Page 162 - Haematologica3

Correspondence:
john_koreth@dfci.harvard.edu
Received: July 18, 2017. Accepted: January 10, 2018. Pre-published: January 11, 2018.
doi:10.3324/haematol.2017.176859
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/3/522
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Stem Cell Transplantation
Bortezomib-based immunosuppression after reduced-intensity conditioning hematopoietic stem cell transplantation: randomized phase II results
John Koreth,1 Haesook T. Kim,2 Paulina B. Lange,1 Samuel J. Poryanda,1 Carol G. Reynolds,1 Sharmila Chamling Rai,1 Philippe Armand,1
Corey S. Cutler,1 Vincent T. Ho,1 Brett Glotzbecker,1 Rushdia Yusuf,1
Sarah Nikiforow,1 Yi-Bin Chen,3 Bimalangshu Dey,3 Malgorzata McMasters,4 Jerome Ritz,1 Bruce R. Blazar,5 Robert J. Soiffer,1 Joseph H. Antin1 and Edwin P. Alyea III1
1Division of Hematologic Malignancies, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA; 2Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard School of Public Health, Boston, MA; 3Massachusetts General Hospital Cancer Center, Boston, MA; 4Beth Israel Deaconess Hospital Cancer Center, Boston, MA and 5University of Minnesota Masonic Cancer Center and Department of Pediatrics, Division of Blood and Marrow Transplantation, Minneapolis, MN, USA
ABSTRACT
Aprior phase I/II trial of bortezomib/tacrolimus/methotrexate pro- phylaxis after human leukocyte antigen (HLA)-mismatched reduced intensity conditioning allogeneic hematopoietic stem cell transplantation documented low acute graft-versus-host disease inci- dence, with promising overall and progression-free survival. We performed an open-label three-arm 1:1:1 phase II randomized con- trolled 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 transplanta- tion recipients lacking HLA-matched related donors. The primary end- point 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-ver- sus-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 inci- dence 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 out- comes compared with tacrolimus/methotrexate therapy. clinicaltrials.gov Identifier: 01754389
Introduction
Allogeneic hematopoietic stem cell transplantation (HSCT) is curative in advanced or aggressive hematologic malignancies despite associated toxicities. While a sibling matched at human leukocyte antigen (HLA)-A, -B, -C, and -DRB1 is optimal, only a minority of patients who may benefit from HSCT have such a donor available.1 Utilizing a 7/8 HLA-matched graft increases the likelihood of obtaining an adult donor for all racial and ethnic groups,1 but at the expense of worse outcomes. In reduced-intensity conditioning (RIC) HSCT, retrospective reg- istry studies document increased rates of grade II-IV acute graft-versus-host disease
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