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Clinical Trial
. 2024 Jun;38(6):1307-1314.
doi: 10.1038/s41375-024-02254-2. Epub 2024 Apr 27.

The addition of bortezomib to rituximab, high-dose cytarabine and dexamethasone in relapsed or refractory mantle cell lymphoma-a randomized, open-label phase III trial of the European mantle cell lymphoma network

Luca Fischer #  1 , Linmiao Jiang #  2 , Jan Dürig  3 , Christian Schmidt  4 , Stephan Stilgenbauer  5 , Krimo Bouabdallah  6 , Philippe Solal-Celigny  7 , Christian W Scholz  8 , Pierre Feugier  9 , Maike de Wit  10 , Ralf Ulrich Trappe  11 , Michael Hallek  12 , Ullrich Graeven  13 , Mathias Hänel  14 , Martin Hoffmann  15 , Vincent Delwail  16 , Margaret Macro  17 , Jochen Greiner  18 , Aristoteles A N Giagounidis  19 , Beate Dargel  20 , Eric Durot  21 , Charles Foussard  22 , Elisabeth Silkenstedt  4 , Oliver Weigert  4 , Christiane Pott  23 , Wolfram Klapper  24 , Wolfgang Hiddemann  4 , Michael Unterhalt  4 , Eva Hoster #  4   2 , Vincent Ribrag #  25 , Martin Dreyling #  4
Affiliations
Clinical Trial

The addition of bortezomib to rituximab, high-dose cytarabine and dexamethasone in relapsed or refractory mantle cell lymphoma-a randomized, open-label phase III trial of the European mantle cell lymphoma network

Luca Fischer et al. Leukemia. 2024 Jun.

Abstract

The therapy of relapsed or refractory (r/r) mantle cell lymphoma (MCL) patients remains a major clinical challenge to date. We conducted a randomized, open-label, parallel-group phase-III trial hypothesizing superior efficacy of rituximab, high-dose cytarabine and dexamethasone with bortezomib (R-HAD + B) versus without (R-HAD) in r/r MCL ineligible for or relapsed after autologous stem cell transplant (ASCT). Primary endpoint was time to treatment failure (TTF), secondary endpoints included response rates, progression free survival, overall survival, and safety. In total, 128 of 175 planned patients were randomized to R-HAD + B (n = 64) or R-HAD (n = 64). Median TTF was 12 vs. 2.6 months (p = 0.045, MIPI-adjusted HR 0.69; 95%CI 0.47-1.02). Overall and complete response rates were 63 vs. 45% (p = 0.049) and 42 vs. 19% (p = 0.0062). A significant treatment effect was seen in the subgroup of patients >65 years (aHR 0.48, 0.29-0.79) and without previous ASCT (aHR 0.52, 0.28-0.96). Toxicity was mostly hematological and attributable to the chemotherapeutic backbone. Grade ≥3 leukocytopenia and lymphocytopenia were more common in R-HAD + B without differences in severe infections between both arms. Bortezomib in combination with chemotherapy can be effective in r/r MCL and should be evaluated further as a therapeutic option, especially if therapy with BTK inhibitors is not an option. Trial registration: NCT01449344.

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Conflict of interest statement

JD served on advisory boards and received speakers’ honoraria from Janssen and Roche. C Schmidt received support for consultancy from BMS and Janssen, honoraria from BMS and Astra Zeneca and meeting or travel support from Kite Gilead. SS received advisory board honoraria, research support, travel support, speaker fees and support for trial participation from AbbVie, Acerta, Amgen, AstraZeneca, BeiGene, BMS, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Lilly, Novartis, Sunesis. C Scholz received consultancy fees from GILEAD, Incyte, Janssen-Cilag, MSD, Miltenyi Biotec, Novartis, Roche, Takeda, honoraria from BeiGene, GILEAD, Janssen-Cilag, Roche, Lilly, Takeda and travel expenses from BeiGene, Roche and Takeda. MH received honoraria from Novartis, Sobi, Gilead Sciences and Falk Foundation, has consulted for Novartis, BMS/Celgene, Gilead Sciences, Pfizer, Incyte, Sanofi/Aventis, Roche, Amgen, Sobi and Janssen. VR received research funding from Astex and GSK, consulting fees from Servier, honoraria from Abbvie and Pharmamar, meeting/travel support from AZD and GSK and participated on a Data Safety Monitoring Board or Advisory Board of BMS, AZD and Gilead. MD received research funding from Abbvie, Bayer, BMS/Celgene, Kite/Gilead, Janssen and Roche, speakers’ honoraria from Astra Zeneca, Beigene, Gilead/Kite, Janssen, Lilly, 1 Novartis and Roche, and served on scientific advisory boards of Abbvie, Astra Zeneca, Beigene, BMS/Celgene, Gilead/Kite, Janssen, Lilly/Loxo, Novartis and Roche. All remaining authors declare no competing financial interests.

Figures

Fig. 1
Fig. 1. CONSORT flow diagram for the 128 randomized patients.
mITT modified intention to treat cohort. PP per protocol cohort.
Fig. 2
Fig. 2. Time to treatment failure for R-HAD + B vs. R-HAD.
Kaplan-Meier plots for time to treatment failure in the (a) modified intention to treat (mITT) and the (b) per protocol (PP) population. aHR Adjusted hazard ratio.
Fig. 3
Fig. 3. Progression free and overall survival for R-HAD + B vs. R-HAD.
Kaplan-Meier plots for (a) progression free survival (PFS) in the modified intention to treat (mITT) population; (b) PFS in the per protocol population (PP) and (c) overall survival (OS) in the mITT population. aHR Adjusted hazard ratio.
Fig. 4
Fig. 4. Forest plot of time to treatment failure (TTF) in subgroups of modified intention to treat (mITT) patients, adjusted for MIPI (except MIPI subgroups).
P values are interaction p values, indicating possible effect differences across subgroups. The solid blue vertical line marks the treatment effect in the whole cohort. The dashed vertical line marks HR = 1. CI confidence interval, MIPI Mantle cell lymphoma international prognostic index, ASCT autologous stem cell transplant, POD24 progression of disease within 24 months of initial treatment.
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