Anaheim, CA—Despite significant progress in stem-cell transplantations over the past decade, graft-versus-host disease (GVHD) remains the leading cause of nonrelapse death in this patient population. Developing safe and effective strategies to prevent and treat acute GVHD is thus critically important for successful allogeneic transplants.
At the 2017 Hematology/Oncology Pharmacy Association (HOPA) Annual Conference, Alex Ganetsky, PharmD, BCOP, Hematology/Oncology Clinical Pharmacy Specialist, Hospital of the University of Pennsylvania, Philadelphia, shared several novel strategies currently under investigation.
“The incidence of GVHD still remains unacceptably high. Clearly, we need new therapies that are well-tolerated and have the capability of reducing the risk of GVHD further,” said Dr Ganetsky.
“I feel like we’re at the precipice of several significant advances with new and innovative concepts that may significantly impact the probability of patients getting GVHD on a large scale,” he added.
Lymphocyte Migration
As Dr Ganetsky reported, one promising strategy of prevention is the trafficking of lymphocytes away from the target organs of GVHD. Maraviroc, a drug used for the combination treatment of patients with HIV infection, blocks the C-C chemokine receptor type 5 (CCR5), mediates lymphocyte entry into the gut and liver—2 of the key targets of GVHD, and 2 of the most problematic to treat.
“If we can utilize a drug that inhibits CCR5, we can potentially prevent T-cells from trafficking into the gut and liver, which may help prevent visceral GVHD,” Dr Ganetsky explained.
In a phase 1/2 single-center clinical trial of 38 patients undergoing reduced-intensity conditioning hematopoietic cell transplant from a sibling or unrelated donor with fludarabine plus busulfan conditioning, the addition of maraviroc to a standard drug regimen of tacrolimus and methotrexate resulted in rates of grade 2 to grade 4 GVHD at day 100 that were <15%.
Proteasome Inhibition
Meanwhile, investigators at Dana-Farber Cancer Institute, Boston, MA, are pioneering the use of bortezomib, a proteasome inhibitor, to prevent GVHD. As Dr Ganetsky explained, bortezomib selectively depletes proliferating alloreactive T lymphocytes, reduces T-helper type 1 cytokines, and inhibits antigen-presenting cell activation.
In a phase 1/2 single-center clinical trial of 45 patients undergoing reduced-intensity conditioning hematopoietic cell transplants from mismatched unrelated donors with fludarabine plus busulfan conditioning, patients received standard tacrolimus and methotrexate plus 1 dose of bortezomib on days 1, 4, and 7. Incidence of grade 2 to grade 4 GVHD at 6 months following transplant was just 22%.
“This is quite remarkable given the donor status. These are patients who all had mismatched unrelated donor transplants, where the risk of GVHD is upwards of 60% to 70%,” said Dr Ganetsky.
High-Dose Cyclophosphamide
Finally, researchers at Johns Hopkins Hospital, Baltimore, MD, have been investigating the use of cyclophosphamide administered posttransplant for GVHD prophylaxis.
“Cytoxan is being incorporated more and more in standard related and unrelated donor transplants,” said Dr Ganetsky, who noted that administering cyclophosphamide on days 3 and 4 posttransplant appears to be the most favorable.
In a phase 1/2 single-center clinical trial of 117 patients undergoing human leukocyte antigen–matched related and unrelated myeloablative conditioning hematopoietic cell transplant with busulfan plus cyclophosphamide conditioning, patients received cyclophosphamide alone without any other immune suppression. At 50 mg/kg, the incidence of GVHD was 46% in recipients of unrelated donor grafts and 42% in recipients of related donor grafts.
“With these impressive, single-center, small-scale studies, we now have 3 innovative concepts for GVHD prevention, with the addition of maraviroc, bortezomib, and possibly using Cytoxan posttransplant,” said Dr Ganetsky.
A phase 2 trial randomizing patients to either regimen, with the cyclophosphamide arm being co-administered with tacrolimus and mycophenolate mofetil, is currently ongoing.
“This trial has been the fastest accruing trial in the history of the Blood and Marrow Transplant Clinical Trials Network. It finished accrual a year ahead of schedule, and results are expected in the next few months. Hopefully, we’ll learn if any of these innovative concepts are superior to the standard approach,” said Dr Ganetsky.