Pediatric Phase II Study of Maraviroc for Acute Graft Versus Host Disease Prophylaxis

Background CCR5 inhibition is a promising approach to prevent visceral acute GVHD in adults after allogeneic hematopoietic stem cell transplant (HSCT). Objective We performed a phase I/II study of maraviroc, an oral CCR5 inhibitor, to prevent visceral GVHD in children undergoing HSCT and have reported results of the phase I study previously. Methods We used our previously established dose (∼ 300 mg/m2) of maraviroc in the phase II study. Oral maraviroc was added to standard acute GVHD prophylaxis from day-3 twice daily for eligible patients until day+30 after HSCT. Trough levels of maraviroc were collected on day 0 +7, 14 and 21. Patients were observed until day+100 for acute GVHD. We assessed functional CCR5 blockade by our previously published pharmacodynamic assay. We explored mechanisms of resistance to maraviroc by comparing serum IL-15 levels, plasma CXCL9 and CXCL10 at day+30 between GVHD and no GVHD patients. CD38 expression on CD4+ T-cells measured by flow cytometry at day+30. Results Thirty-one patients were enrolled prospectively, 14 on the phase I and 17 on the phase II study. Phase II study Demographics are shown in Figure 1. Median maraviroc trough concentrations were therapeutic at > 100 ng/mL on day+7 and day+14 (Figure 2A). Functional CCR5 blockade was observed in all except one patient at day zero and day+14 (Figure 2B, 3A). Two patients developed grade 1 acute skin GVHD and were successfully treated with corticosteroids. Four patients developed gastrointestinal (GI) GVHD (Upper GI GVHD n=2, lower GI GVHD n=2). Two of these 4 patients with GI GVHD did not receive the planned 34 days of maraviroc. No adverse effects to maraviroc were observed. Seven patients discontinued maraviroc at a median of day+14 (range day+1- day+29) due to study rules regarding hepatotoxicity (n=5), renal function decline (n=1) and withdrawal from study (n=1). Phase I± Phase II study Incidence of GI GVHD in all 31 patients who received maraviroc was 19% (n=6) compared to 22% in historic controls (p=0.29). Four of the 6 GI GVHD patients did not complete maraviroc treatment. CD38 expression on CD4+ T-cells was elevated on day+30 in patients who developed GVHD compared to patients without GVHD (Figure 3B). We observed no difference in IL-15, CXCL10 and CXCL9 levels in patients with and without GVHD. Conclusion Maraviroc administration was feasible in children but was limited by elevated bilirubin levels and transaminases, unrelated to maraviroc. We achieved successful CCR5 blockade but also observed breakthrough of GVHD due to failure to administer maraviroc consistently. Peripheral blood activation of T-cell lymphocytes occurs in patients with imminent acute GVHD despite maraviroc prophylaxis, as might be expected since maraviroc regulates lymphocyte homing but does not suppress activation.