Although the combination of fludarabine and busulfan is commonly used for non-myeloablative, reduced intensity (RIC), and myeloablative conditioning prior to sibling and unrelated allotransplantation, there is a wide spectrum of reported doses which range in fludarabine dose between 120 – 180mg/m2 and busulfan doses between 3.2 and 16mg/kg. Many reports include third agents or serotherapy for T-cell depletion, making retrospective comparisons difficult. Across the spectrum of published fludarabine/busulfan regimens, our investigation of fludarabine at 120mg/m2 falls into the lower range of reported flu doses, while 6.4mg/kg IV Busulfan (bu) has been studied at only a few centers. Very little busulfan pharmacokinetic data has been reported at this dose.
We report our experience with fludarabine (30mg/m2/d × 4 days =120mg/m2) and IV busulfan (0.8mg/kg × 8 doses =6.4mg/kg) in 76 consecutive patients (pts) undergoing RIC with Peripheral Blood Stem Cell (PBSC) allografting for hematologic malignancy transplanted at our center from 2006 to March, 2010. GvHD prophylaxi included methotrexate in all pts with either CSA (37) or tacrolimus (38); 13 recipients of tacrolimus also received maraviroc through d30 on a phase I/II trial, and 1 pt received CSA/MMF. Therapy was not modified for unrelated donor source or mismatch. Median age was 60. Donor graft source was sibling PBSC in 35, sibling bone marrow (BM) in 1, unrelated PBSC in 39 and unrelated BM in 1. 47% (36/76) of patients had either AML (19) or MDS (17). The remaining diagnoses included CLL (4), MCL (3), CTCL (6), T-NHL (2), follicular NHL (7), HD (8), MM (3), MF (3), other (4).
With a median follow-up of 8.2m (range 0–39m) for all patients, and median f/u for surviving pts of 10.7m (range 0–39m), probability of overall survival at 2 years is 35%. Early non-relapse mortality at 100 days was 9% (7/76). Disease progression accounted for 55% (24/44) of deaths to date. The incidence of grade II-IV acute graft vs host disease (GvHD) was 53% and there was no statistically significant difference in acute GvHD between patients receiving csa/mtx and tac/mtx. Of note, no difference in survival or incidence of GvHD was noted between recipients of 36 sibling vs 40 unrelated stem cells grafts. Donor chimerism of greater than 95% at day 100 was achieved in 39/52 (75%) patients and greater than 90% in 45/52 (86%) patients.
Very limited pharmacokinetic data has been reported after RIC conditioning using busulfan; we therefore calculated steady state concentrations in 25 patients. Busulfan pharmacokinetic analysis following the initial dose achieved a concentration steady state between 600–900ng/mL in 56% (14/25) of patients, which is consistent with our full dose busulfan PK experience, but over 2 days instead of 4. In 25 pts, median busulfan level was 856 ng/mL., average busulfan level was 852 ng/mL with a range 610–1544ng/mL. Correlation of bu levels to outcomes will be presented.
We conclude that fludarabine 120mg/m2 and IV busulfan 6.4mg/kg provides durable engraftment with acceptable treatment related toxicity in both sibling and unrelated recipients. There was no difference in GVHD between recipients of MTX with either CSA or Tac. Our data suggests that additional agents such as TBI, or ATG, may not be required during conditioning in the unrelated setting in light of the similar outcomes between sibs and unrelated recipients using a two-drug regimen.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.