Extended CCR5 Blockade for Graft-versus-Host Disease Prophylaxis Improves Outcomes of Reduced-Intensity Unrelated Donor Hematopoietic Cell Transplantation: A Phase II Clinical Trial

Abstract

Graft-versus-host disease (GVHD) remains the most common treatment-related complication after allogeneic hematopoietic cell transplantation (allo-HCT). Lymphocyte migration plays a critical role in the pathogenesis of GVHD. A previous phase I/II trial demonstrated that CCR5 blockade with maraviroc in the first 30 days after allo-HCT resulted in a low incidence of early acute GVHD, primarily in visceral organs, but with no impact on late acute or chronic GVHD. We conducted a phase II trial to examine the efficacy of an extended course of maraviroc, administered through post-transplantation day +90 in addition to standard prophylaxis in 37 recipients of reduced-intensity-conditioned unrelated donor allo-HCT performed to treat hematologic malignancies. Extended maraviroc treatment was safe and feasible. The primary study endpoint, day +180 rate of grade II-IV acute GVHD, was 22 § 7%, liver GVHD was not observed, and gut GVHD was uncommon. The day +180 rate of grade III-IV acute GVHD was 5 § 4%. The 1-year rate of moderate to severe chronic GVHD was 8 § 5% and that of disease relapse was 30 § 8%. Overall survival at 1 year was 70 § 8%. Compared with the previously studied short course of maraviroc, the extended course resulted in a significantly higher GVHD-free, relapse-free survival (adjusted hazard ratio [HR], .45; 95% confidence interval [CI], .25 to .82; P = .009) and overall survival (adjusted HR, .48; 95% CI, .24 to .96; P = .037). A combined analysis of both trials showed that high maraviroc trough concentrations on the day of hematopoietic cell infusion were associated with lower rates of acute GVHD. An extended course of maraviroc after reduced-intensity-conditioned unrelated donor allo-HCT is safe and effective in preventing acute and chronic GVHD and is associated with favorable survival.

Variable selection methods for predicting clinical outcomes following allogeneic hematopoietic cell transplantation

“…As with the CSH model, we found that the time-dependent AUC of the selected model was higher that the AUC from a model containing only the maraviroc treatment variable, but confidence intervals overlapped; at , the selected model’s AUC was 0.78 (0.43–1.0) versus 0.60 (0.36–0.80); and at , 0.84 (0.58–1.0) versus 0.72 (0.56–0.84). We also found that patients treated with maraviroc were less likely to experience aGVHD24 than controls, consistent with previous studies 41 . We estimated a SHR of 0.25 (0.08–0.78), considering relapse and cGVHD as competing risks; the earlier point estimate of 0.42 was derived with only death as a competing risk 27 .…”

Achievement of Tolerance Induction to Prevent Acute Graft-vs.-Host Disease

“…Short-term addition of CCR5 antagonist, maraviroc added to standard GVHD prophylaxis resulted in reduced GI and liver GVHD in allo-HSCT patients given reduced intensity conditioning ( 72 ). Compared to this short-term treatment of 1 month ( 72 ), the extended course of maraviroc (3 months) was also safe and resulted in a significantly improved survival and higher GVHD-free ( 73 ). The relationship between conditioning regimen intensity and efficacy of CCR5 antagonism in allo-HSCT patients is unknown and warrants investigation.…”

The Biological and Clinical Relevance of G Protein-Coupled Receptors to the Outcomes of Hematopoietic Stem Cell Transplantation: A Systematized Review

“…Two phase I/II trials have now tested the safety and the efficacy of CCR5 blockade using maraviroc for the prevention of aGvHD. The first trial, conducted in adults [197], proved successful and led to follow-up studies by the same group of researchers [198,199,200,201,202] as well as an ongoing phase II study (NCT01785810). Another trial [203], published in 2019, included adults and children but had inconclusive findings due to unrelated toxicities.…”