Chemo-Free Options Abound for Transplant-Ineligible MCL, Kumar Explains

Bendamustine and rituximab (BR) remains a standard of care in frontline treatment of patients with transplant ineligible mantle cell lymphoma (MCL), but adding acalabrutinib is now an option, and the number of chemotherapy-free doublets and triplets is rising.

That’s how Anita Kumar, MD, of Memorial Sloan Kettering Cancer Center in Basking Ridge, New Jersey, summed up the rapidly evolving treatment landscape for patients who are older or otherwise ineligible for autologous stem cell transplantation. Kumar presented options during a talk, “New Options for Transplant Ineligible Mantle Cell Lymphoma,” at a June 1, 2026, session on MCL at the American Society of Clinical Oncology Annual Meeting.

The Established Standard: BR and Rituximab Maintenance

Following an overview from session co-presenter Martin Dreyling, MD, of the European MCL Network, Kumar opened with a clinical case involving a 69-year-old woman presenting with classical MCL and the following biomarkers: a score of 20%–30% for Ki67, a protein that is a marker of cellular proliferation; complex cytogenetics, IGHV unmutated, an ATM mutation, and no TP53 aberrancy. By the end of the session, Kumar would have a solution for this patient.

She reviewed the STiL (NCT00991211) and BRIGHT (NCT00877006) phase 3 trials,^1,2 which established BR's superiority over R-CHOP in progression-free survival (PFS) and tolerability, cementing its status as the chemotherapy backbone for transplant-ineligible patients.

On the question of rituximab maintenance, Kumar said trial data are mixed. The MAINTAIN substudy (NCT00877214) showed no PFS or OS benefit, while noting that subsequent retrospective and real-world analyses have consistently favored maintenance.³ These include the MCL Elderly Trial,⁴ Flatiron real-world data,⁵ and a retrospective pooled from 27 academic centers by Yucai Wang, MD, PhD, et al, published in Blood Advances,⁶ all showing median OS improvements of roughly 2–3 years with rituximab maintenance after BR.

“In my practice, I do typically use rituximab maintenance after BR induction,” Kumar said. “However, I do follow patients closely for acquired hypogammaglobulinemia or recurrent sinopulmonary infections.”

Adding a BTK Inhibitor: SHINE vs ECHO

The next evolutionary step was combining BR with a covalent Bruton tyrosine kinase (BTK) inhibitor. The SHINE trial (NCT01776840) added ibrutinib (Imbruvica) to BR in 523 patients at least 65 years of age or older, achieving a statistically significant PFS improvement (6.7 vs 4.4 years) but no OS benefit. Also, ibrutinib generated excess treatment-emergent adverse event (TEAE) deaths (10.7% vs 6.1%) and higher rates of grade 3–4 pneumonia and atrial fibrillation.⁷ These safety concerns drove ibrutinib's withdrawal from the US market for MCL and limited SHINE's clinical uptake.

The ECHO trial, with an otherwise similar design, substituted the more selective, second-generation BTK inhibitor acalabrutinib (Calquence; AstraZeneca).⁸ Among 598 patients, an updated analysis shows acalabrutinib-BR achieved a median PFS of approximately 6 years versus 4 years with BR alone (HR 0.68, P = .0022) and showed no excess in treatment-related deaths; there were numerically fewer deaths in the acalabrutinib-BR arm. While OS was not improved due to crossover, the safety profile was deemed acceptable.

“Adding acalabrutinib to BR does add some toxicity. There are increased rates of diarrhea, COVID-19 infection, headache, fatigue, atrial fibrillation, and infection,” she said. “In general, these toxicities were well-managed. However, in an older patient population with coexisting comorbidities, it is important to keep this in mind.”

Kumar pointed to an analysis by MD Anderson’s Michael Wang, MD, presented in December 2025 at the American Society of Hematology annual meeting (ASH 2025) that showed the upfront triplet was associated with a decreased need for additional therapy.

“So only 10% of patients treated with [acalabrutinib]-BR required third-line treatment, versus 37% of patients who received upfront bendamustine and rituximab. This suggests that an initial intensive treatment approach can reduced the need for multiple successive lines of therapy. And in regions where there’s limited access to CAR T or bispecific options, this is an important clinical consideration.”

This leads us to an ongoing debate, Kumar said: should BTK inhibitors be saved in a sequential approach, with BR induction coming first followed by rituximab maintenance? Or should a BTK inhibitor be used right away in a a concurrent strategy?

“There are legitimate arguments on both sides,” she said.

The Chemotherapy-Free Frontier: Doublets and Triplets

Kumar then turned to what she called the most exciting area of development. The ENRICH phase 3 trial showed that ibrutinib-rituximab (IR) improved PFS over chemoimmunotherapy overall (HR 0.69), but the benefit was primarily vs R-CHOP; IR and BR yielded essentially equivalent outcomes.⁹ For patients who cannot tolerate chemotherapy, however, single-institution experiences with acalabrutinib-rituximab, including an MD Anderson series (ORR/CR 92%; 2-year PFS 92%) and the Nordic ALTAMIRA study (NCT05214183),¹⁰ demonstrate strong efficacy in standard-risk patients. However, the ALTAMIRA study revealed substantially inferior outcomes in patients with TP53 mutation or blastoid variant (2-year PFS 32%). Results from the MANGROVE phase 3 trial (NCT04002297), randomizing 500 patients to zanubrutinib (Brukinsa; BeOne Medicines) with rituximab versus BR, are pending.

Chemotherapy-free triplets — combining an anti-CD20 antibody, a covalent BTK inhibitor, and venetoclax—show the highest activity to date. Kumar summarized 4 trials (OASIS II, TrAVeRse, BOVen, and MAVO) with ORRs of 88% to 98%, CR rates of 54% to 94%, and impressive early PFS and OS curves. She highlighted her own BOVen trial (NCT03824483),¹¹combining zanubrutinib, obinutuzumab, and venetoclax, including the older-patient cohort presented at ASH 2025: ORR 98%, CR 96%, 2-year PFS 86%, and 2-year OS 92%, with an MRD-driven approach allowing treatment discontinuation after 24 cycles in patients achieving undetectable MRD. The 69-year-old clinical case patient discussed at the start of Kumar’s talk was enrolled in BOVen, achieved CR and undetectable MRD, stopped therapy, and remains in remission 18 months off treatment.

Using a Treatment Algorithm

Kumar proposed a 2026 algorithm stratifying older MCL patients by TP53 status: those with TP53 mutations should be directed to BOVen or other triplet strategies, ideally on clinical trial. For patients without TP53 mutations, options include BR with rituximab maintenance, BR-acalabrutinib per ECHO, or rituximab with a covalent BTK inhibitor doublet for those ineligible for chemotherapy. MRD-guided, time-limited approaches should be integrated where feasible.

“Chemo-free options are poised to be new standards of care for older patients in the future,” she said. “We hope we can use MRD-driven and time-limited approaches to limit treatment assocated with toxicity and reduce the development of therapy associated resistance."

“And really, we hope that we are moving towards individualized treatment protocols that integrate baseline biologic factors as well as patient factors,” she said, which would include age, fitness, and comorbidities, along with patient preferences and the integration of “depth of response utilizing minimal residual disease therapy.”

References

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