“Care more particularly for the individual patient than for the special features of the disease.”—Sir William Osler
Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is the most common leukemia in the Western hemisphere. The majority of patients who require treatment are older than age 65. The treatment of CLL/SLL has significantly advanced over the past decade with the introduction of novel targeted therapies. However, although outcomes have improved in the current era, the disease remains incurable, and questions about optimal therapies for both the front-line and relapsed/refractory settings for CLL/SLL continue to be explored.
To complement The ASCO Post’s coverage of the 2024 American Society of Hematology (ASH) Annual Meeting & Exposition, two important abstracts focusing on treating CLL/SLL were selected from the meeting proceedings and are discussed in detail here.
Acalabrutinib-Based Regimen in the Front-Line Setting
ABSTRACT 1009: Fixed-duration acalabrutinib plus venetoclax with or without obinutuzumab vs chemoimmunotherapy for the first-line treatment of fit patients with CLL/SLL without del(17p) or TP53 mutation: Interim analysis of the multicenter, open-label, randomized, phase III AMPLIFY trial (ClinicalTrials.gov identifier NCT03836261).1
Background: In the phase III GAIA/CLL13 study,2 with more than 4 years of follow-up, venetoclax plus obinutuzumab as well as the triplet venetoclax, obinutuzumab, and ibrutinib significantly extended progression-free survival compared with both types of chemoimmunotherapy regimens (the combination of fludarabine, cyclophosphamide, and rituximab in younger adults and bendamustine plus rituximab in patients older than age 65) and venetoclax plus rituximab in previously untreated, fit patients without del(17p) or TP53 mutation in CLL/SLL. These results support their use and further evaluation in this patient group, while still considering the higher toxicities observed with the doublet and triplet combinations.
The estimated 4-year progression-free survival rates were 85.5% (97.5% confidence interval [CI] = 79.9%–91.1%; 37 [16%] events) with the triplet, 81.8% (75.8%–87.8%; 55 [24%] events) with venetoclax plus obinutuzumab, 70.1% (63.0%–77.3%; 84 [35%] events) with venetoclax plus rituximab, and 62% (54.4%–69.7%; 90 [39%] events) with chemoimmunotherapy.
Another study3 (n = 37) from two academic centers in Boston investigated front-line, time-limited, measurable residual disease (MRD)-guided triplet therapy with acalabrutinib, venetoclax, and obinutuzumab. The primary endpoint was complete remission with undetectable MRD in the bone marrow (defined as < 1 CLL cell/10,000 leukocytes as measured by four-color flow cytometry) at cycle 16 day 1. At cycle 16 day 1, 14 of 37 participants (38% [95% CI 22%–55%]) had complete remission with undetectable MRD in the bone marrow. The primary endpoint of this phase II study was not met; however, the results supported further investigation of this regimen in the phase III AMPLIFY trial.1
Methods: Investigators hypothesized that front-line, time-limited, MRD-guided triplet therapy with acalabrutinib, venetoclax, and obinutuzumab would induce deeper and durable remissions with less toxicity than the triplet using ibrutinib. Chemoimmunotherapy (n = 290) with the triplet fludarabine, cyclophosphamide, and rituximab or bendamustine plus rituximab was compared with a combination of acalabrutinib plus venetoclax (n = 291) or the triplet acalabrutinib, venetoclax, and obinutuzumab (n = 286) in patients without del(17p) or TP53 mutation, previously untreated fit patients with CLL who would ordinarily be considered for chemoimmunotherapy. Patients were randomly assigned in a 1:1:1 manner, and no crossover was built into the protocol. The primary endpoint was progression-free survival with acalabrutinib plus venetoclax vs chemoimmunotherapy.
Results:
Efficacy: At a median follow-up of 41 months, both acalabrutinib plus venetoclax and the combination of acalabrutinib, venetoclax, and obinutuzumab provided a statistically significant improvement in progression-free survival over the control arm (hazard ratios [HRs] vs chemoimmunotherapy = 0.65 and 0.42, P = .0038 and P < .0001, respectively). Median progression-free survival was not reached in the acalabrutinib-plus-venetoclax or acalabrutinib-venetoclax-obinutuzumab arms and was 47.6 months with chemoimmunotherapy. Of note, the differences in progression-free survival were most pronounced in patients with unmutated IGHV (82% vs 68% vs 56%, with the combination of acalabrutinib, venetoclax, and obinutuzumab vs acalabrutinib plus venetoclax vs chemoimmunotherapy, respectively), at the 3-year time point—but not in the patients with mutated IGHV—although there was a trend toward improved outcomes with the targeted therapies. Acalabrutinib plus venetoclax demonstrated an overall survival benefit trend over chemoimmunotherapy (HR = 0.33, nominal P < .0001).
Safety: The triplet therapy had the highest incidence of grade ≥ 3 COVID-19 infections at 6% and COVID-19 pneumonia at 11%. Serious adverse events leading to death were also highest in the triplet arm at 6%, mostly secondary to COVID-19 infections. The rate of grade ≥ 3 cardiac adverse events was less than 3% across all arms, as was hypertension. Bleeding events and hemorrhage were mostly seen in the acalabrutinib arms, as expected, with less than 3% of patients experiencing a grade ≥ 3 event. Deaths that occurred prior to the data cutoff of April 2024 were reported in 18, 37, and 42 patients in the doublet, triplet, and chemoimmunotherapy groups, respectively, of which COVID-related deaths occurred in 10, 25, and 21 patients, respectively.
Clinical Implications: The phase III AMPLIFY trial met its primary endpoint. This study establishes the efficacy of the nonchemotherapy acalabrutinib plus venetoclax as well as the regimen of acalabrutinib, venetoclax, and obinutuzumab as time-limited options compared with chemoimmunotherapy in fit patients without del(17p) or TP53 mutation. Given the higher undetected MRD rates and improved progression-free survival with the use of time-limited triplet therapy, it has the potential to become a standard first-line treatment for fit patients with CLL/SLL who do not have del(17p) or TP53 mutation. However, the benefit of improved progression-free survival and deep remissions would need to be balanced with the potentially high risk of infectious complications, especially COVID-19–related complications.
CD3 × CD20 Bispecific Antibody in Relapsed or Refractory Disease
ABSTRACT 883: Epcoritamab monotherapy in patients with relapsed or refractory CLL/SLL: Results from CLL expansion and optimization cohorts of EPCORE CLL-1 (NCT04623541).4
Background: Although treatment of CLL/SLL continues to improve outcomes, these patients eventually relapse with progressive disease and become refractory to both B-cell lymphoma 2 (BCL2) and Bruton’s tyrosine kinase (BTK) inhibitors. Limited options are available for patients in that space, and outcomes are generally dismal. Novel approaches such as chimeric antigen receptor T-cell treatment of relapsed or refractory CLL/SLL offer limited benefits, with complete remission in up to 20%, underscoring the urgent need for novel, effective, and easily available treatments.
Epcoritamab is a subcutaneously administered bispecific antibody currently available for patients with relapsed diffuse large B-cell lymphoma and follicular lymphoma. Epcoritamab has shown single-agent efficacy in both relapsed or refractory CLL and Richter’s syndrome in early data from EPCORE CLL-1 (phase Ib/II). Safety was reported to be manageable; however, ongoing efforts aim to reduce the incidence and severity of cytokine-release syndrome and immune effector cell–associated neurotoxicity syndrome and enhance the safety and accessibility of epcoritamab. Investigators presented data from the fully enrolled CLL expansion cohort and the first data from a cycle 1 optimization cohort.
Methods: Patients with relapsed or refractory CLL/SLL with at least two prior lines of therapy (including treatment with or intolerance to a BTK inhibitor) were included in this early phase I/II clinical trial. The median number of prior lines of therapy was four; 70% of the patients had unmutated IGHV, and almost 60% had TP53 aberrations. All patients had received prior BTK inhibitors, and almost 90% had refractory disease. More than 80% of the patients had received prior BCL2 inhibitors, and more than 40% of those patients had progressive disease while on these agents. This represented a particularly heavily pretreated cohort of patients with a generally poor outcome.
Patients were treated either in the expansion cohort (n = 23) or the optimization cohort (n = 17) of EPCORE CLL-1. The optimization cohort included an additional step-up dose to mitigate the adverse event of cytokine-release syndrome observed with the first full dose of epcoritamab. The primary endpoint for the expansion cohort was overall response rate per the International Workshop on CLL. Primary endpoints for the optimization cohort included the incidence and severity of cytokine-release syndrome, neurotoxicity, and clinical tumor-lysis syndrome. Efficacy data and other adverse events from the optimization cohort are not yet mature; these data are reported for the expansion cohort alone.
Results: Treatment was reported to be primarily well tolerated with expected adverse events. Of note, the optimization cohort successfully mitigated the incidence of grade ≥ 3 cytokine-release syndrome from 17% to 0%. There was also a significant decline in the use of tocilizumab, from 87% to 35%. None of the patients experienced grade ≥ 3 neurotoxicity. The onset of cytokine-release syndrome was predictable with the first full dose of treatment and could be managed with supportive care thereafter. A subset of patients was evaluable for response assessment, and 43% of the expansion cohort and 60% of the optimization cohort achieved a complete response. These responses were also durable and sustained, with a median progression-free survival of 12.8 months.
Clinical Implications: This early report of using epcoritamab provided encouraging complete remission and undetectable MRD rates in heavily pretreated patients with relapsed or refractory CLL/SLL, regardless of high-risk features. Immune-related toxicities were markedly improved with an adapted step-up dose schedule, with primarily grade 1 cytokine-release syndrome without immune effector cell–associated neurotoxicity syndrome.
Dr. Abutalib is Director of the Malignant Hematology and Transplantation & Cellular Therapy Programs at the Advocate/Aurora St. Luke’s Medical Center, Milwaukee, and Associate Professor at Rosalind Franklin University of Medicine and Science, Chicago. Dr. Awan is Associate Director, Section of Hematologic Malignancies/Transplantation and Cellular Therapy and Director of the Lymphoid Malignancies Program at Harold C. Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas.
DISCLOSURE: Dr. Abutalib reported a financial relationship with AstraZeneca. Dr. Awan has served as a consultant to Loxo Oncology, BeiGene, Dava Oncology, AstraZeneca, Genmab, Adaptive Biotechnologies, BMS, AbbVie, Incyte, Miltenyi Biomedicine, Invivyd, and Pierre Fabre; has received research funding from AbbVie/Pharmacyclics; and has served on the data safety monitoring committee for Ascentage Pharma and AstraZeneca.
REFERENCES
1. Brown JR, Seymour JF, Jurczak W, et al: Fixed-duration acalabrutinib plus venetoclax with or without obinutuzumab versus chemoimmunotherapy for first-line treatment of chronic lymphocytic leukemia: Interim analysis of the multicenter, open-label, randomized, phase 3 AMPLIFY trial. 2024 ASH Annual Meeting & Exposition. Abstract 1009. Presented December 9, 2024.
2. Fürstenau M, Kater AP, Robrecht S, et al: First-line venetoclax combinations versus chemoimmunotherapy in fit patients with chronic lymphocytic leukaemia (GAIA/CLL13): 4-Year follow-up from a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol 25:744-759, 2024.
3. Davids MS, Lampson BL, Tyekucheva S, et al: Acalabrutinib, venetoclax, and obinutuzumab as frontline treatment for chronic lymphocytic leukaemia: A single-arm, open-label, phase 2 study. Lancet Oncol 22:1391-1402, 2021.
4. Danilov A, Fakhri B, Awan FT, et al: Epcoritamab monotherapy in patients with relapsed or refractory chronic lymphocytic leukemia: Results from CLL expansion and optimization cohorts of EPCORE CLL-1. 2024 ASH Annual Meeting & Exposition. Abstract 883. Presented December 9, 2024.
