A phase I/II study of the safety and efficacy of the addition of sirolimus to tacrolimus/methotrexate graft versus host disease prophylaxis after allogeneic haematopoietic cell transplantation in paediatric acute lymphoblastic leukaemia (ALL)

Abstract

Sirolimus has been shown to have activity against human acute lymphoblastic leukaemia at serum levels used for immunosuppression. We hypothesized that the addition of sirolimus to a tacrolimus/methotrexate graft-versus-host disease (GVHD) prophylaxis regimen would decrease relapse after haematopoietic stem cell transplantation and initiated a phase I/II study to demonstrate safety, feasibility, and efficacy. The study cohort included 18 patients in high-risk (HR) first complete remission (CR1), 16 in HR CR2, 17 in intermediate risk (IR) CR2, and 12 in CR3+. The 2-year event-free survival (EFS) of the cohort was 66% (standard error 6.4). EFS of risk groups was 74%, 81%, 44% and 46% for CR1, IR CR2, HR CR2 and CR3+ patients respectively, and did not differ by stem cell source. Cumulative incidence of acute GVHD grade II-IV and III-IV was 38% and 21% respectively, while the cumulative incidence of chronic GVHD was 32%. Cumulative incidence of transplant-related mortality and relapse was 10% and 25% respectively. Significant toxicities included veno-occlusive disease [seven patients (11%)], transplant-associated microangiopathy (three patients), and idiopathic pneumonitis (one patient). In summary, sirolimus-based GVHD prophylaxis can be given safely in this population and early survival results are promising. A phase III trial to test whether sirolimus decreases relapse and improves outcome after transplantation for ALL is ongoing.

Conflict of interest statement

Authorship and conflict of interest statement

Contribution: Michael A. Pulsipher had primary responsibility for study design, data analysis, data interpretation, and manuscript writing. Also, Dr Pulsipher had primary responsibility for the entire paper as an accurate and verifiable report. Donna Wall participated in study design, patient accrual, data analysis, interpretation of data, and manuscript writing. Michael Grimley participated in patient accrual, interpretation of data and manuscript writing. Rakesh Goyal participated in study design, patient accrual, interpretation of data and manuscript writing. Ken Boucher had responsibility for study design, data file preparation, statistical analysis and manuscript writing. Patricia Hankins participated in study design, protocol writing, patient accrual, data analysis, interpretation of data and manuscript writing. Stephan A. Grupp participated in study design, patient accrual, data analysis, interpretation of data and manuscript writing. Nancy Bunin had responsibility for study design, patient accrual, data analysis, data interpretation and manuscript writing. Also, Dr Bunin had responsibility for the entire paper as an accurate and verifiable report.

Figures

Fig 1

Event-free and overall survival. Two-year EFS and OS for the cohort were 64% [standard error (SE) 6·3] and 73% (SE 5·8).

Fig 2

Event-free survival by risk group. Two-year EFS for the risk groups were 74% [standard error (SE) 11] for CR1, 81% (SE 10) for IR CR2, 44% (SE 12) for HR CR2 and 46% (SE 16) for CR3+.

Fig 3

Event-free survival by risk group/stem cell source. Recipients of related donor (RD) transplants were more often CR1 or intermediate risk CR2 (21 RD vs. 13 URD), while recipients of unrelated donor (URD) transplantation were more often high risk CR2 or CR3 (20 URD vs. 5 RD). When stratified by risk, survival after related or unrelated donor transplantation was similar {2-year EFS 81% [standard error (SE) 8·5] vs. 73% (SE 13·4), RD versus URD CR1 or intermediate risk (dashed line URD, solid line RD); 2-year EFS 50% (SE20) vs. 44% (SE 11), RD versus URD high risk CR2 or CR3 (dotted line RD, dot-dash line URD)}.