Phase II Trial of Reduced Intensity Busulfan / Clofarabine Conditioning with Allogeneic Hematopoietic Stem Cell Transplantation for Patients with AML, MDS, and ALL

Introduction: Disease relapse remains the primary obstacle to success after reduced intensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (HSCT) for patients with acute leukemia and MDS.  The ideal RIC regimen has not been defined.  Clofarabine is a nucleoside analogue with potent anti-leukemia activity and its inclusion in RIC HSCT could potentially lead to decreased rates of disease relapse. 

Methods: We conducted a phase II clinical trial of reduced intensity busulfan (6.4 mg/kg IV total) with clofarabine (40 mg/m2 IV daily x 4 days) conditioning before allogeneic 8/8 HLA-matched related or unrelated donor HSCT. GVHD prophylaxis was with tacrolimus and methotrexate (5 mg/m² on days 1, 3, 6).  The primary endpoint was donor neutrophil engraftment by day +40 after HSCT.  Secondary endpoints included non-relapse mortality, rates of acute and chronic GVHD, PFS, and OS.

Results: 34 patients with AML (n=24), MDS (n=6), and ALL (n=4) were enrolled and underwent RIC HSCT.  Patients with AML or ALL were in CR and patients with MDS had < 10% bone marrow blasts.  The median age of patients was 63.5 (range 25, 74) and median HCT-CI score was 1 (range 0, 9).  Engraftment with donor chimerism by day +40 was achieved in 33 of 34 patients with one patient dying before successful count recovery.  Of the patients who engrafted and had chimerism data available (n=30), median donor chimerism measured at approximately day +30 after HSCT was 97% (range 85%, 100%) for all leukocytes and median 80% (50%, 100%) for the CD3⁺ population.  Of those who have been followed for at least 100 days after HSCT (n=28), the probability of NRM at day 100 was 6.4% and 1-year was 36% (95% CI, 15%, 57%).  Causes of NRM included acute GVHD (n=4), infection (n=2), and multi-organ failure (n=2).  Four of the six patients with MDS died of NRM, all of whom were older than 65 and had HCT-CI scores 4 or above.  The other two non-relapse deaths were due to acute GVHD in the setting of early taper of tacrolimus, one for decreasing chimerism and the other for neurological complications.  There were no cases of hepatic VOD.  The 12-month cumulative incidence of disease relapse was 27% (95% CI, 12%, 44%).  The 6-month cumulative incidence of acute GVHD was 35% (95% CI, 18%, 53%) and the 12-month cumulative incidence of chronic GVHD was 24% (95% CI, 9.2%, 43%).  The 12-month probability of PFS was 38% (95% CI, 18%, 59%) and OS was 41% (95% CI, 19%, 62%). 

Conclusion: Reduced intensity conditioning with busulfan and clofarabine engenders successful donor engraftment with acceptable rates of toxicity, NRM, and GVHD, although caution should be used in older patients with significant comorbidities.  Longer follow-up and comparison of outcomes with fludarabine-based regimens will be important in defining the role of this RIC regimen.