“The practice of medicine is an art, not a trade….” —Sir William Osler
Mantle cell lymphoma (MCL) accounts for approximately 5% to 7% of all lymphomas; the median age of patients with MCL is between 60 and 70 years. This lymphoma is generally considered incurable. Median survival in retrospective studies from the late 1990s ranged from 3 to 5 years; this outcome has improved with intensive induction and maintenance rituximab, and a median survival of 10 or more years can now be expected for many younger patients.
Syed A. Abutalib, MD
Timothy S. Fenske, MD, MS
Although the role of autologous hematopoietic cell transplantation (auto-HCT) remains an area of debate in newly diagnosed MCL, younger patients with symptomatic/high-volume disease and without significant comorbidities are usually treated with chemoimmunotherapy, often consolidated by auto-HCT and followed by maintenance rituximab. Older patients with symptomatic/high-volume disease or those with significant comorbidities are typically treated with chemoimmunotherapy and maintenance rituximab without auto-HCT.
To complement The ASCO Post’s extensive coverage of the 2023 American Society of Hematology (ASH) Annual Meeting & Exposition, here are two important abstracts selected from the meeting proceedings focusing on the treatment of MCL. For full details of the study abstracts, visit www.hematology.org/meetings/annual-meeting/abstracts.
Transplant-Ineligible Older Adults
Abstract 979: Induction (n = 620) and maintenance therapy (n = 495) in transplant-ineligible older adults with MCL: Double-randomized MCL study on behalf of the European Mantle Cell Lymphoma Network.1
Background: Recent trials in younger (age ≤ 65 years) transplant-eligible patients have demonstrated the clinical benefit of a cytarabine-containing induction therapy2 and combined rituximab and lenalidomide (R2) maintenance.3 The role of cytarabine-containing induction and R2 maintenance in older transplant-ineligible patients is unclear.
Methods: Patients with stage II to IV MCL who were older than age 60 and ineligible for auto-HCT were included in this study. The trial investigated whether induction with an intermediate dose of cytarabine improves long-term outcomes over R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) alone in transplant-ineligible older adults. In addition, those who responded to induction therapy (partial response or better) were randomly assigned to a 2-year maintenance therapy with R2 vs rituximab alone. The primary endpoint was overall survival for the induction therapy and event-free-survival for the maintenance therapy.
Results: The median age of patients was 71 years, 69% were male, 85% had stage IV disease, 47% had an intermediate-risk score on the MCL International Prognostic Index (MIPI), and 46% had a high-risk MIPI score.
First Randomization: Response rates at the end of induction were similar in the two groups. At the time of reporting, survival endpoints did not differ between the two induction regimens (progression-free survival = 70.6% vs 66.8%, P = .28; overall survival = 83% vs 83%, P = .92).
Second Randomization: Second randomization was stratified for induction regimen (8 × R-CHOP vs 6 × R-CHOP/R-HAD [rituximab, high-dose cytarabine, dexamethasone]), study group, age, MIPI score, and complete or partial response. After a median follow-up of 4.2 years from maintenance randomization, patients in the R2 maintenance arm had a significantly improved progression-free survival compared with rituximab alone (60.9% vs 42.9%, P = .0002). Adverse events were more pronounced in the R2 maintenance arm. The overall survival did not differ between the two maintenance arms (at 2 years, R2 group = 87.6%, rituximab monotherapy group = 85.1%).
Clinical Implications: Although no efficacy or toxicity differences were observed between the two induction regimens, R2 maintenance significantly prolonged progression-free survival compared with rituximab alone in older adults who were ineligible for auto-HCT. However, no difference in overall survival was observed, and toxicity was increased in the R2 arm.
TP53-Mutated MCL
Abstract 738: Multicenter phase II trial of zanubrutinib, obinutuzumab, and venetoclax (BOVen) in patients (n = 25; age range = 29–82 years) with treatment-naive, TP53-mutated MCL (ClinicalTrials.gov identifier NCT03824483).4
Background: TP53-mutated MCL is associated with poor survival with chemoimmunotherapy followed by auto-HCT, which yields a median progression-free survival of less than 1 year and overall survival of 1.8 years.5 The combination of Bruton’s tyrosine kinase (BTK) inhibition and BCL2 inhibition was synergistic and active in relapsed or refractory MCL, including in patients with a TP53 mutation.6 Obinutuzumab, ibrutinib, and venetoclax were well tolerated and efficacious in patients with relapsed or refractory MCL.7 Investigators therefore hypothesized that treatment with BOVen would be well tolerated and efficacious in treatment-naive, TP53-mutated MCL.
Methods: BOVen was administered in 28-day cycles: zanubrutinib at 160 mg twice a day starting on day 1; obinutuzumab at 1,000 mg intravenously on day 1 (or split, at 500 mg on days 1 and 2), and 1,000 mg on days 8 and 15 of cycle 1, and 1,000 mg on day 1 of cycles 2 to 8; venetoclax ramp-up was initiated on day 1 of cycle 3 (target = 400 mg daily). Treatment duration was a minimum of 2 years, and the primary endpoint was 2-year progression-free survival.
Peripheral blood measurable residual disease (MRD) assessment was performed using the clonoSEQ assay. After 24 cycles, zanubrutinib and venetoclax could be discontinued if an undetectable MRD (< 10−6) complete response was achieved. All 25 patients in the study had stage IV disease.
Results: The median patient age was 65 years (range = 29–82 years); 76% were male; various histologic subtypes were included (15 had conventional MCL, 5 had non-nodal leukemic MCL, and 5 had blastoid-variant MCL); and 68% had high-risk MIPI scores, 28% had intermediate-risk scores, and 4% had low-risk scores.
Efficacy: The overall response rate was 95%, with 88% achieving a complete response. Before the start of venetoclax, 17 of 25 patients (68%) achieved a positron-emission tomography (PET) complete response, and after cycle 3, 5 additional patients converted to a PET complete response. The 16-month progression-free and overall survival rates were 75% (95% confidence interval [CI] = 60%–95%) and 87% (95% CI = 75%–100%), respectively.
Seven patients completed 24 treatment cycles. Of these patients, five were in complete response and had undetectable MRD (treatment was discontinued), and two patients were in complete response with detectable MRD (on continued treatment). Outcomes after cycle 24 will be presented in the future.
Safety: Median follow-up was 16.1 months. Grade 3 or higher treatment-related adverse events included neutropenia (12%), infusion-related reaction (8%), COVID-19 infection (8%), diarrhea (4%), transaminitis (4%), thrombocytopenia without bleeding (4%), and rash (4%). Five patients had disease progression, and four died on study (two were COVID-19–related: one from postoperative aspiration pneumonia and one from an unknown cause). All deaths occurred in patients who were in ongoing response at the time of death.
Clinical Implications: The early progression-free survival and overall survival estimates with BOVen compare favorably with historical outcomes of chemoimmunotherapy in TP53-mutated MCL. Based on these data, BOVen has emerged as a promising treatment option for TP53-mutated MCL; therefore, the study was expanded to include an additional 25 patients with TP53-mutated MCL. Currently, MRD-
guided therapy in MCL remains experimental.
DISCLOSURE: Dr. Abutalib has reported a financial relationship with AstraZeneca. Dr. Fenske has served as a speaker for and/or consultant to Adaptive Biotechnologies, ADCT, AstraZeneca, BeiGene, Kite/Gilead, Lilly/Loxo, MorphoSys, Ono Pharmaceuticals, Pharmacyclics/AbbVie, Seagen, and TG Therapeutics.
REFERENCES
1. Ribrag V, Safar V, Kluin-Nelemans H, et al: Induction and maintenance therapy in elderly patients with mantle cell lymphoma: Double-randomized MCL R2 elderly clinical trial by the European Mantle Cell Lymphoma Network. 2023 ASH Annual Meeting & Exposition. Abstract 979. Presented December 11, 2023.
2. Hermine O, Jiang L, Walewski J, et al: High-dose cytarabine and autologous stem-cell transplantation in mantle cell lymphoma: Long-term follow-up of the randomized Mantle Cell Lymphoma Younger trial of the European Mantle Cell Lymphoma Network. J Clin Oncol 41:479-484, 2023.
3. Ladetto M, Cortelazzo S, Ferrero S, et al: Lenalidomide maintenance after autologous haematopoietic stem-cell transplantation in mantle cell lymphoma: Results of a Fondazione Italiana Linfomi multicentre, randomised, phase 3 trial. Lancet Haematol 8:e34-e44, 2021.
4. Kumar A, Soumerai J, Abramson JS, et al: A multicenter phase 2 trial of zanubrutinib, obinutuzumab, and venetoclax (BOVen) in patients with treatment-naive, TP53-mutant mantle cell lymphoma. 2023 ASH Annual Meeting & Exposition. Abstract 738. Presented December 11, 2023.
5. Eskelund CW, Dahl C, Hansen JW, et al: TP53 mutations identify younger mantle cell lymphoma patients who do not benefit from intensive chemoimmunotherapy. Blood 130:1903-1910, 2021.
6. Tam CS, Anderson MA, Pott C, et al: Ibrutinib plus venetoclax for the treatment of mantle-cell lymphoma. N Engl J Med 378:1211-1223, 2018.
7. Le Gouill S, Morschhauser F, Chiron D, et al: Ibrutinib, obinutuzumab, and venetoclax in relapsed and untreated patients with mantle cell lymphoma: A phase 1/2 trial. Blood 137:877-887, 2018.
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. Fenske is Professor of Medicine in the Division of Hematology and Oncology at the Medical College of Wisconsin, Milwaukee.
