Initial Results of a Phase II Study of Sequential Chemotherapy and Lenalidomide Followed By Rituximab and Lenalidomide Maintenance for Untreated Mantle Cell Lymphoma

Introduction: Cytarabine-containing induction chemotherapy followed by high dose therapy and autologous stem cell transplant (ASCT) is currently a standard treatment approach for younger patients with mantle cell lymphoma (MCL). This approach, however, may be associated with lesser efficacy in patients with high-risk disease biology (i.e. with elevated proliferative index, blastic morphology, or TP53 alteration). Older patients are treated with rituximab-based chemotherapy regimens without stem cell transplant. In this single-center prospective phase II study, we treated MCL patients, irrespective of their age, with immunochemotherapy combined with lenalidomide without ASCT to evaluate the safety and efficacy of this regimen.

Methods: Treatment consisted of 3 parts: A) 4 cycles of lenalidomide (15mg orally days 1-14) and standard RCHOP chemotherapy in a 21-day cycle B) rituximab and high-dose cytarabine (RHIDAC) administered at a dose of 1,000-3,000 mg/m² every 12 hours x 4 doses for a total of 2 cycles C) rituximab plus lenalidomide maintenance for 6 months. Eligible patients were untreated MCL, stage II-IV, KPS≥70%, and with adequate organ function. We enriched study enrollment for high risk patients, 31 of a total 47 patients, as defined by Ki-67 ≥30% and/or blastic/blastoid/pleomorphic morphologic subtype. PET/CT after each phase of treatment was completed and interpreted with the 5-point Deauville scale (negative=1-3). The primary endpoint of the study was to evaluate the 3-year progression free survival. Herein we are presenting preliminary data on the end-of-treatment (EOT) response rate and the toxicity of the regimen, including the interim and EOT PET data.

Results: Interim data (as of June 1, 2018) for the first 45 of a planned 47 patients are presented here. Median age was 63 (range 30-79); 82% stage IV; MIPI low, intermediate and high risk were 31%, 31%, and 38%, respectively; 64% of patients had high-risk disease per our definition (28 patients with a Ki-67 ≥30% and 6 patients with blastic morphology).

Of the 39 patients who completed Len-RCHOP induction, 85% were PET-negative and after RHIDAC, 95% of patients achieved a negative PET scan (Figure 1). Of the 26 patients who have completed Len-R maintenance, 92% were PET-negative, 8% PET-positive (Table 1). At EOT, 24 patients (92%) achieved a complete remission, 1 patient achieved a partial response, and 1 patient had progressive disease. Among the 24 patients who achieved a CR, the median follow-up is 9 months. Two relapses have occurred at 18 months and 25 months. The patients with a treatment failure (one PR at EOT, one progressive disease at EOT, and 2 relapses), occurred in patients either with a TP53 mutation (3/3 tested, 1 pending) or blastic morphology (3/4 patients). Overall the treatment program was well-tolerated and predominantly hematologic toxicities were observed, particularly during the RHIDAC phase consistent with past experience with this treatment regimen in MCL. During each phase (Len-RCHOP, RHIDAC, and Len-R maintenance), grade 3/4 neutropenia was observed at a rate of 13%, 52%, 16%, respectively; febrile neutropenia 1%, 4%, 0%, respectively; grade 3/4 anemia 11%, 32%, 1%, respectively; and grade 3/4 thrombocytopenia 8%, 75%, 2%, respectively. Comparing to our historical data in a cohort of 23 MCL patients (57% low risk), Len-RCHOP resulted in a higher PET-negative rate compared to RCHOP alone, 85% versus 65%, respectively.

Conclusion: The addition of lenalidomide to RCHOP chemotherapy appeared to increase the rate of PET-negativity compared to historical results with RCHOP alone. Toxicity occurred as expected and was manageable. Early failures were observed in patients with TP53 mutation or blastic morphology. Although follow-up is limited, early results with this approach are promising.

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