Intravenous Busulfan As A Preparative Regimen Before Allogeneic Hematopoietic Stem Cell Transplantation For Adult Patients With Acute Leukemia1

ObjectiveThe use of i.v. busulfan(BU) instead of the oral formulation can improve outcomes in patients undergoing allogeneic hematopoietic stem cell transplantation(allo-HSCT) by reducing toxicity and transplantation- related mortality(TRM). There are limited reports of i.v. BU used to treat patients with acute lymphoblastic leukemia(ALL). The present study was performed to evaluate the efficacy and toxicity of i.v. BU/cyclophosphamide(CY) conditioning in adult ALL.MethodsWe retrospectively analyzed 42 consecutive patients who underwent allo-HSCT with BU/CY conditioning between January 2007 and October 2010 with an HLA- matched donor(sibling, n=18; unrelated, n=24). Thirty-three patients were in first complete remission(CR1), 2 were in second complete remission(CR2), and 7 were in a more advanced stage. Median patient age was 28 years(range, 17~55 years).ResultsThe median follow-up was 15 months(range, 1~48 months). Overall, 13 patientsdied, for a 30-month overall survival of 56.5%±10.6%(65.7%±12.5% for patients in CR1 vs 25.4%±15.5% for those in CR2 or beyond; P <.001). Eleven patients experienced relapse between 2 and 26 months after allo-HSCT, with a 30-month relapse rate(RR) of 40%±10.9%(32.0%±12.7% for patients in CR1 vs 71.4%±17.1% for those in CR2 or beyond; P =.001). The incidence of grade II-IV acute graft-versus-host disease(GVHD) was 39.2%±8.8%, and that of grade III-IV acute GVHD was 7.4%±4.1%. The incidence of chronic GVHD was 63.9%±11.7%, and that of extensive chronic GVHD was 19.3%±7.9%. Only 2 cases of clinically diagnosed veno-occlusive disease(VOD) were documented(4.7%), and 1 of these patients died of severe VOD. Other BU/CY conditioning–associated toxicities were diffuse alveolar hemorrhage in 1 patient and hemorrhagic cystitis in 8 patients. Four patients died due to TRM, for a 30-month TRM of 9.7%±4.6%.ConclusionsThis study demonstrates that i.v. BU/CY can be considered a fea- sible conditioning regimen for adult ALL, with low incidences of VOD and TRM.ObjectiveTo improve the outcome of allogeneic stem cell transplantation in refractory AML, we conducted a single arm phase II clinical trial to evaluate the efficacy and feasibility of conditioning regimen following cytoreduction chemotherapy with 7-day interval.MethodsAdult patients with refractory AML were enrolled in the study and received FLAGIDA as cytoreductive chemotherapy followed by Flu-BU conditioning regimen and transfusion of mobilized peripheral stem cells from HLA-matched sibling or unrelated donor. The primary endpoint of the study was 2-year leukemia-free survival(LFS) and secondary endpoints included complete-remission rate, 2-year overall survival(OS), nonrelapse mortality(NRM) and relapse rate.ResultsResults A total of 16 patients were enrolled with median age of 36(16~60) which included 9 primary induction failure, 2 early relapse and 5 with relapse/refractory disease. The median cycles of previous chemotherapy were 4(3~10) with a median of 55%(1~90%) blasts in bone marrow. Six patients received transplantation from matched sibling and 10 from matched unrelated donors. After transplantation, 15 patients achieved bone marrow remission(11 CR and 4 CRp) at day+28. A total of 8 patients remained alive in CR with median LFS of 29.5 months(9.5~40.5 months). Four patients relapsed and 3 of them died of disease and another 4 patients died due to transplantation related toxicity. The 2-year NRM and relapse rate were 25.0±10.8% and 33.4±13.8% respectively with 2-year OS at 53.5±13.1% and LFS at 50.0±12.5%. Based on the Simon’s two-stage design, 5 out of first eligible 14 patients remained leukemia-free for more than 2 years after alloHSCT, thus the null hypothesis of the study will be rejected and the study protocol is accepted as being warranted for further study.ConclusionsBased on the above data, our phase II study demonstrated that the sequential FLAGIDA cytoreduction chemotherapy followed by Flu-BU conditioning regimen given at the hematological nadir was feasible and has sufficient activity to warrant further investigation prospectively with a larger patient sample.(clinicaltrials.gov identifier: NCT01496547).