Clofarabine Plus Busulfan is an Effective Conditioning Regimen for Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Acute Lymphoblastic Leukemia: Long-Term Study Results

Abstract

<p class="first" id="P1">We investigated the long-term safety and disease-control data obtained with intravenous busulfan (Bu) combined with clofarabine (Clo) in patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic stem cell transplantation (SCT). 107 patients with median age 38 years (range 19–64 years) received a matched sibling (n=52), or matched unrelated donor transplant (n=55) for ALL in first complete remission (n=62), second complete remission (n=28), or more advanced disease (n=17). Nearly half of the patients had high-risk cytogenetic profiles as defined by the presence of t(9;22) (n=34), t(4;11) (n=4), or complex cytogenetics (n=7). Clo 40 mg/m ² was given once daily, each dose followed by pharmacokinetically-dosed Bu infused over three hours daily for 4 days, followed by hematopoietic cell infusion after two rest days. The Bu dose was based upon the drug clearance determined by a test Bu dose, 32 mg/m ², given 48 hours prior to the high dose regimen. The target daily area under the curve (AUC) was 5,500 microMol-min for patients less than 60 years of age and 4000 microMol-min for patients older than 59 years of age. With a median follow-up of 3.3 years among surviving patients (1–5.8 years), the 2-year progression-free survival (PFS) rates for patients transplanted in CR1, CR2, or more advanced disease were 62%, 34%, and 35%, respectively. The regimen was well tolerated with non-relapse mortality (NRM) rates of 10% and 31% and at 100 days and 2 years, respectively. The incidence of grades II–IV and III–IV acute graft versus host disease (GVHD) were 35% and 10%, respectively; 18% patients developed extensive chronic GVHD. The 2-year overall survival (OS) rates for patients transplanted in CR1, CR2, or more advanced disease were 70%, 57%, and 35%, respectively. Among 11 patients older than 59 years treated with reduced dose Bu in CR1 (n=7) or CR2 (n=4), 4 remain alive and disease-free with a median follow up of 2.6 years (2–4.7 years). Only the presence of MRD at time of transplant was associated with significantly worse PFS and OS on multivariate analysis. The Clo-Bu combination provides effective disease control while maintaining a favorable safety profile. Overall survival and NRM rates compare favorably with traditional myeloablative TBI-based conditioning regimens. </p>