Myeloablative Fractionated Busulfan Conditioning Regimen in Older Patients: Results of a Phase II Study

Abstract

Background Traditionally, pre-transplant conditioning regimen is given over 4-6 days before hematopoietic cell transplant (HCT). Delivering higher dose chemotherapy preparative regimen over a longer time period has not been tested previously. We hypothesized that the delivery of myeloablative dose of busulfan over a 3-week period may reduce toxicity and non-relapse mortality (NRM), without affecting relapse, and tested this in a prospective phase II study. Methods Patients between 18 and 70 years of age with hematological malignancies and adequate organ function, with 8/8-HLA matched related or unrelated donor were eligible. They received a fixed dose of busulfan 80mg/m2 as outpatient on days -20 and -13. Then, fludarabine 40mg/m2 was given on days -6 to -2 followed by busulfan dosed to achieve target area under the curve (AUC) of 20,000 mol/min for the whole course based on pharmacokinetic studies. GVHD prophylaxis was cyclophosphamide (PTCy) 50mg/kg on days 3 and 4 and tacrolimus. Mycophenolate mofetil (MMF) was added to later unrelated donor recipients. All patients received standard supportive care. The primary endpoint was day 100 NRM. Results We enrolled 52 patients with a median age of 62 (range, 39-69) years. Almost half (n=25, 48%) had AML or MDS and the other half (n=26, 50%) had had CML or MPD; 1 (2%) had multiple myeloma. Low, intermediate, high and very-high disease risk index (DRI) was present in 3 (6%), 34 (65%), 14 (27%) and 1 (2%). HCT-comorbidity index was ≥3 in 23 (44%) and 1-2 (n=23, 44%). A majority (n=32, 62%) had an unrelated donor. With a median follow up of 14 months (range, 3-23), NRM at day 100 was 1.9% (n=1) and 8% (95% CI, 0-15) at 1 year. Overall survival, progression-free survival and relapse at 1-year were 83% (95% CI, 73-95%), 78% (95% CI, 67-91%), and 14% (95% CI, 4-24%), respectively [Table]. There were no graft failures. The median time to neutrophil engraftment was 17 days (range, 13-33) and that of platelets (≥ 20K/µL, n=45) was 24 days (range, 9-266). Day 100 grade II-IV and III-IV acute GVHD rates were 37% (95% CI, 23-50%) and 6% (95% CI, 0-12%), respectively; 1-year chronic GVHD and extensive chronic GVHD rates were 9% (95% CI, 0-17%) and 7% (95% CI, 0-14%), respectively. Overall survival at 1-year differed significantly among patients with low/intermediate DRI (94%; 87-100%) and those with high/very high DRI (53%; 31-91%), P=0.001. Conclusion Myeloablative fractionated busulfan regimen with PTCy GVHD prophylaxis is feasible in older patients, has low incidence of severe acute GVHD, chronic GVHD, and NRM and results in promising overall survival.