Post-Transplant Outcome in Patients with Acute Myeloid Leukemia and Myelodysplasic Syndrome Who Received Conditioning Regimen Based On Fludarabin, Busulfan and Anti-Thymoglobulin Prior to Allogeneic Hematopoietic Stem Cell Transplantation

Purpose: Over the years, we have tuned the chemotherapy dose intensity of a busulfan based RIC regimen with the aim to better control disease while retaining a low toxicity profile. Here, we retrospectively analyzed a cohort of patients with myeloid malignancies treated identically in two French centers.

Patients and methods: From 2005 to 2010 in Marseille and Nantes we transplanted 165 patients (median age: 56.8 years (range:18-71); males: 83, females: 82) presenting AML (N=124) or MDS (N=41) following a similar conditioning regimen but for the dose of busulfan (Bu): 1/Fludarabine (30 mg/m²/day over 5 days) 2/, rabbit ATG (r-ATG) (2.5mg/kg/day over 2 days) and 3/ i.v. or oral Busulfan (Bu) (130 mg/m²/day or 3.2 mg/kg respectively over 2 to 4 days) (table 1). Cyclosporin A was given as post graft immunosuppression. Initially higher Bu doses were proposed to patients under the age of 55, without comorbidities and with higher risk diseases.

Results: With a median follow up of 20.7 months, 2 year overall survival (OS) and PFS were 59.6% (95% CI: 51.8-68.6) and 54.9% (95% CI: 47-64) respectively. Grade 2-4 and 3-4 acute graft-versus-host diseases (aGvhD) at day 100 was 19.4% and 7.9% respectively. cGvhD (all grades) and extensive cGvhD were 25% and 14.4% at 1 year post transplantation respectively. Non relapse mortality (NRM) was 11.7 and 15.4% at 12 and 24 months. Relapse (CIR) was 24% and 29.7% at 1 and 2 years.

Overall neither the patient age, nor the donor type or the dose of Busulfan influenced significantly OS, PFS or CIR in the whole cohort. Surprisingly, NRM was lower after 3 or 4 days busulfan conditioning regimen (3.6% vs 21.3%, p=0.009).

The 93 CR1 AML patients had 2-year OS and PFS of 63.4% (95% CI: 53.3-75.3) and 60.9% (95%CI: 50.8-72.9) respectively. Two-year OS reached 66.4% (95%CI: 56.4-81.8) for AML patients with favorable or intermediate karyotype and 50.5% (95%CI: 33-77.3) for unfavorable, p=0.08. AML patients with favorable or intermediate karyotype tend to have a better 2-year PFS (63.8%, 95%CI: 52.2-78.1) than unfavorable karyotype (52%, 95%CI: 34.5-78.3), p=0.2.

Patients under the age of 55 (n=76) present overall a better outcome than older (OS: 63.9 (CI: 52.7-74.4) vs 56% (CI: 45.6-68.7), p=0.2, PFS: 60.5 (49.7-73.8) vs 50.4% (CI: 40-63.5), p=0.2, NRM: 9.4 vs 20.3%, p=0.07). In addition higher doses of BU improved OS (77.5% vs 47.9%, p=0.058), PFS (71.6 vs 46.4%, p=0.1), without increase of NRM (2.2% vs 18.7%, p=0.03).

Conclusion: this conditioning regimen using Fludarabin, Busulfan and r-ATG can result in good OS and PFS probabilities, in myeloid malignancies. Given the patient population characteristics the NRM can be considered as low. The good NRM profile of higher doses invite to further developments.