Once Daily Busulfan and Fludarabine Is Well Tolerated and Effective in Older Heavily Treated Patients Prior to Unrelated Donor Allogeneic Peripheral Blood Stem Cell Transplant.

Reduced-intensity (RI) preparative regimens are used to treat patients (pts) unable to receive standard myeloablative allogeneic hematopoietic stem cell transplants (HCT) due to risk factors such as older age, prior treatments, and co-morbidity. We report the results of a prospective phase II study using a RI regimen and unrelated donor HCT. The RI regimen consisted of intravenous busulfan (Bu) 3.2 mg/kg daily for 2 doses, fludarabine 30mg/m² daily for 5 doses, and ATG 15mg/kg daily for 4 doses. GVHD prophylaxis was tacrolimus and methotrexate 15mg/m² on day 1, and 10 mg/m² on days 3 and 6. Twenty-one patients (median age 60, range 39–67) with acute myelogenous leukemia (n=10), non-Hodgkin’s lymphoma (n=5), chronic lymphocytic leukemia (n=2), myelodysplasia (n=2), and multiple myeloma (n=2) were admitted to the study between 2002 and 2007. Nineteen pts were HLA matched with unrelated donors at A, B, C, DR, and DQ, and two pts had unrelated donors mismatched at one HLA class I allele. Nine pts had one or more autologous HCTs prior to beginning the study. Bu pharmacokinetics (pk) were performed on each dose of Bu for the first 3 pts and revealed a median Bu AUC of 5620 uM*min (range 4717–7148), Cmax 3.13 mcg/ml (range 2.68–4.62) and clearance 86.8 ml/min/kg (range 76.2–98.7). Engraftment, toxicity and follow up data is available on 20 pts. Grade II or higher regimen related toxicity (RRT) was reported in seventeen (85%) pts; gastrointestinal (n=14), mucositis (n=7), hepatic function (n=4), fever and infection (n=3), pulmonary function (n=2), and renal function (n=1). Veno-occlusive disease did not manifest in any pts. Six pts did not receive the full prescribed dosage of ATG because of ATG related toxicities, including fever and chills, hypotension, capillary leak syndrome, and elevated bilirubin levels. One pt’s ANC never dropped below 0.5 x 10⁹/L, and in the remaining nineteen patients the median day of engraftment was 15 days. Nineteen (95%) of twenty pts achieved 100% donor chimerism by day 80. Three pts subsequently lost donor chimerism and one never achieved higher than 90% donor chimerism; all 4 pts relapsed. Thirteen pts (65%) developed grade II or higher overall acute GHVD and chronic GVHD developed in five pts. Treatment related mortality (TRM) was 15% (95% confidence interval [CI], 5%–40%) at 3 months, and 35% (95% CI, 17%–63%) at 12 months. The most common cause of TRM was GVHD and infection. Actuarial overall survival at 3 years was 52% (95% CI, 27%–71%). All six pts who received reduced ATG dosages developed acute GVHD and one had relapse of disease, while of the remaining fourteen pts who received full ATG dosages 7 developed acute GVHD and 5 had relapse of disease. In conclusion, this small phase II study of a once daily Bu and fludarabine RI regimen and unrelated donor HCT demonstrated good long term survival and disease control. Once daily Bu pk studies demonstrated no unexpected AUC or clearance parameters. Significant TRM still exists with this RI regimen in this heavily treated older pt population, and future use of a co-morbidity scoring tool may help select pts more suitable for this regimen. ATG significantly contributed to RRT, while GVHD and its treatment and complications primarily resulted in the TRM. Removing ATG and using other measures for GVHD prophylaxis and treatment may improve this RI regimen.