Bortezomib-based immunosuppression after reduced-intensity conditioning hematopoietic stem cell transplantation: randomized phase II results

John Koreth, Haesook T Kim, Paulina B Lange, Samuel J Poryanda, Carol G Reynolds, Sharmila Chamling Rai, Philippe Armand, Corey S Cutler, Vincent T Ho, Brett Glotzbecker, Rushdia Yusuf, Sarah Nikiforow, Yi-Bin Chen, Bimalangshu Dey, Malgorzata McMasters, Jerome Ritz, Bruce R Blazar, Robert J Soiffer, Joseph H Antin, Edwin P Alyea 3rd, John Koreth, Haesook T Kim, Paulina B Lange, Samuel J Poryanda, Carol G Reynolds, Sharmila Chamling Rai, Philippe Armand, Corey S Cutler, Vincent T Ho, Brett Glotzbecker, Rushdia Yusuf, Sarah Nikiforow, Yi-Bin Chen, Bimalangshu Dey, Malgorzata McMasters, Jerome Ritz, Bruce R Blazar, Robert J Soiffer, Joseph H Antin, Edwin P Alyea 3rd

Abstract

Aprior phase I/II trial of bortezomib/tacrolimus/methotrexate prophylaxis after human leukocyte antigen (HLA)-mismatched reduced intensity conditioning allogeneic hematopoietic stem cell transplantation documented low acute graft-versus-host disease incidence, with promising overall and progression-free survival. We performed an open-label three-arm 1:1:1 phase II randomized controlled trial comparing grade II-IV acute graft-versus-host disease between conventional tacrolimus/methotrexate (A) versus bortezomib/tacrolimus/methotrexate (B), and versus bortezomib/sirolimus/tacrolimus (C), in reduced intensity conditioning allogeneic transplantation recipients lacking HLA-matched related donors. The primary endpoint was grade II-IV acute graft-versus-host disease incidence rate by day +180. One hundred and thirty-eight patients (A 46, B 45, C 47) with a median age of 64 years (range: 24-75), varying malignant diagnoses and disease risk (low 14, intermediate 96, high/very high 28) received 7-8/8 HLA-mismatched (40) or matched unrelated donor (98) grafts. Median follow up in survivors was 30 months (range: 14-46). Despite early immune reconstitution differences, day +180 grade II-IV acute graft-versus-host disease rates were similar (A 32.6%, B 31.1%, C 21%; P=0.53 for A vs B, P=0.16 for A vs C). The 2-year non-relapse mortality incidence was similar (A 14%, B 16%, C 6.4%; P=0.62), as were relapse (A 32%, B 32%, C 38%; P=0.74), chronic graft-versus-host disease (A 59%, B 60% C 55%; P=0.66), progression-free survival (A 54%, B 52%, C 55%; P=0.95), and overall survival (A 61%, B 62%, C 62%; P=0.98). Overall, the bortezomib-based regimens evaluated did not improve outcomes compared with tacrolimus/methotrexate therapy. clinicaltrials.gov Identifier: 01754389.

Trial registration: ClinicalTrials.gov NCT01754389.

Copyright© 2018 Ferrata Storti Foundation.

Figures

Figure 1.
Figure 1.
CONSORT Diagram. *1 patient with relapse and infection. Tac: tacrolimus; Mtx: methotrexate; Bort: bortezomib; Sir: sirolimus.
Figure 2.
Figure 2.
aGvHD: non-relapse mortality and relapse outcomes. Cumulative incidence of (A) grade II-IV aGvHD*, (B) grade III-IV aGvHD*, (C) non-relapse mortality (NRM), and (D) relapse per treatment arm. Black indicates arm A (tac/mtx), red indicates arm B (bort/tac/mtx), and blue indicates arm C (bort/sir/tac). Gray’s test for comparing the entire distributions was used. *: Acute graft-versus-host disease (GvHD) after relapse with IS taper included. Tac: tacrolimus; Mtx: methotrexate; Bort: bortezomib; Sir: sirolimus.
Figure 3.
Figure 3.
cGvHD: survival and GRFS outcomes. Cumulative incidence of (A) all cGvHD, and Kaplan-Meier survival plots of (B) progression-free survival (PFS), (C) overall survival (OS), and (D) grade III-IV aGvHD/cGvHD requiring systemic IS agents/relapse-free survival (GRFS) per treatment arm. Black indicates arm A (tac/mtx), red indicates arm B (bort/tac/mtx), and blue indicates arm C (bort/sir/tac). Tac: tacrolimus; Mtx: methotrexate; Bort: bortezomib; Sir: sirolimus; GvHD: graft-versus-host disease.
Figure 4.
Figure 4.
Immune reconstitution outcomes. Reconstitution of (A) median of absolute CD3+ T-cell count/μL, and (B) median values of CD4+ Treg:Tcon cell ratio per treatment arm. Blue indicates arm A (tac/mtx), red indicates arm B (bort/tac/mtx), and green indicates arm C (bort/sir/tac). Treg: regulatory T cells; Tcon: conventional T cells; Tac: tacrolimus; Mtx: methotrexate; Bort: bortezomib; Sir: sirolimus; W1: week 1; W2: week 2; M: month.

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