Maraviroc, an ingredient in retroviral cocktails used to treat HIV, might also have a role in preventing acute graft-vs.-host disease after allogeneic hematopoietic stem-cell transplantation.
Adding a 1-month course of maraviroc (Selzentry), an inhibitor of T-cell chemotaxis, to standard prophylaxis appeared to reduce the incidence of acute graft-vs.-host disease (GVHD) after allogeneic transplants in a single-center study of 38 adults with hematologic cancers, which was published online July 11 in the New England Journal of Medicine.
At the same time, maraviroc did not disrupt hematopoietic engraftment, raise the incidence of cancer recurrence, or increase infectious complications, said Dr. Ran Reshef of the Abramson Cancer Center and the division of hematology and oncology at the University of Pennsylvania, Philadelphia, and his associates.
Maraviroc is the first drug available in the class of chemokine (C-C motif) receptor 5 (CCR5) antagonists. It prevents the signaling of CCR5 and its ligands, "which have been implicated in the pathogenesis of GVHD and solid-organ rejection." CCR5 is crucial to lymphocyte recruitment to tissues involved in GVHD. Blockade of CCR5 protects against GVHD in mouse models, and human genetic studies have shown that certain polymorphisms in the gene that encodes CCR5 are protective against GVHD.
Currently, maraviroc is used in combination antiretroviral therapy for a subtype of HIV that uses only the CCR5 coreceptor to enter cells. "We hypothesized that CCR5 blockade with maraviroc early after allogeneic hematopoietic stem-cell transplantation might inhibit lymphocyte trafficking and decrease the incidence of acute GVHD," Dr. Reshef and his colleagues said (N. Engl. J. Med. 2012;367:135-45).
They conducted a phase I clinical trial to confirm that the established dose for HIV patients was safe, and achieved target drug levels in patients who have undergone reduced-intensity conditioning and stem-cell transplantation. The cohort included patients with acute myeloid leukemia, non-Hodgkin’s lymphoma, myelodysplastic syndromes, myeloproliferative disorder, chronic lymphocytic leukemia, aplastic anemia, multiple myeloma, Hodgkin’s lymphoma, and chronic myeloid leukemia.
All the study subjects received standard GVHD prophylaxis including oral tacrolimus and IV methotrexate, as well as standard antimicrobial prophylaxis with voriconazole, acyclovir, and trimethoprim-sulfamethoxazole.
Most of the study subjects were considered high risk for GVHD because of their age (68% were older than 60 years), donor-recipient HLA incompatibility, cancer severity, and heavy burden of comorbidity. "The anticipated incidence of acute GVHD in similar patients is typically more than 50%," the investigators noted.
After the dose-confirming study, the researchers then performed a phase II clinical trial evaluating 35 of the same patients. Maraviroc (300 mg) was given orally twice daily from 2 days before transplantation until day 30. The study subjects were followed for a median of 20 months (range, 14-35 months).
Engraftment was rapid, and maraviroc produced few toxic effects. "Administration of the drug was briefly suspended in 7 patients because of grade 3 abnormalities on liver-function testing (in 2 patients) or grade 3 or 4 mucositis (in 5). Liver-function abnormalities did not recur when the drug was restarted," Dr. Reshef and his associates said.
The primary end point – the cumulative incidence of GVHD at day 100 – was 14.7% for grade II-IV acute disease. Remarkably, there were no cases of GVHD involving the liver or gut.
Similarly, at 6 months GVHD remained largely confined to the skin, and involved the liver in only 2.9% of cases and the gut in only 8.8%. At this point the incidence of moderate disease was 23.6% and severe disease only 5.9%. In comparison, these rates at their institution typically are 38.5% and 21.9%, the researchers said.
In the subset of 11 patients who received stem cells from an HLA-matched sibling, there were no cases of acute GVHD at day 100 and no moderate to severe GVHD at 6 months.
Thus, cases of skin GVHD developed at the expected rates, but the absence of liver or gut GVHD lead to a low incidence of severe disease.
"The outcomes of this study are especially favorable considering the study population, which included older patients and a high proportion of matched unrelated donors and HLA-mismatched donors." In addition, almost half the study subjects had major coexisting illnesses.
Cumulative rates of relapse and death were not higher than expected for patients with these disease characteristics who were given reduced-intensity regimens, the authors said.
Because this was a single-center, phase-I/phase-II trial involving only 38 patients, "the value of maraviroc in lowering the rate of acute GVHD will need to be assessed in a prospective, randomized trial," Dr. Reshef and his colleagues added.
This study was supported by Pfizer, maker of maraviroc; the Leukemia and Lymphoma Society; the National Institutes of Health; the Abramson Cancer Center; the American Society of Hematology; and the American Society of Clinical Oncology. Dr. Reshef’s associates reported ties to Pfizer, Bristol-Myers Squibb, Celgene, and Millennium.