Objectives

The BMT CTN 0302 trial evaluated the effectiveness of each of four new drugs (etanercept, mycophenolate mofetil (MMF), denileukin diftitox (denileukin), and pentostatin) in combination with corticosteroids, as initial therapy for acute graft-versus-host disease.

Background

Acute graft-versus-host disease (GVHD) is the major complication of allogeneic hematopoietic stem cell transplantation. Acute GVHD produces significant morbidity and complicates patient management resulting in organ toxicity, frequent infections, malnutrition, and substantial delay in recovery from transplantation. Corticosteroids have been the primary therapy for acute GVHD for over three decades. Various additional immunosuppressive strategies have been tested as GVHD therapy but neither anti-thymocyte globulin, CD5-immunotoxins, IL-1 antagonists nor other agents have proven effective in either control of GVHD symptoms or improvement in survival. Published response rates of complete response (CR) to acute GVHD therapy with corticosteroids range from 25-41%. These rates were used as benchmarks for assessing efficacy of promising new agents. New immunosuppressive agents and strategies are required to improve the management of GVHD and decrease the toxicities of the immunosuppressive regimens. Thus the BMT CTN 0302 trial was initiated to assess the safety and efficacy of four new treatment agents, in combination with corticosteroids. The goal was to identify the most promising agent(s) to further evaluate in a definitive phase 3 trial.

Participants

Eligible patients were at least 6 years of age who had undergone an allogeneic hematopoietic cell transplantation and had newly diagnosed acute GVHD requiring systemic therapy. No previous systemic immune suppressive therapy for acute GVHD was allowed except for a maximum 48 hours of prior corticosteroid therapy. Patients who received denileukin, pentostatin, or etanercept within 7 days of screening were excluded. Patients must have had an absolute neutrophil count greater than 500/µL and an estimated creatinine clearance greater than 30 mL/minute. A total of 180 patients were enrolled with 46 patients randomized to treatment with etanercept, 45 to MMF, 47 to denileukin, and 42 to pentostatin.

Design

The study was a multicenter, randomized, 4-arm phase 2 trial. The study was not designed or powered for direct comparison across the study arms. Rather each treatment arm was assessed for efficacy against historical data indicating an expected day 28 complete response (CR) rate of 35% with steroids alone. Eligible patients who had not received MMF for GVHD prophylaxis within 7 days of enrollment were randomized to treatment with MMF, etanercept, denileukin, or pentostatin, each in combination with methylprednisolone 2 mg/kg per day intravenously (or prednisone 2.5 mg/kg per day orally) in a 2:1:1:1 ratio, respectively. Patients who had received MMF for GVHD prophylaxis within 7 days of onset of GVHD were randomized to the three non-MMF arms in a 1:1:1 ratio. Study treatment began within 48 hours of randomization.

Acute GVHD was scored by use of the consensus criteria. Evaluation for chronic GVHD was performed and reported at 3, 4, 6, and 9 months after study enrollment, as was discontinuation of all immunosuppression by day 270. The primary outcome measure was the rate of complete response (CR) at day 28 of therapy. CR was defined as resolution of all signs and symptoms of GVHD in all evaluable organs without intervening salvage therapies, in comparison to day 1 scoring. A partial response was an improvement of one stage in one or more organs without progression in any organ. Mixed response was considered an improvement in at least one organ with progression or newly developed GVHD in another organ(s). No response was defined as absence of improvement or deterioration within 14 days of therapy initiation.

Conclusions

In this randomized Phase II study, the cumulative incidence of CR by day 28 was greatest for patients randomized to MMF followed by denileukin, pentostatin, and etanercept. MMF patients also had the highest 9-month overall survival rates, and lowest cumulative incidences of severe infections. Thus, MMF plus corticosteroids was identified as the most promising treatment combination for direct comparison with corticosteroids alone in a phase 3 study for initial acute GVHD therapy.

Blood. 2009 Jul 16;114(3):511-7.

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