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
References
- Gragert L, Eapen M, Williams E, et al. HLA match likelihoods for hematopoietic stem-cell grafts in the U.S. registry. N Engl J Med. 2014;371(4):339–348.
- Verneris MR, Lee SJ, Ahn KW, et al. HLA mismatch is associated with worse outcomes after unrelated donor reduced-intensity conditioning hematopoietic cell transplantation: an analysis from the Center for International Blood and Marrow Transplant Research. Biol Blood Marrow Transplant. 2015;21(10):1783–1789.
- Nencioni A, Schwarzenberg K, Brauer KM, et al. Proteasome inhibitor bortezomib modulates TLR4-induced dendritic cell activation. Blood. 2006;108(2):551–558.
- Blanco B, Perez-Simon JA, Sanchez-Abarca LI, et al. Bortezomib induces selective depletion of alloreactive T lymphocytes and decreases the production of Th1 cytokines. Blood. 2006;107(9):3575–3583.
- Pai CC, Hsiao HH, Sun K, et al. Therapeutic benefit of bortezomib on acute graft-versus-host disease is tissue specific and is associated with interleukin-6 levels. Biol Blood Marrow Transplant. 2014;20(12):1899–1904.
- Sun K, Welniak LA, Panoskaltsis-Mortari A, et al. Inhibition of acute graft-versus-host disease with retention of graft-versus-tumor effects by the proteasome inhibitor bortezomib. Proc Natl Acad Sci USA. 2004;101(21):8120–8125.
- Kim JS, Lee JI, Shin JY, et al. Bortezomib can suppress activation of rapamycin-resistant memory T cells without affecting regulatory T-cell viability in non-human primates. Transplantation. 2009;88(12):1349–1359.
- Sun K, Wilkins DE, Anver MR, et al. Differential effects of proteasome inhibition by bortezomib on murine acute graft-versus-host disease (GVHD): delayed administration of bortezomib results in increased GVHD-dependent gastrointestinal toxicity. Blood. 2005;106(9):3293–3299.
- Vodanovic-Jankovic S, Hari P, Jacobs P, Komorowski R, Drobyski WR. NF-kappaB as a target for the prevention of graft-versus-host disease: comparative efficacy of bortezomib and PS-1145. Blood. 2006;107(2):827–834.
- Liang Y, Ma S, Zhang Y, et al. IL-1beta and TLR4 signaling are involved in the aggravated murine acute graft-versus-host disease caused by delayed bortezomib administration. J Immunol. 2014;192(3):1277–1285.
- Koreth J, Stevenson KE, Kim HT, et al. Bortezomib, tacrolimus, and methotrexate for prophylaxis of graft-versus-host disease after reduced-intensity conditioning allogeneic stem cell transplantation from HLA-mismatched unrelated donors. Blood. 2009;114(18):3956–3959.
- Koreth J, Stevenson KE, Kim HT, et al. Bortezomib-based graft-versus-host disease prophylaxis in HLA-mismatched unrelated donor transplantation. J Clin Oncol. 2012;30(26):3202–3208.
- Zeiser R, Leveson-Gower DB, Zambricki EA, et al. Differential impact of mammalian target of rapamycin inhibition on CD4+CD25+Foxp3+ regulatory T cells compared with conventional CD4+ T cells. Blood. 2008;111(1):453–462.
- Johnston L, Florek M, Armstrong R, et al. Sirolimus and mycophenolate mofetil as GVHD prophylaxis in myeloablative, matched-related donor hematopoietic cell transplantation. Bone Marrow Transplant. 2012;47(4):581–588.
- Cutler C, Logan B, Nakamura R, et al. Tacrolimus/sirolimus vs tacrolimus/methotrexate as GVHD prophylaxis after matched, related donor allogeneic HCT. Blood. 2014;124(8):1372–1377.
- Gray R. A class of k-sample tests for comparing the cumulative incidence of a competing risk. Annals of Statistics. 1988;16(3):1141–1154.
- Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc. 1999;94:496–509.
- Kiehl MG, Kraut L, Schwerdtfeger R, et al. Outcome of allogeneic hematopoietic stem-cell transplantation in adult patients with acute lymphoblastic leukemia: no difference in related compared with unrelated transplant in first complete remission. J Clin Oncol. 2004;22(14):2816–2825.
- Yakoub-Agha I, Mesnil F, Kuentz M, et al. Allogeneic marrow stem-cell transplantation from human leukocyte antigen-identical siblings versus human leukocyte antigen-allelic-matched unrelated donors (10/10) in patients with standard-risk hematologic malignancy: a prospective study from the French Society of Bone Marrow Transplantation and Cell Therapy. J Clin Oncol. 2006;24(36):5695–5702.
- Ringden O, Pavletic SZ, Anasetti C, et al. The graft-versus-leukemia effect using matched unrelated donors is not superior to HLA-identical siblings for hematopoietic stem cell transplantation. Blood. 2009;113(13):3110–3118.
- Soiffer RJ, Kim HT, McGuirk J, et al. A prospective randomized double blind phase 3 clinical trial of anti-T lymphocyte globulin (ATLG) to assess impact on chronic graft-versus-host disease (cGVHD) free survival in patients undergoing HLA matched unrelated myeloablative hematopoietic cell transplantation (HCT). Blood. 2016;128(22):505.
Source: PubMed