Safety and Efficacy of FLAMSA Regimen Followed by Allogeneic Hematopoietic Stem Cell Transplantation From Related and Unrelated Donors in High Risk Acute Leukemia and MDS Patients: A Study From the Societe Française De Greffe De Moelle Et De Therapie Cellulaire (SFGM-TC) Registry.

Primary induction failure or relapse in AML patients maintains a very poor prognosis despite the cytogenetic stratification and the introduction of new molecules. Nevertheless, allo-HSCT can improve the overall survival of some of these patients, although new strategies are needed especially in conditioning to allow a better outcome in this high risk population of patients.

The aim of this analysis was to investigate the safety and efficacy of FLAMSA sequential regimen in patients with high-risk acute leukaemia and MDS, in a multicenter retrospective French study.

We analyzed 79 patients, 44 males & 35 females with a median age of 55 years (19-69), there were 50 de novo acute leukaemias, 3 secondary leukaemias and 26 MDS, who underwent allo-HSCT after FLAMSA conditioning [fludarabine (30 mg/m²), high-dose AraC(2 g/m²), and amsacrine (100 mg/m²) from day -12 to -9 + cyclophosphamide (40 mg/kg with related donors, 60 mg/kg with unrelated or mismatched donors) on days -4 and -3, ATG 2.5mg/kg on days -4, -3, and -2 + TBI 4 Gy on day -5 (n=42) or Busilvex 3.2 mg/kg on days -4 & -5(n=37)] who were reported to the Societe Francaise Greffe de Moelle et de Therapie Cellulaire (SFGM-TC) registry. Thirteen patients had undergone previous HSCT (10 allogeneic and 3 autologous). The disease status at transplantation were: 19 (24%) of the patients in primary induction failure (PIF) or refractory disease, 14 (17,7%) in second relapse, 25 (32%) in early relapse, 8 (10%) in untreated disease and 13 (16.3%) in progressive disease. Thirty-four patients were transplanted from HLA identical siblings and 45 from unrelated donors. Sixty four grafts were PBSC, 5 bone marrow and 8 cord blood cells.

After HSCT, 73 patients engrafted (6 non valuable early deaths) with a median time to neutrophil recovery of 16 days (8-41). There were 31 aGVHD (grade I: n=10, grade II: n=12, grade III: n=4 and grade IV: n=5) and 18 chronic GvHD (10 limited, 5 extensive and 3 unclassified). At the last follow-up, 32 patients are alive, after a median follow-up of 4.2 months, the probability of OS for the whole population at 2 years was 22.8% with 43.8% for untreated patients, 13.8% for patient in relapse, it was 47% for progressive and 23% for PIF patients. The univariate analysis showed a better significant OS according to 4 factors: disease status (untreated patients) (p= 0.04), kind of disease (p<0.001); HLA matching (p=0.03) and HSC source (PBSC) (p=0.004) without any significant impact of age, sex-matching, CMV matching, ABO matching, conditioning regimen (TBI or Busilvex) and interval between diagnosis and transplantation. The multivariate analysis using Cox regression model showed the significant impact of 2 factors on OS: kind of disease; HR=0.284 [0.09-093] (p=0.03) and minor ABO incompatibility HR=2.55 [0.99-6.61] (p=0.05). The cumulative incidence of relapse and TRM at 6 months, 1 & 2 years were: 33%, 39.2% & 40.5% and 20.2%, 21% & 21.5% respectively without any TRM in the untreated group. The multivariate analysis showed also the significant impact of disease status on TRM (p<0.001), and minor ABO incompatibility on relapse HR=5.35 [1.81-15-81] (p=0.002). The estimated cumulative incidence of death from leukaemia at 1 and 2 years from transplant was 62,7% (95% CI, 48,4%-73,1%) and 72,2% (95% CI, 57,3%-87,8%).

Our study showed a total OS of 23% at 2 years with a better survival in the untreated patients (44%) and progressive patients (47%); a worse survival for the PIF and relapsed patients group (23% & 12% respectively). When comparing to the German study, we observed similar results regarding TRM and relapse incidence, the only difference was the leukemia mortality with a higher rate in our patients which could be explained with the different relapse treatment.

No relevant conflicts of interest to declare.