December 13, 2022.
10. Byrd, JC, Hillmen, P, Ghia P et al: Acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia: Results of the first randomized phase III trial. J Clin Oncol 39:3441-3452, 2021.
11. Abramson JS, Solomon SR, Arnason JE, et al: Lisocabtagene maraleucel versus standard of care with salvage chemotherapy followed by autologous stem cell transplantation as second-line treatment in patients with relapsed or refractory large B-cell lymphoma: Primary analysis of the randomized, phase 3 TRANSFORM study. 2022 ASH Annual Meeting and Exposition. Abstract 655. Presented December 11, 2022.
12. Kamdar, M, Solomin SR, Arnason J et al: Lisocabtagene maraleucel versus standard of care with salvage chemotherapy followed by autologous stem cell transplantation as second-line treatment in patients with relapsed or refractory large B-cell lymphoma (TRANSFORM): Results from an interim analysis of an open-label, randomized, phase 3 trial. Lancet 399:2294-2308, 2022.
