Work

273: Safety and efficacy of high-dose busulfan by 90-hour continuous infusion in hematologic malignancy patients undergoing allogeneic stem cell transplants

Year: 2007

Type: article

Abstract: Busulfan is used in allotransplantation for patients with hematologic malignancies. IV busulfan has recently become available and is widely used qd or qid x 4 with fludarabine in both ablative and reduced-intensity regimens. We have previously demonstrated the benefit of using a test-dose of IV busulfan to predict the systemic exposure of this drug (Walko, ASCO, 2005) and report here on this approach in pts receiving a 90 hr continuous infusion of full-dose busulfan. Methods: All pts received a 0.8 mg/kg test dose administered over 2 hours and PK sampling at times 0, 2.5, 4, 5, and 6 hours. Pts began treatment with 30 mg/m2 fludarabine qd x 5 and either 0.8 mg/kg ABW IV busulfan (18 pts) or targeted busulfan to achieve an AUC of 4800 (6 pts) or 5700 (5 pts) umole/min/hr/day on days –7 to –3. PK sampling was done at hours 0, 12, 16, 18, 48, 60, 72, and 89.5. All pts received tacrolimus and 0 (9 pts), 1 (10 pts), 2 (8 pts) or 3 (2 pts) doses of 30 mg of IV alemtuzamab based on disease and donor type for prevention of GVHD prior to initiation of chemotherapy. The initial 18 pts were studied without dose adjustments, followed by dose escalation with targeted systemic exposure of the busulfan and dose adjustments as needed in the last 11 pts treated. Results: 29 pts (15 MRD, 14 MUD) ages 18-55 (median 40) with high-risk AML (15), ALL (5), CML (2), IMF (2), MDS (2), or other diseases (3) were enrolled. All pts engrafted with a median of 14 days to an ANC > 500 and 7 days to a platelet count > 20K. No regimen-related deaths were observed in the first 100 days post-transplant. Two patients had transient grade 3 hepatitis and two had grade 3 mucositis. There have been no cases of VOD, pulmonary fibrosis, alveolar hemorrhage or CNS toxicity. One death at day 190 from pneumonia and one at day 191 from hemorrhagic cystitis and enterococcal sepsis occurred for a non-relapse mortality rate of 7%. 14 pts have developed grade 2, one grade 3 and one grade 4 aGVHD. 6 have extensive and 2 have limited cGVHD. 12 pts have relapsed at a median of 128 days (range 76-512) post transplant with a one year actuarial OS of 65%. Conclusion: This approach permits accurate delivery of a targeted systemic exposure to IV busulfan, is well-tolerated, and will allow additional dose escalation. Relapse, as opposed to toxicity, remains the major challenge.

Source: Transplantation and Cellular Therapy

DOI: 10.1016/j.bbmt.2006.12.278