Fludarabine, IV Busulfan and Antithymocyte Globulins-Based Reduced-Toxicity Conditioning Regimen Prior to Allogeneic Stem Cell Transplantation (allo-SCT): Results of a Multicenter Prospective Trial

In the last decade, the so-called reduced intensity or reduced-toxicity conditioning (RTC) regimens prior to allo-SCT have emerged as an attractive modality to decrease allo-SCT-related toxicities and non-relapse mortality (NRM). In the context of RTC allo-SCT, IV Busulfan proved to be a key drug, because of its safety profile and potential anti-tumor activity that can allow for early disease control while waiting for the immune-mediated GVL effect.

This phase 2 prospective multicenter trial (ClinicalTrials.gov Identifier:NCT00841724) aimed to assess at one year the efficacy and safety of a “submyeloablative” conditioning regimens based on IV Busulfan 130mg/m²/d (administered as a single daily infusion over 3 hours) for 3 days (total dose equivalent to 9.6 mg/Kg), Fludarabine 30mg/m²/d for 5 days, and ATG (Thymoglobuline*) 2.5mg/Kg/d for 2 days (the “FB3” regimen) in patients with high risk hematological malignancies candidate for allo-SCT but not eligible for a standard myeloablative conditioning regimen. For GVHD prophylaxis, patients received cyclosporine alone in case of a family donor, and cyclosporine+mycophenolate mofetil in case of an HLA-matched unrelated donor (MUD: 10/10 or 9/10).

Between 2008 and 2011, a total of 80 patients were included (47 males, 59%). The median age of patients at time of allo-SCT was 53 (range, 25–64) years. Diagnoses included: ALL/AML/biphenotypic acute leukemia (n=5; n=26; n=1; 40%); MDS/MPS (n=6; 8%); CLL (n=3; 4%); NHL and HD (n=24; 30%); and myeloma (n=15; 18%). At time of conditioning, 39 patients (48%) were in first CR, 14 patients (18%) were in CR2/CR3, and 27 patients (34%) were in more advanced disease phases. The donor was an HLA-identical sibling donor in 28 cases (35%) and an HLA MUD in 52 cases (65%). The stem cell source was G-CSF-mobilized PBSC in 77 cases (96%) and unmanipulated bone marrow in 3 cases (4%). Per protocol, comorbidities and performance status were comprehensively assessed at time of inclusion. The Karnofsky score was 70%, 80%, 90%, and 100% in 4 (5%), 11 (14%), 28 (35%), and 37 (46%) patients, respectively. At time of transplant, 54 patients (68%) had at least one comorbidity, while 26 patients (32%) did not have any. In this cohort, the HCT comorbidity index developed previously by Sorror et al. was 0, 1 or 2 and >2 in 27 (34%), 21 (26%) and 32 (40%) patients, respectively.

All patients but one engrafted. ANC>500/μL was achieved at a median of 15 (range, 10–23) days after allo-SCT, and 98% of patients had platelets >50.000/μL by day 60 after transplantation (of whom none was below 20.000/μL at any time point). The cumulative incidences of grade 2–4 and grade 3–4 acute GVHD were 32% (95%CI, 21–43%) and 9% (95%CI, 4–18%), respectively. The cumulative incidence of relapse/disease progression (RI) at one year was 26% (95%CI, 17–36%), while the cumulative incidence of NRM was 10% (95%CI, 5–18%) at one year. The Kaplan-Meier estimates of overall (OS) and progression-free survival (PFS) at one year were 71% (95%CI, 61–81%) and 64% (95%CI, 53–74%), respectively. In terms of prognostic factors for outcome, patient age, diagnosis, donor type, gender, presence or absence of comorbidities and the HCT comorbidities index, did not have any statistically significant impact on NRM, RI, PFS and OS. Only a Karnofsky score <90% at time of allo-SCT had a negative impact on OS (47% vs. 77%; p=0.008), while only disease status (CR1 vs. other) impacted RI (p=0.02).

Results from this phase 2 prospective multicenter trial validated the safety and efficacy of a so-called reduced-toxicity conditioning regimen which could overcome the deleterious impact of comorbidities since no statistically significant impact of the HCT comorbidity index on outcome could be shown. Such FB3 regimen appears to be safe with a 10% NRM at one year in high risk patients, and exhibits an efficient disease control both in myeloid and lymphoid malignancies, warranting further investigations as part of phase 3 trials.

Mohty:Pierre-Fabre: Consultancy, Honoraria, Speakers Bureau. Blaise:Genzyme/Sanofi: Honoraria, Research Funding; Pierre Fabre: Honoraria, Research Funding; Otsuka: Honoraria.