Challenging the “One-Size-Fits-All” Approach in Early MCL Treatment

In the United States, about 4000 people per year are diagnosed with mantle cell lymphoma (MCL), a cancer that develops from malignant B-lymphocytes in an area of the lymph node known as the mantle zone.¹

As Anita Kumar, MD, a medical oncologist with Memorial Sloan Kettering Cancer Center explained to lead off a session at the 2022 Annual Meeting of the American Society of Clinical Oncology (ASCO), MCL is associated with chronic activation of the B-cell receptor complex. “This,” she said, “has allowed for the development of Bruton tyrosine kinase (BTK) inhibitors, such as ibrutinib, as well as PI3 kinase inhibitors.”

Many factors guide decisions on initial treatment after diagnosis, such as the patient’s age, fitness, and especially transplant eligibility. In recent years, the chemoimmunotherapy combination of bendamustine and rituximab has become the standard of care for patients who are not eligible for autologous stem cell transplant (ASCT).

“However, mantle cell lymphoma is both clinically and biologically heterogeneous,” Kumar said. “And this really challenges the one-size-fits-all approach using chemoimmunotherapy across the board. We know this from our clinical practice.”

Kumar’s talk on approaches for treatment-naïve MCL anchored the ASCO session she chaired, “New Directions for Mantle Cell Lymphoma in 2022.” The June 6 session also featured talks by Toby Eyre, MBChB, MRCP, consultant hematologist at the Department of Hematology, University of Oxford, who discussed prognostic markers in MCL; and Chan Cheah, clinical professor of medicine, University of Western Australia. Cheah focused on novel therapies in relapsed/refractory settings, including the use of chimeric antigen receptor (CAR) T-cell therapy and bispecific antibodies to treat MCL.

Eyre offered an overview of current risk stratification of MCL patients, which highlighted the importance of the TP53 mutation as an extremely strong predictor of inferior overall survival (OS) in trials across several new therapeutic classes. Clinical factors can be useful, but not at the expense of testing for TP53 mutations, he said.

The use of the MCL International Prognositic Index (MIPI), combined with a measure of proliferation of the Ki-67 protein allows clinicians to group MCL patients into one of 4 risk categories for diagnostic, treatment, and clinical trial purposes, he said.

Kumar followed with a case for stratification, as she discussed the range of conditions among newly diagnosed MCL patients. There are patients with non-nodal leukemic MCL whose disease is indolent; often, these patients can be monitored for years. “And on the other end of the spectrum, we see blastoid mantle cell lymphoma that's highly aggressive with high proliferation; oftentimes with evidence of chemoresistance and inferior survival,” she said.

Investigators are learning more about the biology of these different presentations, Kumar said. More conventional MCL is associated with greater genomic instability and TP53 mutation, along with inferior OS. “In addition, minimal residual disease assessment has allowed for novel treatment paradigms to be explored in mantle cell lymphoma,” she said, as she reviewed studies that linked MRD status to remission duration. MRD, she said, has the potential as a surrogate end point, as a marker to predict relapse during surveillance or therapeutic resistance, and to potentially help doctors decide when treatment can cease or less treatment is needed.

A case in point: in the Cooperative Group Study EA4151, newly diagnosed transplant eligible patients are randomized after induction therapy to ASCT with rituximab maintenance or just rituximab.² “This is an exciting clinical trial design, because it leverages MRD assessment as a prognostic biomarker, and potentially in patients who achieve a deep molecular remission investigates whether we can omit upfront autologous stem cell transplant,” she said.

As with other types of lymphoma, there’s discussion whether to move newer targeted therapies and other non-chemotherapy treatments into earlier lines of treatment, where they might be more effective with fewer toxic effects. Kumar outlined this discussion in light of results from the SHINE trial, presented earlier at ASCO, which showed adding ibrutinib to bendamustine and rituximab offered a progression-free survival (PFS) benefit but no OS benefit.³

She said the Triangle study will examine 870 younger, fitter patients examine 3 arms: one with alternating regimens of well-known chemotherapy combinations followed by ASCT, one with ibrutinib added to one of the chemotherapy combinations followed by ASCT, and one with the chemotherapy combinations and ibrutinib only.⁴ Again, Kumar said, the trial may demonstrate an ability to achieve better outcomes without ASCT.

Chemotherapy-free combinations, including those that include BTK inhibitors, are a major area of study. Kumar reviewed these findings:

• A study of lenalidomide with rituximab in 38 patients (median age, 65 years), with 78% low-to-intermediate MIPI and 21% Ki-67 ≥30%, showed a 5-year PFS of 64% and 5-year OS of 77%.⁵
• Ibrutinib and rituximab in 50 patients at least 65 years of age (36% low-to-intermediate MIPI and 24% Ki-67 ≥30%; no blastoid patients), showed 3-year PFS of 87%; however, 34% of patients developed atrial fibrillation and 10 had to stop taking the ibrutinib.

Concern about the cardiovascular effects of ibrutinib has led to trials with zanubrutinib, a second-generation BTK inhibitor. A 500-patient, phase 3 clinical trial of 2 different regimens of zanubrutinib with bendamustine vs zanubrutinib alone is under way.⁶

Triplet combinations are now being studied in MCL. Kumar reviewed the results for OASIS, which studied ibrutinib, obinutuzumab, and venetoclax in 15 mostly low-to-intermediate MIPI patients, of whom 2 had a TP53 mutation.⁷ The idea here is to leverage dual BTK and BCL2 inhibition, which is known to be synergistic in MCL, Kumar said. The PET complete response (CR) at 6 months was 86.6%; after a median follow-up of 14 months, 1-year PFS was 93%.

“This establishes this triplet combination as a highly active treatment program in mantle cell lymphoma, and it was also demonstrated that this was well tolerated,” she said. “Of great interest, we see that this combination was active in patients who had a TP53 mutation as well as blastoid disease.”

Kumar concluded with 2 other trials of interest to payers:

• For low-risk patients, a study involving ibrutinib and rituximab for indolent MCL, called IMCL-2015, could shed light on use of MRD to tell when ibrutinib can be stopped. After 12 treatment cycles, the overall response rate was 84%, and 36-month PFS was 93%. Ibrutinib was stopped in 24 of 35 cases after cycle 24.⁸
• For high-risk patients—who have no current standard of care—the BOVEN study offers a variation on the OASIS regimen; using zanubrutinib instead of ibrutinib. This is a higher-risk group of patients; in the first patient group presented at ASH in 2021,⁹ 100% had the TP53 mutation, median age was 68, and only 35% were low-to-intermediate MIPI. But so far, the results are encouraging: 17 patients were evaluated for toxicity and 14 for efficacy; of the 14, 12 had a response and 9 had a complete response. One responding patient was lost to follow-up and died of an unknown cause.

“We really recommend enrollment in a clinical trial for patients who have a TP53 mutation,” Kumar said. “Insights into mantle cell lymphoma disease biology have improved our biologic risk stratification, and certainly identification of a TP53 mutation at time of initial diagnosis is of great importance.”

References

1. Lymphoma Research Foundation announces publication of Mantle Cell report. News release. Lymphoma Research Foundation. February 9, 2010. Accessed June 17, 2022. https://www.eurekalert.org/news-releases/713600
2. Ritixumab with or without stem cell transplant in treating patients with minimal residual disease negative mantle cell lymphoma in first complete remission. ECOG-ACRIN Cancer Research Group. Accessed June 17, 2022. https://ecog-acrin.org/clinical-trials/ea4151-mantle-cell-lymphoma/
3. Wang M. Jurczak W, Jerkeman M, et al. Ibrutinib plus bendamustine and rituximab in untreated mantle-cell lymphoma. N Engl J Med. Published and updated June 3, 2022. doi:10.1056/NEJMoa2201817
4. Dreyling M, Ladetto M, Doorduijn JK et al. Triangle: autologous transplantation after rituximab/ara-c Containing Induction in generalized mantle cell lymphoma—a randomized European MCL Network Trial. Blood. 2019;134(suppl_1):2816. https://doi.org/10.1182/blood-2019-12786
5. Ruan J, Martin P, Christos P, et al. Five-year follow-up of lenalidomide plus rituximab as initial treatment of mantle cell lymphoma. Blood. 2018;132(19):2016-2025. doi:10.1182/blood-2018-07-859769
6. Dreyling M, Tam CS, Wang M, et al. A phase III study of zanubrutinib plus rituximab versus bendamustine plus rituximab in transplant-ineligible, untreated mantle cell lymphoma. Future Oncol. 2021;17(3):255-262. doi: 10.2217/fon-2020-0794
7. LeGouill S, Morschhauser F, Chiron D, et al. Ibrutinib, Obinutuzumab, and venetoclax in relpased and untreated patients with mantle cell lymphoma: a phase 1/2 trial. Blood. 2021;137(7):877-887. doi: 10.1182/blood.2020008727
8. Giné E, de la Cruz F, Ubieta AJ, et al. Ibrutinib in combination with rituximab for indolent clinical forms of mantle cell lymphoma (IMCL-2015): a multicenter, open-label, single-arm, phase II trial. J Clin Oncol. 2022;40(11):1196-1205. doi:10.1200/JCO.21.02321.
9. Kumar A, Soumerai JD, Abramson JS, et al. Preliminary safety and efficacy from a multicenter, investigator initiated phase II study in untreated TP53 mutant mantle cell lymphoma with zanutbrutinib, Obinutuzumab, and venetoclax (BOVen). Presented at: 63rd American Society of Hematology Meeting & Exposition; Atlanta, GA; December 13, 2021; Poster 3540. https://ash.confex.com/ash/2021/webprogram/Paper151831.html