The past several months have brought significant advances within the field of hematologic oncology. Here we will review some key updates focusing on pivotal clinical trials and new drug approvals.
Advances in Lymphoma
Presented at the 2023 ASCO Annual Meeting, SWOG S1826 compared nivolumab plus doxorubicin, vinblastine, and dacarbazine (N-AVD) to brentuximab vedotin plus AVD in both pediatric and adult patients (aged 12 and older) with newly diagnosed advanced-stage classical Hodgkin lymphoma. The study demonstrated improved progression-free survival for patients receiving N-AVD (1-year progression-free survival, 94% vs 86%), although no difference in overall survival has been seen at this early time point (median follow up of 12.1 months).1 Patients who received N-AVD also had significantly less peripheral neuropathy. As such, N-AVD is poised to become a new standard of care for advanced-stage classical Hodgkin lymphoma, though it has not yet been approved by the U.S. Food and Drug Administration (FDA) for this indication.
There have also been updates related to the use of multiple chimeric antigen receptor (CAR) T-cell products in relapsed or refractory diffuse large B-cell lymphoma (DLBCL). First, the TRANSFORM study includes patients with either primary refractory or early relapsed DLBCL who were randomly assigned to receive either a standard-of-care treatment including chemotherapy followed by autologous stem cell transplantation (for responders) or lisocabtagene maraleucel (where one cycle of bridging therapy was permitted; used in 63% of patients). At a median follow-up of 17.5 months, patients receiving lisocabtagene maraleucel experienced longer median event-free survival compared with those receiving the standard of care (52.6% vs 20.8% at 18 months). Patients receiving lisocabtagene maraleucel had longer progression-free survival (not reached vs 6.2 months), were more likely to attain complete response (74% vs 43%), and had a greater degree of durable responses (not reached vs 9.3 months). Overall survival was not statistically different, though it may have been limited by crossover.2,3
Next, the primary overall survival analysis from the ZUMA-7 trial, comparing axicabtagene ciloleucel vs the standard of care, was presented as a late-breaking abstract at the 2023 ASCO Annual Meeting.4 This trial included patients with early relapsed or refractory DLBCL, and the standard-of-care arm consisted of two to three cycles of chemoimmunotherapy followed by autologous transplantation for responders. At a median follow-up of 47.2 months, the median overall survival was not reached with axicabtagene ciloleucel compared with 31.1 months with the standard of care, establishing the superiority of axicabtagene ciloleucel for patients with early relapsed or refractory DLBCL.4,5
Catherine C. Coombs, MD
Susan M. O’Brien, MD
Dr. Coombs is Associate Clinical Professor, Division of Hematology/ Oncology, at the University of California, Irvine. She has clinical expertise in treating patients with chronic lymphocytic leukemia and small lymphocytic lymphoma, as well as leukemia precursor conditions. Dr. O’Brien is Professor, Division of Hematology/Oncology, at the University of California, Irvine. She is an internationally recognized leader in the research of treatments for both chronic and acute leukemias.
Novel Therapies and Approvals in Leukemia
ECOG-ACRIN E1910, a late-breaking abstract presented at the 2022 American Society of Hematology (ASH) Annual Meeting and Exposition,6 demonstrated an overall survival advantage for adults (aged 30–70 years) with measurable residual disease (MRD)-negative, Philadelphia chromosome (Ph)-negative B-cell acute lymphoblastic leukemia (ALL) who received blinatumomab combined with chemotherapy. Median overall survival was not reached among patients receiving blinatumomab plus chemotherapy vs 71.4 months for those receiving chemotherapy alone.6 The chemotherapy used in this trial was a Berlin-Frankfurt-Münster–like induction regimen modified from the E2993/UKALLXII protocol; therefore, although the results are clearly positive, it is unclear whether they can be extrapolated to other commonly used induction regimens for ALL.
Of note, the FDA recently granted full approval to blinatumomab for MRD-positive B-cell precursor ALL (following accelerated approval in March 2018), based on additional data from two other trials: AALL1331, which compared blinatumomab with standard combination chemotherapy in younger patients with relapsed B-cell ALL,7 and study 20120215, which compared blinatumomab with standard chemotherapy in pediatric patients with high-risk B-cell precursor ALL (in first relapse).8
ALPINE, another late-breaking abstract presented at the 2022 ASH meeting and published in The New England Journal of Medicine in 2023,9 compared zanubrutinib and ibrutinib in patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Treatment with zanubrutinib resulted in a superior overall response rate and progression-free survival. Zanubrutinib also demonstrated improved cardiac safety with lower rates of atrial fibrillation or flutter and no cardiac deaths (compared with six cardiac deaths for ibrutinib-treated patients); the rates of hypertension were similar.9 In January 2023, zanubrutinib was approved by the FDA for use in CLL/SLL and is also listed as a category 1 recommendation in the NCCN Clinical Practice Guidelines in Oncology.
Chronic myelomonocytic leukemia (CMML) is a rare disease with few dedicated trials. Padron and co-investigators presented data on a phase II trial using ruxolitinib in patients with CMML who had splenomegaly or high symptom burden.10 They demonstrated a clinical benefit in 66% of enrolled patients (19 of 29).
Bispecific Antibodies and CAR T-Cell Advances in Multiple Myeloma
CARTITUDE-4 examined the use of ciltacabtagene autoleucel in patients with lenalidomide-refractory multiple myeloma, with phase III results being presented as a late-breaking abstract at the 2023 ASCO Annual Meeting.11 The standard of care used in this trial was investigator’s choice of either pomalidomide, bortezomib, and dexamethasone or daratumumab, pomalidomide, and dexamethasone. The primary endpoint of progression-free survival was met with ciltacabtagene autoleucel leading to a 74% reduced risk of disease progression or death compared with the standard of care (hazard ratio = 0.26), with a median follow-up of 16 months. Improved rates of overall response, complete response, and MRD negativity were also seen, although no statistically significant improvement in overall survival has been noted at this time.11
Bispecific antibodies have made significant strides in the therapeutic armamentarium for patients with relapsed or refractory multiple myeloma. In the phase II trial MagnetisMM-3 trial, elranatamab, a bispecific antibody targeting CD3 and B-cell maturation antigen (BCMA), led to a high response rate in patients with treatment-resistant multiple myeloma (median prior lines of therapy of five). In the cohort of patients who had not previously received prior BCMA therapies (n = 123), after a median follow-up of 6.8 months, an overall response rate of 61% was reported, with a median time to objective response of 1.2 months; the median duration of response has not yet been reached.12 The FDA granted elranatamab Breakthrough Therapy designation in November 2022.
Lastly, results from MonumenTAL-1 were also reported at the 2022 ASH meeting. This is a phase I/II trial of talquetamab, a novel T-cell–redirecting bispecific antibody that targets CD3 and G protein–coupled receptor, class C, group 5, member D (GPRC5D); the latter antigen is highly expressed on malignant plasma cells. In this heavily pretreated population with a median of five prior lines of therapy, talquetamab led to a median progression-free survival of 7.5 months, with durable responses between 9.3 and 13 months noted for patients receiving the 0.4 mg/kg weekly dose and the 0.8 mg/kg every-2-week dose, respectively.13
In closing, an extraordinary amount of progress has been made for patients with hematologic malignancies, with several recent FDA approvals based on these well-conducted clinical trials. We expect to see more approvals in the near future based upon early exciting results.
DISCLOSURE: Dr. Coombs has received honoraria from AbbVie, AstraZeneca, BeiGene, Genentech, Janssen, LOXO/Lilly, MEI Pharma, MingSight, Novartis, Octapharma, Pharmacyclics, and TG Therapeutics; has served in a consulting or advisory role for AbbVie, Genentech, and Lilly; has served on speakers’ bureaus for AbbVie, AstraZeneca, BeiGene, and Genentech; and has received research funding from LOXO/Lilly and AbbVie. Dr. O’Brien has received honoraria from AbbVie, Alexion Pharmaceuticals, Amgen, Aptose Biosciences, Astellas Pharma, Celgene, Eisai, Gilead Sciences, GlaxoSmithKline, Janssen, NOVA Research Company, Pfizer, Pharmacyclics, Sunesis Pharmaceuticals, TG Therapeutics, and Vaniam Group; has served in a consulting or advisory role for AbbVie/Genentech, Alexion Pharmaceuticals, Amgen, Aptose Biosciences, Astellas Pharma, Celgene, Gilead Sciences, GlaxoSmithKline, Janssen Oncology, Pfizer, Pharmacyclics, Sunesis Pharmaceuticals, TG Therapeutics, and Vaniam Group; has received research funding from Acerta Pharma, Caribou, Gilead Sciences, Kite Pharma, Lilly, Pfizer, Pharmacyclics, Regeneron, Sunesis Pharmaceuticals, and TG Therapeutics; and reported travel, accommodations, and expenses from Celgene, Gilead Sciences, Janssen Oncology, and Regeneron.
1. Herrera AF, LeBlanc ML, Castellino SM, et al: SWOG S1826, a randomized study of nivolumab-AVD versus brentuximab vedotin-AVD in advanced stage classic Hodgkin lymphoma. 2023 ASCO Annual Meeting. Abstract LBA4. Presented June 4, 2023.
2. Abramson JS, Solomon SR, Arnason J, et al: Lisocabtagene maraleucel as second-line therapy for large B-cell lymphoma: Primary analysis of the phase 3 TRANSFORM study. Blood 141:1675-1684, 2023.
3. 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. Blood 140(suppl 1):1581-1583, 2022.
4. Westin J, Oluwole OO, Kersten MJ, et al: Primary overall survival analysis of the phase 3 randomized ZUMA-7 study of axicabtagene ciloleucel versus standard-of-care therapy in relapsed/refractory large B-cell lymphoma. 2023 ASCO Annual Meeting. Abstract LBA107. Presented June 5, 2023.
6. Litzow MR, Sun Z, Paietta 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 trial conducted by the NCI National Clinical Trials Network. 2022 ASH Annual Meeting and Exposition. Abstract LBA-1. Presented December 13, 2022.
7. Brown PA, Ji L, Xu X, et al: Effect of postreinduction therapy consolidation with blinatumomab vs chemotherapy on disease-free survival in children, adolescents, and young adults with first relapse of B-cell acute lymphoblastic leukemia: A randomized clinical trial. JAMA 325:833-842, 2021.
8. Locatelli F, Zugmaier G, Rizzari C, et al: Effect of blinatumomab vs chemotherapy on event-free survival among children with high-risk first-relapse B-cell acute lymphoblastic leukemia: A randomized clinical trial. JAMA 325:843-854, 2021.
9. Brown JR, Eichhorst B, Hillmen P, et al: Zanubrutinib or ibrutinib in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med 388:319-332, 2023.
10. Padron E, Tinsley-Vance SM, DeZern AE, et al: Efficacy and safety of ruxolitinib for treatment of symptomatic chronic myelomonocytic leukemia: Results of a multicenter phase II clinical trial. 2022 ASH Annual Meeting and Exposition. Abstract 457. Presented December 11, 2022.
11. Dhakal B, Yong K, Harrison SJ, et al: First phase 3 results from CARTITUDE-4: Cilta-cel versus standard of care (PVd or DPd) in lenalidomide-refractory multiple myeloma. 2023 ASCO Annual Meeting. Abstract LBA106. Presented June 5, 2023.
12. 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. Blood 140(suppl 1):391-393, 2022.
13. 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. Blood 140(suppl 1):384-387, 2022.