Autologous Stem Cell Transplantation after FLAG-IDA Chemotherapy for High-Risk Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemias Secondary to MDS (sAML) Does Not Improve Outcome: A PETHEMA Experience in 103 Patients.

Background. AML conventional chemotherapy followed or not by autologous stem cell transplantation could be curative for high risk MDS and sAML.

Aim. To evaluate outcome in 103 patients enrolled in PETHEMA’s FLAG-IDA protocol achieving complete remission (CR) followed by intensive chemotherapy and autologous transplantation compared to those with no further treatment.

Patients and methods. 103 patients were recruited from 15 institutions starting December 1997 till December 2004. Eligibility criteria: de novo MDS with Spanish score >2 and/or International Prognostic Scoring System (IPSS) >1; or sAML. Induction chemotherapy was the FLAG-IDA regime (Fludarabine, cytarabine (ARA-C), idarubicin (IDA) and G-CSF). Patients achieving complete remission (CR) had consolidation chemotherapy with IDA+ARAC+G-CSF. Patients younger than 65 yrs old who mobilized enough hematopoietic progenitors proceeded to autologous stem cell transplantation. Poor mobilizers were treated further either with allogeneic transplantation, if an appropriate donor was available, or with carboplatin (CBDCA) intensification. For patients older than 65 yrs CBDCA intensification was the only therapeutic option.

Results. Patients had a median age of 62 yr (range, 17–79) with a M:F ratio of 2.4:1. According to FAB classification, 2 patients had refractory anemia (RA), 1 had refractory anemia with ringed sideroblastos (RARS), 37 had refractory anemia with excess of blasts (RAEB), 23 had RAEB in transformation (RAEB-t) and 40 (39%) had sAML. Unfavorable cytogenetics according to the IPSS was found in 46 patients (45%). According to IPSS (if suitable), 9 patients were Intermediate-1, 21 Intermediate-2 and 23 were high-risk. According to the Spanish score, 3 patients had low-risk, 29 had intermediate-risk and 31 had high-risk. Sixty-six patients (64%) achieved CR and 37 patients (46%) failed (13 patients achieved partial remission; 12 had refractory disease and 12 patients died in aplasia). No variable correlated with the achievement of CR. With a median follow-up of 16 months (range, 1–80), 31 patients remained alive in continuous CR. The median event-free survival (EFS) was 11 months (range, 2–59) and the projected 3-year EFS was 29% (95% CI, 14–44). Multivariate analysis for EFS revealed poor-risk cytogenetics according to IPSS (P=0.005) as the only independent prognostic factor associated with relapse or death. Actuarial median and 3-year EFS for the 23 patients who proceeded to autologous transplantation were 10 months and 34%, not clearly different to the 10 months and 22% observed for the 35 patients treated with chemotherapy alone (P=0.67).

Conclusions. CR rate after FLAG-IDA induction chemotherapy for patients with MDS is as high as that achieved with standard chemotherapy regimes in elderly patients with AML, but treatment-related toxicity remains a serious threat. Autologous stem cell transplantation did not provide any advantage in terms of EFS in comparison with chemotherapy alone in high risk MDS or sAML. These results in a homogeneous population of patients with MDS strongly disagree with those previously reported by the EBMT group.