Rituximab/Bendamustine and Rituximab/Cytarabine (RB/RC) Induction Chemotherapy for Transplant-Eligible Patients with Mantle Cell Lymphoma: A Pooled Analysis of Two Phase 2 Clinical Trials and Off-Trial Experience
Authors: Merryman Reid W , Kahl Brad S , Redd Robert A. , Bsat Jad , Chase Matthew Lewis , LaCasce Ann S. , Freedman Arnold S. , Jacobson Caron A. , Fisher David C. , Ng Samuel Y. , Crombie Jennifer L , Kim Austin I , Odejide Oreofe O. , Davids Matthew S. , Brown Jennifer R. , Jacene Heather A. , Neha Mehta-Shah , Edwin Natasha , Cashen Amanda F , Bartlett Nancy L. , Ghobadi Armin , Armand Philippe , Joyce Robin M. , Jacobsen Eric D 
Published: October 2019

Abstract
Background: Induction chemoimmunotherapy followed by autologous stem cell transplantation (ASCT) is a standard of care for transplant eligible (TE) patients (pts) with untreated mantle cell lymphoma (uMCL); however, there is no consensus on the optimal induction regimen. The addition of rituximab + high-dose cytarabine (RC) to an RCHOP-like regimen is associated with better outcomes. In addition, two randomized trials have demonstrated superior efficacy and tolerability for rituximab/bendamustine (RB) compared to RCHOP for uMCL. Based on this, we conducted a phase 2 trial of 3 cycles of RB followed by 3 cycles of RC in 23 TE pts with uMCL, with encouraging preliminary results (Armand, BJH 2016). Pts continued to be followed for relapse and survival. Meanwhile, RB/RC became the standard frontline regimen at Dana-Farber Cancer Institute (DFCI). Simultaneously, investigators at Washington University in St. Louis (WUSTL) initiated a similar study of alternating cycles of RB/RC for uMCL. Herein, we report the results of both phase 2 trials as well as the off-trial experience.
Methods: In the DFCI trial, TE pts (age 18-69) with uMCL were treated with 3 cycles of RB (R 375 mg/m2 d1, B 90 mg/m2 d1-2) followed by 3 cycles of RC (R 375 mg/m2 d1, C 3gm/m2 BID d1-2 with dose reductions for age, renal dysfunction, or pre-existing neurotoxicity). Off-trial pts treated with RB/RC at DFCI or in consulting community practices were retrospectively identified using clinical and pharmacy databases. In the WUSTL trial, TE pts (age 18-65) received alternating cycles of RB (cycles 1, 3, 5) and RC (cycles 2, 4, 6) (same dosing as above). Response assessments were made using CT scans for the DFCI trial and PET/CT for the WUSTL trial and DFCI off-trial pts.
Results: In total, 86 pts (23 DFCI trial, 49 DFCI off-trial, 14 WUSTL trial) were treated with RB/RC. The median age was 57 (range 30-72). Pts in the WUSTL cohort were more likely to be male, have a high MIPI score, and have blastoid variant (Table). 94% of pts completed 6 cycles of RB/RC therapy. Off-trial pts were more likely to receive a lower starting dose (≤ 2gm/m2) of cytarabine (76%) compared to trial pts (38%). At the EOI, the overall response rate and CRR were 98% and 92%, respectively, with similar response rates across cohorts (Table). 73 pts (85%) subsequently underwent ASCT and 4 additional pts (5%) have ASCTs planned. 9 pts did not undergo ASCT because of persistent or PD (n=3), prolonged cytopenias (n=3), an incidentally identified ASXL1 mutation without cytopenias (n=1), pt preference (n=1), and inadequate stem cell collection (n=1). Delayed platelet engraftment after ASCT was seen for pts receiving alternating cycles of RB/RC compared to sequential RB/RC at day 30 (plts <50: 70% vs 16%, p=0.001) and at day 100 (plts <100: 60% vs 21%, p=0.017). An initial cytarabine dose >2gm/m2 was also associated with reduced 30-day platelet count (plts <50: 41% vs 8%, p=0.004). There was 1 treatment-related death from respiratory failure and RSV infection (Day 56 after ASCT).
Median follow-up was 32m (range 4-69m) among survivors overall (54m for DFCI trial, 28m for DFCI off-trial, 19m for WUSTL trial). The 24m and 48m PFS for the entire cohort were 88% (95CI 77-93) and 80% (95CI 66-89), respectively (Figure, panel A); the 24m and 48m OS were 96% (95CI 89-99) and 92% (95CI 81-97), respectively. PFS and OS were similar across cohorts with a trend towards inferior PFS in the higher-risk WUSTL cohort (Figure, panel B). PFS was similar among non-trial pts treated at DFCI (n=32) and in community centers (n=17). In univariate analyses, a higher cytarabine dose (>2gm/m2) was not associated with improved PFS, while blastoid or pleomorphic variant (HR 4.5, p=0.016) and high-risk MIPI score (HR 4.0, p=0.034) were both associated with inferior PFS.
Conclusions: Induction therapy with RB/RC followed by ASCT achieved high rates of durable remissions in two phase 2 clinical trials. Similarly favorable outcomes were observed with off-trial use of this regimen both at an academic center and in community practices. RB/RC is therefore an excellent choice of induction therapy for TE pts with uMCL, and could be further tested in comparative prospective trials. Sequential, rather than alternating, RB/RC cycles and lower dose cytarabine may reduce the risk of prolonged thrombocytopenia post-ASCT.
Figure 1. Figure 1.

Disclosures
Kahl: Juno: Consultancy; Seattle Genetics: Consultancy; Celgene: Consultancy; Abbvie: Consultancy; AstraZeneca: Consultancy; Genentech: Consultancy; Acerta: Consultancy; ADC Therapeutics: Consultancy; CTI: Consultancy; Gilead: Consultancy. LaCasce:Research to Practice: Speakers Bureau; Bristol-Myers Squibb: Other: Data safety and monitoring board; Seattle Genetics: Consultancy, Honoraria; Humanigen: Consultancy, Honoraria. Jacobson:Bayer: Consultancy; Novartis: Consultancy; Precision Bioscience: Consultancy; Humanigen: Consultancy; Kite: Consultancy; Pfizer: Consultancy. Davids:Gilead: Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Research Funding; Surface Oncology: Research Funding; Merck: Consultancy; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Brown:Sun Pharmaceutical Industries: Research Funding; Roche/Genentech: Consultancy; Pharmacyclics: Consultancy; Morphosys: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Invectys: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Research Funding; Genentech: Consultancy; Celgene: Consultancy; Boehringer: Consultancy; Beigene: Membership on an entity's Board of Directors or advisory committees; Acerta / Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy; Verastem: Consultancy, Research Funding; Loxo: Consultancy; TG Therapeutics: Consultancy; Sunesis: Consultancy. Bartlett:Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; Celgene: Research Funding; Forty Seven: Research Funding; Pharmacyclics: Research Funding; Merck & Co: Research Funding; Affimed: Research Funding; Novartis: Research Funding; ImaginAB: Research Funding; Astra Zeneca: Research Funding; Bristol-Meyers Squibb: Research Funding; Immune Design: Research Funding; Genentech: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; Novartis: Research Funding; Millennium: Research Funding. Armand:Merck: Consultancy, Research Funding; Adaptive: Research Funding; Otsuka: Research Funding; Affimed: Consultancy, Research Funding; Pfizer: Consultancy; Infinity: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Roche: Research Funding; Tensha: Research Funding. Jacobsen:Seattle Genetics: Consultancy; Merck: Consultancy.