Clofarabine (Clo) +/− Fludarabine (Flu) with IV Busulfan (Bu) and Allogeneic Stem Cell Transplantation (Allo-SCT) for Relapsed, Refractory Myeloid Leukemia (ML) and MDS

Fludarabine (Flu) combined with IV Busulfan (Bu) is a safe, reduced toxicity pretransplant conditioning program. To enhance the cytoreductive effect of the conditioning regimen, we decided to replace Flu with Clofarabine (Clo), a (superior) second generation nucleoside analog/antileukemic agent, whose immunosuppressive capability in support of allogeneic progenitor cell engraftment is unknown. In 2006 we initiated a trial where Clo would gradually replace Flu combined with IV Bu in a myeloablative program, aimed at

1. retaining the safety profile, while

2. evaluating the engraftment-promoting capacity, and hopefully

3. improving the antileukemic activity.

METHODS and PATIENTS: Patients were enrolled/randomized as follows: Arm I: Clo:Flu 10:30 mg/m2, Arm II 20:20 mg/m2, Arm III 30:10 mg/m2, and Arm IV single-agent Clo at 40 mg/m2, the nucleoside analog(s) were/was infused over 60 min each once daily for 4 days on each day followed by Bu infused over 3 hours to an average daily AUC of 6,000 mcMol-min +/− 10%. So far, 20 patients have been enrolled, 12 males and 8 females, with a median age of 43 years (range: 6–57). Seven patients had CML (BC: 1, first AP: 3, second AP: 2, and late first CP: 1). Thirteen patients had AML: 5 with induction failure, 3 were in chemotherapy-refractory relapse, 3 in untreated relapse, 1 had a second PR, and, finally 1 was in a high-risk CR1 [cytogenetics of −7 and t(3;12)]. Of the 13 AML patients 1 had a favorable cytogenetic (CG) pattern, 6 were intermediate, and 4 had poor prognosis CG, while 2 had unknown CG data. GVHD-prophylaxis was based on tacrolimus and mini-MTX, and those who had an unrelated or one antig-mism. related donor received rabbit-ATG (Thymoglobulin^™).

RESULTS: One patient died of pneumonia, there was no other treatment-related death in the first 100 days, the main toxicity was mucositis grade 2–3 in about half the patients. Specifically there was no significant hepatic or neurologic toxicity. All 19 evaluable patients engrafted uneventfully (one had recurrent AML before day +30). Marrow and blood (T-cell) chimerism studies at day +30 revealed that groups I+II (lower Clo doses; n=9) had a median of 87% (range 17–100) donor (T-cell)-derived DNA, groups III+IV (higher Clo-doses, n=11) had a median of 100% range (64–100) donor-DNA. By day +100 both cohorts had a median of 100% donor-derived DNA, maintained beyond 6 months in all evaluable patients. 16 of the 19 patients with active disease at SCT entered CR, and 11 patients remain in clinical CR (August 2008) with a median duration of 8 mos (range, 2–19). One previously TKI-resistant CML patient (SCT in second AP) progressed by CG at 4 mos, but responded to dasatinib, with a maintained CG CR exceeding 22 mos. Median disease-free and overall survival has not been reached with 11 patients in unmaintained CR, and 12/20 being alive. The projected overall and disease-free survival at one year of 70% and 55%, respectively.

CONCLUSION: We conclude that a Clo-Bu-based regimen appears safe in (relapsed, chemotherapy-refractory) high-risk patients, 2) there should be little or no concern about the immunosuppressive capability of Clo in support of allo-SCT in myeloid leukemia, and 3) (an) additional study(-ies) is/(are) warranted to fully evaluate the antileukemic efficacy of Clo combined with IV Bu + ATG as pretransplant conditioning therapy for myeloid leukemia and MDS.