Advances in Hematologic Malignancies Issue 3, Spring 2014
Allogeneic hematopoietic stem cell transplantation (HSCT) represents a potentially curative option for patients with advanced or aggressive hematologic malignancies. Powerful donor-derived immune responses underlie its therapeutic graft-versus-tumor (GVT) effect; however, donor immune responses to allogeneic and autologous antigens also underlie graft-versus-host disease (GVHD), a major transplantation-associated complication.
Acute GVHD (aGVHD) is characterized clinically by inflammation of the skin (rash, blistering), gut (diarrhea, ulceration, bleeding, ileus) or liver (transaminitis, jaundice), which can be minor or life-threatening. GVHD prophylaxis utilizing the combination of a calcineurin-inhibitor (CNI; e.g. tacrolimus) and methotrexate is currently standard-of-care.
However, clinically significant aGVHD still occurs in 34 to 52% of recipients of HLA-matched related and unrelated donor (MRD, MUD) grafts, with an even higher aGVHD incidence and markedly impaired survival in recipients who lack HLA-matched donor grafts. Only approximately 40% of patients with aGVHD have a durable response to glucocorticoids, and attempts over the past 20 years to add or substitute other immunosuppressive drugs have resulted in little improvement in aGVHD. The prognosis of the 60% of aGVHD patients without long-lasting corticosteroid response remains poor; therefore, novel GVHD prevention and treatment strategies are required.
The proteasome inhibitor bortezomib (Velcade) is well recognized for its anti-tumor effects in hematologic malignancies such as multiple myeloma, but it also offers immunomodulatory benefits that may be useful in the aGVHD setting. Bortezomib can selectively deplete proliferating alloreactive T lymphocytes (conventional CD4+ T cells or "Tcon"), reduce por-inflammatory Th1 (type 1 helper T cell) cytokines, and block activation of antigen-presenting cells (APC), all of which are central to GVHD pathogenesis. In preclinical models of major histocompatibility complex (MHC)-mismatched mouse HSCT, bortezomib prevents aGVHD while maintaining curative GVT responses.
Clinically, in the context of reduced-intensity conditioning (RIC) HSCT, we undertook a phase I/II trial of short-course bortezomib-based GVHD prophylaxis for HLA-mismatched unrelated donor (MMUD) HSCT (Dana-Farber Cancer Institute Protocol # 06-065). In phase I of this study, we demonstrated that bortezomib was well-tolerated at a dose of 1.3 mg/m2 administered intravenously on days +1, +4, and +7 after stem cell infusion (Koreth et al, Blood 2009).
In the next phase of the trial, we confirmed efficacy of bortezomib in aGVHD prophylaxis — with low rates of aGVHD despite HLA-mismatched transplantation, no impairment of GVT responses or immune reconstitution, and patient overall survival comparable to that seen with HLA-matched donor grafts (Figure 1: Koreth et al, JCO 2012).
Figure 1: Cumulative incidence of aGVHD, non-relapse mortality (NRM) and relapse with bortezomib–based GVHD prophylaxis in MMUD RIC HSCT.
Left: aGVHD grade II-IV (blue line) and grade III-IV (yellow line) are indicated.
Right: Relapse (blue line) and NRM (yellow line) are indicated.
Bortezomib-based GVHD prophylaxis thus appears suitable for further evaluation. We are now undertaking a prospective randomized trial evaluating bortezomib vs. standard-of-care GVHD prophylaxis (Dana-Farber Cancer Institute Protocol # 12-404). The goal of this study is to compare two bortezomib-based regimens versus standard-of-care tacrolimus/methotrexate GVHD prophylaxis in RIC HSCT recipients lacking HLA-matched related donors. We will compare efficacy of bortezomib, tacrolimus and methotrexate vs. tacrolimus/methotrexate control.
Given the reported synergy between sirolimus and bortezomib, we are also excited to assess the bortezomib, sirolimus and tacrolimus regimen alongside the tacrolimus/methotrexate control.
Furthermore, we will attempt to pick a superior regimen between the two bortezomib-based treatment arms if their aGVHD rates appear lower than the control arm. The study design is an open-label 3-arm (1:1:1) randomized phase II trial; the primary endpoint is the rate of grade II-IV aGVHD; and the accrual goal is 138 patients, which we hope to accomplish in 2 to 3 years.
A novel GVHD prophylaxis regimen that better controls aGVHD while preserving GVT responses and immune reconstitution would represent a major advance in transplantation. We are excited to offer trial participation to all RIC HSCT recipients of unrelated and HLA-mismatched donor grafts at Dana-Farber/Brigham and Women’s Cancer Center.