Bone marrow conditioning with the combination of myeloablative doses of intravenous busulfan (IVBu) with fludarabine (Flu) has gained wide acceptance as a viable alternative to the conventional busulfan and cyclophosphamide combination. When followed by transplantation with peripheral blood stem cells from matched related or unrelated donors, IVBu/Flu facilitates reliable engraftment with reduced toxicity (
). Whether this combination provides sufficient immunosuppression to facilitate engraftment of partially matched umbilical cord blood (UCB) grafts has yet to be reported. Ten patients with median age of 41 years (range 21–54 years) were enrolled in an IRB approved clinical trial with a primary endpoint to assess donor engraftment. Stopping rules were constructed to prevent graft failure from exceeding 20%. Disease characteristics include AML; CR1-1pt, CR2-3pts, MDS-4pts, CML-2pts. Seven of 10 patients had high-risk cytogenetic abnormalities. Conditioning consisted of fludarabine 40mg/m2 daily × 4 days and intravenous busulfan 130mg/m2 once daily × 4 days. Six patients received the drugs sequentially, and 4 concurrently. GvHD prophylaxis was provided by tacrolimus and mycophenolate mofetil. The cord blood grafts were at least 4 of 6 HLA-matched with the recipient and 3 of 6 HLA matched between grafts (low resolution class I, high resolution class II). The median combined cryopreserved total nucleated cell dose was 3.5 × 107/kg recipient body weight (range 2.1 to 4.4 × 107/kg). Engraftment of one or both UCB grafts was detected in only 4 of 10 recipients resulting in premature closure of the study as per graft failure stopping rules. None of the patients with donor engraftment achieved full donor chimerism and all ultimately died of relapsed disease. Of the 6 patients that experienced primary graft failure, 5 underwent second transplants (1 autologous, 4 haploidentical). One haploidentical and one autologous graft recipient remain alive and disease free 18 months and 13 months post transplant, respectively. In summary, 5 of 10 patients died of relapsed disease and 3 patients from treatment-related toxicity. Busulfan pharmacokinetic measurements were performed on the first and fourth dose. Interdose PK variability between day 1 and 4 was less than 15%. The mean and median AUCs were 4181 and 4195 μmol-min, respectively (range, 2634–5279 μmol-min). These levels are comparable to what has been previously reported for once daily IVBu dosing. We conclude that the myeloablative conditioning regimen of once daily IVBu with Flu provides insufficient immunosuppression to allow for engraftment of a partially matched umbilical cord blood graft.
This feature is available to Subscribers Only
Sign In or Create an Account Close Modal