The two first/last authors contributed equally

Background The phase 3 SHINE trial (NCT01776840 ) showed that I+BR significantly prolonged progression free survival (PFS) versus BR with R maintenance (BR) in older patients with previously untreated mantle cell lymphoma (1L MCL) (Wang ML et al. NEJM 2022).

Other commonly used 1L MCL regimens in older patients in Europe also include rituximab + cyclophosphamide + doxorubicin + vincristine + prednisone (R-CHOP) or a modified version of this regimen where bortezomib is substituted for vincristine (VR-CAP). In the phase 3 LYM-3002 trial (NCT00722137), VR-CAP showed improved PFS, and overall survival (OS) compared to R-CHOP (Robak T et al. Lancet 2018). In the absence of a randomized comparison of I+BR versus these treatments, we performed an adjusted comparative analysis of PFS and OS with the I+BR arm from the SHINE study and the R-CHOP and VR-CAP arms from the LYM-3002 trial.

Methods In SHINE trial, patients were treated with ibrutinib once daily until disease progression or unacceptable toxicity, plus 6 cycles of BR, and patients with a partial or complete response received rituximab maintenance every 8 weeks for up to 12 additional doses. In LYM-3002 trial, patients were treated with 6-8 cycles of R-CHOP or VR-CAP and did not receive maintenance therapy. PFS was the primary endpoint for both trials. To address potential confounding bias due to lack of randomization, individual patient level data of the 2 trials were used to estimate propensity scores and apply inverse probability weighting where the R-CHOP and VR-CAP arms are reweighted to match the I+BR arm to estimate the average treatment effect of the treated (ATT) (Phillippo D et al. NICE 2019, Schneeweiss S et al. Clin Pharmacol Ther 2007). Standardized mean differences (SMD) for each baseline characteristic were calculated and considered balanced between treatment cohorts if SMD ≤ 0.25 (Li F et al. JASA 2019). Relative treatment effects are presented as hazard ratios (HR) and 95% confidence intervals (CI).

Results Overall, 261 patients treated with I+BR, 134 patients with R-CHOP and 130 patients with VR-CAP were included in the analyses. Baseline characteristics (Age, Morphology, Eastern Cooperative Oncology Group (ECOG), Bone Marrow, Stage, Sex, Mantle Cell Lymphoma International Prognostic Index (MIPI)) for ATT-weighted R-CHOP and VR-CAP cohorts were well balanced versus the I+BR patient cohort.

When compared to R-CHOP, the ATT adjusted PFS and OS were both statistically significantly improved with I+BR. Median PFS with I+BR vs R-CHOP is 80.8 [62.0, Not reached (NR)] vs 18.4 [13.9, 20.1] months, respectively; the PFS HR is 0.24 [0.16-0.36], p<0.001. Median OS with I+BR vs R-CHOP is NR [81.2, NR] vs 64.6 [44.6, 79.0] months, respectively; the OS HR is 0.62 [0.43-0.90], p=0.012. (Figure 1)

When compared to VR-CAP, the ATT adjusted PFS was statistically significantly improved with I+BR. Median PFS with I+BR vs VR-CAP is 80.8 [62.0, NR] vs 30.7 [19.6, NR] months, respectively; the PFS HR is 0.50 [0.33-0.76], p=0.001. OS was numerically improved with I+BR. Median OS with I+BR vs VR-CAP is NR [81.2, NR] vs 64.4 [51.5, NR] months, respectively; the OS HR is 0.73 [0.51-1.05], p=0.093 (Figure 1)

With one additional year of follow-up of SHINE results (median follow-up of 94.5 months), there were 110 deaths in the I+BR group and 119 deaths in the BR group, and the OS HR between I+BR vs. BR is 1.00 [95% CI 0.77-1.30]. We plan to present updated adjusted indirect comparison of OS versus VR-CAP and R-CHOP at the meeting.

Conclusion In this adjusted cross-trial comparative analysis, I+BR with R maintenance demonstrated improved PFS versus two commonly used 1L MCL regimens in Europe (R-CHOP and VR-CAP). This finding is consistent with the phase 3 SHINE results where the upfront ibrutinib combination is a highly effective treatment option compared to standard chemo immunotherapies for older patients with previously untreated MCL. In addition, it also potentially supports that R maintenance should be considered routinely in patients with MCL.

Figure 1
Figure 1
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Hernandez-Rivas:Janssen, Roche, Abbvie, AstraZeneca, Beigene, Lilly, Gilead, BMS-Celgene, Amgen, Takeda, Jazz Pharmaceuticals, Rovi, Incyte: Membership on an entity's Board of Directors or advisory committees; BMS-Celgene: Research Funding; Janssen, Roche, Abbvie, AstraZeneca, Gilead, BMS-Celgene, Amgen, Takeda, Astra Zeneca: Speakers Bureau. Zinzani:Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eusapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Secura Bio: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; University of Bologna: Current Employment. Jerkeman:Abbvie: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Genmab: Honoraria; Kite/Gilead: Consultancy, Honoraria, Research Funding; Incyte: Honoraria; Orion: Honoraria; Novartis: Honoraria. Be Harvel:Janssen: Current Employment. Van Sanden:Janssen: Current Employment, Current equity holder in publicly-traded company. Diels:Janssen: Current Employment, Current equity holder in publicly-traded company. Husain:Janssen: Current Employment. Tapprich:Janssen: Current Employment. Deshpande:Johnson & Johnson: Current equity holder in publicly-traded company; Janssen: Current Employment. Le Gouill:Novartis, Kite/Gilead, Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support. Dreyling:Abbvie, Bayer, BMS/Celgene, Gilead/Kite, Janssen, Roche: Research Funding; Amgen, Astra Zeneca, Gilead/Kite, Janssen, Lilly, Novartis, Roche: Honoraria; Astra Zeneca, Beigene, BMS/Celgene, Gilead/Kite, Janssen, Lilly/Loxo, Novartis, Roche: Consultancy.

The combination of ibrutinib and bendamustine plus rituximab with rituximab maintenance therapy is an investigational treatment for patients with previously untreated MCL. Ibrutinib is approved for the treatment of relapsed/refractory MCL

Author notes

*

Asterisk with author names denotes non-ASH members.

© 2022 by The American Society of Hematology
2022
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