Toxicity and efficacy of busulfan and fludarabine myeloablative conditioning for HLA-identical sibling allogeneic hematopoietic cell transplantation in AML and MDS

Abstract

The safety and efficacy of a 4-day myeloablative conditioning (MAC) regimen consisting of Bu 3.2 mg/kg and fludarabine 40 mg/m 2 /day for HLA-identical sibling allogeneic hematopoietic cell transplantation (HCT) in myeloid malignancies was investigated in 133 patients (median age, 47 years; range 19-74 years) with de novo AML (60%), secondary AML (20%) or myelodysplastic syndrome (20%). All patients engrafted. Hepatic veno-occlusive disease occurred in five patients (4%), and severe toxicities, mostly mucositis, occurred in twenty-three (17%) patients. The non-relapse mortality (NRM) at 100 days was 1.5%. The incidences of acute GVHD grade 2-4 and grade 3-4 were 32 and 13%, respectively. At a median follow-up of 38 months, the cumulative incidence of chronic GVHD was 67%. The relapse incidence was 30% (27 and 31%, respectively, in patients with earlyand late-stage disease), and the overall NRM was 15%. The actuarial 4-year disease-free survival (DFS) and overall survival (OS) were 54 and 62%, respectively. Patients aged o 50 years had better outcomes compared with older patients (DFS 64 vs 42%, P = 0.006; OS 73 vs 47%, P o 0.001, respectively).Bone Marrow Transplantation (2016) 51, 961-966;

Impact of in vivo T cell depletion in HLA-identical allogeneic stem cell transplantation for acute myeloid leukemia in first complete remission conditioned with a fludarabine iv-busulfan myeloablative regimen: a report from the EBMT Acute Leukemia Working Party

“…Although a center effect was observed in the incidence of cGVHD and NRM, possibly due to preferential used of ATG and of prophylactic donor lymphocyte infusion in some centers, we did not detect a center effect on LFS, OS, and GRFS. The only other factor associated with worse survivals was recipient age above 50 years, due to higher NRM, as reported by others with such conditioning regimen [7]. …”

“…The Flu-ivBu4 RTC associated with PBSC graft has been reported as effective than conventional Bu-cyclophosphamide MAC regimen but with reduced short- and long-term non-relapse mortality in AML patients transplanted in CR1 with an HLA 10/10-matched related or unrelated donor [8–10]. However, the incidence of chronic GVHD with PBSC (80%) grafts from HLA-identical sibling donors, following such RTC in the absence of ATG, remains high with 68% overall cGVHD and 42% extensive cGVHD incidences at 4 years post-transplant reported recently by the Spanish Cooperative Transplant Group [7]. The current study was limited to AML in CR1 transplanted with HLA-identical donors to reduce bias due to donor type and disease status on transplant outcomes.…”

Pretransplant conditioning with fludarabine and IV busulfan, reduced toxicity and increased safety without compromising antitumor efficacy and overall treatment effect?

“…This article is a commentary on the paper by De La Serna et al 1 entitled ''Toxicity and efficacy of busulfan and fludarabine myeloablative conditioning for HLA Identical-sibling allogeneic hematopoietic cell transplantation in AML and MDS''.…”

“…17 Finally, the use of 1 vs 2 rest days before infusion of the grafted cells may, to some extent, also influence outcome, as Flu has a quite long half-life (410 h), and after 1 rest day, the systemic concentration of activated Flu is high enough that it may impact the establishment of proper graft function, especially if a weak or highly HLA-disparate graft is used. 18 In summary, the reduced-toxicity nucleoside analog-Bu platform concept has contributed to greatly improved safety of both myeloablative and reduced-intensity conditioning therapy as demonstrated by De la Serna et al 1 However, we should recognize that not all conditioning programs are created equal even if different investigators seemingly use the same cytotoxic drugs; sequence and timing of the different agents coupled with interpatient variability in metabolic drug handling lead to variable pharmacokinetics and pharmacodynamics. In addition, molecular interactions not only between the different cytotoxic agents but also with concomitantly used supportive care agents will affect cellular signaling pathways and influence clinical treatment outcome.…”

“…In this issue of Bone Marrow Transplantation, De La Serna et al 1 analyzed the outcome of a multicenter and single-arm study of patients with primary or secondary AML or MDS conditioned with 4 days of once-daily fludarabine (Flu, 40 mg/m 2 /day) in combination with once-daily busulfan (Bu, 3.2 mg/kg or about 130 mg/m 2 ) to a total Bu dose of 12.8 mg/kg. The patients received an allogeneic stem cell transplant using HLA-matched sibling donors.…”