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Sirolimus-calcineurin inhibitor for chronic GvHD
Data and Safety Monitoring Board recommendation to suspend further phase III accrual; however, all 151 enrolled subjects were followed for phase III endpoints (Online Supplementary Figure S2B). The endpoint review committee response adjudication determined that 13 (10%) subjects had not satisfied the NIH criteria for the diagnosis of chronic GvHD at enrollment and were ineli- gible (Online Supplementary Figure S1C); a screening diag- nostic checklist for NIH-defined chronic GvHD was required after July 24, 2013. One-hundred thirty-eight remaining subjects were randomized: 72 were assigned to two drugs and 66 to three drugs. Endpoint review com- mittee-adjudicated complete/partial response rates and provider-reported complete/partial response rates were concordant at 6 months (Cohen κ = 0.78) and at 2 years (κ = 0.88). Participants lost to follow-up, or who relapsed, died, or began secondary immunosuppressive therapy were excluded from these agreement tests.
Patients’ demographic and transplant characteristics were mostly similar between treatment groups (Table 1). The median age was 50.2 years in the two-drug arm and 54.7 years in the three-drug arm. Characteristics that were more frequent in the two-drug arm were male gen- der (66.7% versus 50%), Hispanic ethnicity (11.1% versus 0%), an underlying diagnosis of acute leukemia (65.3% versus 37.9%), transplants done for early stage disease (63.9% versus 40.9%), myeloablative conditioning (65.3% versus 43.9%), and CNI/methotrexate-based GvHD pro- phylaxis (61% versus 33.3%). Lymphoma was less fre- quent in the two-drug arm (6.9% versus 25.8%). Donor or stem cell sources did not differ between arms.
Chronic GvHD characteristics were similar between the two-drug and three-drug arms (Table 2), including the pro- portion of subjects with high-risk chronic GvHD (51.4% versus 48.5%), median time from hematopoietic cell trans- plant to enrollment (7.3 versus 7.7 months), and median time from chronic GvHD diagnosis to enrollment (7 versus 10 days). Sixty-two percent of the study subjects were enrolled within 14 days of a new diagnosis of chronic GvHD and 38% were responding inadequately to initial therapy; classic and overlap subtypes were equally repre- sented. Global severity scores were mainly moderate (67%), then mild (21%) and severe (12%); 43% of the patients had progressive onset chronic GvHD. The organs involved were the skin (76%), mouth (74%), liver (71%), eyes (54%), gastro-intestinal tract (46%), joints/fascia (24%), genital tract (17%), and lungs (15%) with the pat- tern of involvement being similar between the treatment groups except for genital tract involvement, which was more common in the group treated with three drugs (10% versus 26%, but only 63% of the study population were scored).
Response and survival
The treatment success rate at 6 months was 48.6% [95% confidence interval (CI): 36.7%-60.7%] with two drugs versus 50.0% (95% CI: 37.4%-62.6%) with three drugs P=0.87). The rate of more stringently defined treat- ment success at 2 years (complete responses only) was 14.7% (95% CI: 7.3%-25.4%) with two drugs versus 15.5% (95% CI: 7.4%-27.4%) with three drugs (P=0.90) (Table 3). Since very good partial response is clinically rel-
Figure 1. BMT CTN 0801 Consort flow diagram. ECP: extracorporeal photo- pheresis; PDN: prednisone; SRL: sirolimus; CNI: calcineurin inhibitor.
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