Multi-center phase II trial of bortezomib and rituximab maintenance combination therapy in patients with mantle cell lymphoma after consolidative autologous stem cell transplantation

Robert W Chen, Joycelynne M Palmer, Sarah Tomassetti, Leslie L Popplewell, Jessica Alluin, Pritsana Chomchan, Auayporn P Nademanee, Tanya Siddiqi, Ni-Chun Tsai, Lu Chen, Fay Zuo, Rosemarie Abary, Ji-Lian Cai, Alex F Herrera, John J Rossi, Steven T Rosen, Stephen J Forman, Larry W Kwak, Leona A Holmberg, Robert W Chen, Joycelynne M Palmer, Sarah Tomassetti, Leslie L Popplewell, Jessica Alluin, Pritsana Chomchan, Auayporn P Nademanee, Tanya Siddiqi, Ni-Chun Tsai, Lu Chen, Fay Zuo, Rosemarie Abary, Ji-Lian Cai, Alex F Herrera, John J Rossi, Steven T Rosen, Stephen J Forman, Larry W Kwak, Leona A Holmberg

Abstract

Background: Mantle cell lymphoma (MCL) is an aggressive and incurable lymphoma. Standard of care for younger patients with MCL is induction chemotherapy followed by autologous stem cell transplantation (auto-HCT). Rituximab maintenance after auto-HCT has been shown to improve progression-free survival (PFS) and overall survival (OS) in MCL. Bortezomib maintenance therapy has also been shown to be tolerable and feasible in this setting. However, the combination of bortezomib and rituximab as maintenance therapy post-auto-HCT has not been studied.

Methods: We conducted a multicenter, phase II trial of bortezomib given in combination with rituximab as maintenance in MCL patients after consolidative auto-HCT. Enrolled patients (n = 23) received bortezomib 1.3 mg/m2 subcutaneously weekly for 4 weeks every 3 months (up to 24 months) and rituximab 375 mg/m2 intravenously weekly for 4 weeks every 6 months (up to 24 months) for a total duration of 2 years. The primary study endpoint was disease-free survival (DFS).

Results: With a median follow-up of 35.9 months, the 2-year DFS probability was 90.2% (95% CI 66-97), and 2-year OS was 94.7% (95% CI 68-99). The most frequent grade 3/4 toxic events were neutropenia (in 74% of patients) and lymphopenia (in 35%). The incidence of peripheral neuropathy was 48% for grade 1, 9% for grade 2, and 0% for grade 3/4. We also examined the role of quantitative cyclin D1 (CCND1) mRNA in monitoring minimal residual disease.

Conclusion: Combined bortezomib and rituximab as maintenance therapy in MCL patients following auto-HCT is an active and well-tolerated regimen.

Trial registration: ClinicalTrials.gov NCT01267812 , registered Dec 29, 2010.

Keywords: Auto-HCT; Bortezomib; CCND1; MRD; Mantle cell lymphoma; Rituximab.

Conflict of interest statement

Ethics approval and consent to participate

This study was conducted according to the ethical principles for medical research involving human subjects as stated in the Declaration of Helsinki and in the ICH Good Clinical Practice guidelines. The study protocol was reviewed and approved by the Institutional Review Boards of the City of Hope National Medical Center (reference number 10137) and the Fred Hutchinson Cancer Research Center (reference number 2620). All eligible participants had the study, timelines, and outcome measures of the study explained to them. Participants were informed that they are free to discontinue participation at any time without consequence. To indicate consent, all participants signed the written informed consent form.

Consent for publication

Not applicable

Competing interests

RC has received research funding from Takeda/Millennium Pharmaceuticals. RC has been a consultant for Takeda/Millennium. LAH has received research funding from Takeda/Millennium Pharmaceuticals, Seattle Genetics, Merck, and Sanofi. LAH has been a consultant for Seattle Genetics, Jazz, and NCCN. LAH has received royalty from Up-To-Date.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Kaplan-Meier analysis of disease-free and overall survival. The solid line represents overall survival, and the dotted line represents disease-free survival. DFS was calculated from start of treatment to the date of first appearance of disease relapse, or death from any cause. DFS and OS were estimated using the product-limit method of Kaplan and Meier; 95% confidence interval was calculated using Greenwood’s formula
Fig. 2
Fig. 2
Normalized CCND1 levels in patient peripheral blood samples. CCND1 mRNA was assessed using ddPCR on RNA extracted from PBMCs as described in the “Methods” section. Positive controls were the MCL cell line JVM2, and PBMCs from untreated patient with MCL involvement. Negative control was PBMCs from a healthy donor. Shown are results of single samples from patients A1-A18

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