Ibrutinib With Rituximab in First-Line Treatment of Older Patients With Mantle Cell Lymphoma

Preetesh Jain, MD, DM, PhD; Shuangtao Zhao, PhD; Hun Ju Lee, MD; Holly A. Hill, MPH; Chi Young Ok, MD; Rashmi Kanagal-Shamanna, MD; Fredrick B. Hagemeister, MD; Nathan Fowler, MD; Luis Fayad, MD; Yixin Yao, PhD; Yang Liu, PhD; Omar B. Moghrabi, BS; Lucy Navsaria, MBBS; Lei Feng, MS; Graciela M. Nogueras Gonzalez, MPH; Guofan Xu, MD; Selvi Thirumurthi, MD; David Santos, MD; Cezar Iliescu, MD; Guilin Tang, MD, PhD; L. Jeffrey Medeiros, MD; Francisco Vega, MD, PhD; Michelle Avellaneda, BS; Maria Badillo, BS; Christopher R. Flowers, MD; Linghua Wang, PhD; Michael L. Wang, MD


J Clin Oncol. 2022;40(2):202-212. 

In This Article

Abstract and Introduction


Purpose: Most patients with mantle cell lymphoma (MCL) are older. In this study, we investigated the efficacy and safety of a chemotherapy-free combination with ibrutinib and rituximab (IR) in previously untreated older patients with MCL (age ≥ 65 years).

Methods: We enrolled 50 patients with MCL in this single-institution, single-arm, phase II clinical trial (NCT01880567). Patients with Ki-67% ≥ 50% and blastoid morphology were excluded. Ibrutinib was administered with rituximab up to 2 years with continuation of ibrutinib alone. The primary objective was to assess the overall response rate and safety of IR. In evaluable samples, whole-exome sequencing and bulk RNA sequencing from baseline tissue samples were performed.

Results: The median age was 71 years (interquartile range 69–76 years). Sixteen percent of patients had high-risk simplified MCL international prognostic index. The Ki-67% was low (< 30%) in 38 (76%) and moderately high (≥ 30%-50%) in 12 (24%) patients. The best overall response rate was 96% (71% complete response). After a median follow-up of 45 months (interquartile range 24–56 months), 28 (56%) patients came off study for various reasons (including four progression, 21 toxicities, and three miscellaneous reasons). The median progression-free survival and overall survival were not reached, and 3-year survival was 87% and 94%, respectively. None of the patients died on study therapy. Notably, 11 (22%) patients had grade 3 atrial fibrillation. Grade 3–4 myelosuppression was seen in < 5% of patients. Differential overexpression of CCND1, BIRC3, BANK1, SETBP1, AXIN2, and IL2RA was noted in partial responders compared with patients with complete response.

Conclusion: IR combination is effective in older patients with MCL. Baseline evaluation for cardiovascular risks is highly recommended. Randomized trial is needed for definitive conclusions.


Most patients with mantle cell lymphoma (MCL) are elderly with a median age of 69 or 71 years.[1,2] Apart from high-risk disease characteristics,[3] advanced age, poor performance status, and number of comorbidities exhibit an adverse prognostic impact in patients with MCL.[4,5] Patients treated with systemic chemotherapy and advancing age have an inferior outcome compared with young patients with MCL (age ≤ 65 years).[2] The standard-of-care treatment for elderly patients with MCL is rituximab-based chemoimmunotherapy followed by rituximab maintenance (in some studies),[6–9] providing a median progression-free survival (PFS) of 3–5 years and an overall response rate (ORR) of about 90% with 40%-50% complete response (CR; except the combination of bendamustine, rituximab, and cytarabine, which induced a CR of 91%).[6–9] High incidence of grade 3–4 myelosuppression, hospitalization rates, infectious complications, and second cancers (including therapy-related myelodysplasia) after chemoimmunotherapy are significant complications in elderly patients with MCL.

With the advent of orally administered Bruton's tyrosine kinase (BTK) inhibitors such as ibrutinib, acalabrutinib, zanubrutinib, and pirtobrutinib[10–14] alone or ibrutinib with rituximab[15,16] and/or ibrutinib with Bcl2 antagonist venetoclax in treating patients with relapsed MCL,[17,18] many investigators are exploring earlier use of chemotherapy-free novel targeted therapeutic approaches for patients with MCL. On the basis of favorable efficacy and safety data (particularly lack of myelosuppression), ease of administration, our own clinical experience using the ibrutinib-rituximab combination in patients[16] with relapsed MCL (88% ORR, 58% CR after a 4-year follow-up[15] with 16 of 50 [32%] patients' age > 70 years), and the desire to develop chemotherapy-free treatment modalities, we investigated the ibrutinib-rituximab combination (IR) in the frontline therapy for elderly patients with MCL in this single-center, phase II study.

*Relevance section written by JCO Editor-in-Chief Jonathan W. Friedberg, MD.