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Editorials
of AML in adults: 2017 ELN recommendations from an international
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of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood. 2010;115(3):453-474.
6. Cheson BD, Bennett JM, Kopecky KJ, et al. Revised recommenda- tions of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol. 2003;21(24):4642-4649.
7. Stone RM, Mandrekar SJ, Sanford BL, et al. Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a FLT3 Mutation. N Engl J Med. 2017;377(5):454-464.
8. Stein EM, DiNardo C, Altman JK, et al. Safety and Efficacy of AG- 221, a Potent Inhibitor of Mutant IDH2 That Promotes Differentiation of Myeloid Cells in Patients with Advanced Hematologic Malignancies: Results of a Phase 1/2 Trial. Blood. 2015;126:323.
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Bortezomib for prevention of acute graft-versus-host disease: a conclusion reached Paul J. Martin
Fred Hutchinson Cancer Research Center, Seattle and University of Washington, Seattle, WA, USA
E-mail: pmartin@fredhutch.org doi:10.3324/haematol.2018.188052
Prevention of acute graft-versus-host disease (GvHD) after allogeneic hematopoietic cell transplantation (HCT) has long posed a major challenge for the field. In this issue, Koreth et al.1 report results of a randomized three-arm phase II trial testing two different immunosup- pressive regimens using bortezomib to prevent acute GvHD after allogenic hematopoietic cell transplantation. Contrary to expectations, the results did not show major improvement in the experimental groups as compared to the control group.
The impetus to explore the use of bortezomib to pre- vent GvHD came from its mechanism of action to pre- vent signaling through nuclear factor (NF)κB in activated T cells. In resting T cells, the inhibitor (I)-κB binds to NFκB as a complex that is sequestered in the cytoplasm.2 In activated T cells, ubiquitin moieties attach to I-κB, which is delivered to proteasomes. The NFκB molecules released from I-κB translocate to the nucleus where they activate the transcription of genes involved in immune responses. Among other possible mechanisms of action, bortezomib inhibits proteasome activity, allowing I-κB to prevent NFκB-mediated activation of T cells.
Experimental results showed that administration of bortezomib early after allogeneic HCT could prevent acute GvHD in mice.1 These results led to a phase I/II study demonstrating that bortezomib can be combined with tacrolimus and methotrexate in a tolerable post- transplant immunosuppressive regimen after HCT with human leukocyte antigen (HLA)-mismatched donors.
Results of the completed study were published in 20123 and are summarized in Figure 1. The interpretation of the 2012 study was initially informed by historical experi- ence showing a 46% incidence of grade II – IV GvHD in patients with HLA-mismatched unrelated donors.4 The 22% incidence of grade II – IV GvHD in the 2012 study was indeed encouraging when compared against this benchmark, although the comparability of demographic and treatment characteristics of patients in the phase I/II study and the historical group5 was not well documented.
In the current study of HLA-matched unrelated HCT, the benchmark for grade II – IV GvHD was set at 40%.1 The observed 33% incidence of grade II – IV GvHD in patients treated with tacrolimus and methotrexate (Arm A) was somewhat lower than this benchmark, while the 29% incidence in patients treated with bortezomib added to tacrolimus and methotrexate (Arm B) was somewhat higher than the 22% incidence observed in HLA-mis- matched recipients in the phase I/II study (Figure 1). As a result, the current study did not demonstrate a statistical- ly significant improvement following the addition of bortezomib to tacrolimus and methotrexate in patients with HLA-matched unrelated donors.
Results of the current study with HLA-matched unre- lated recipients are similar to those observed in the BMT CTN 1203 PROGRESS study, which enrolled a mixed cohort of HLA-matched related and unrelated recipients and a small proportion of HLA-mismatched unrelated recipients. In this study, the day 180 cumulative inci-
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