Reduction of Relapse Incidence and Improvement of Leukemia Free Survival by Allogeneic Stem Cell Transplantation in Patients with AML and Normal Karyotype Irrespective of the FLT3-ITD Status.

Abstract 1612

Poster Board I-638

Cytogenetically normal AML (CN-AML) is a heterogeneous disease with molecular markers impacting considerably on survival. Acquired gene mutations such as the internal tandem duplication (ITD) of the FLT3 gene has been shown to be associated with poor prognosis. Furthermore, it has been shown that the poor prognosis in the group of patients with high risk cytogenetics could be improved, when a consolidation therapy with allogeneic stem cell transplantation (HCT) was performed. To investigate the importance of a postremission consolidation therapy in CN-AML patients according their mutational status for the FLT3-ITD mutation we compared the clinical outcome in these patients on an intention to treat analysis.

A total of 800 patients have been entered into two OSHO (East German study group for hematology and oncology) studies between 1997 and now. The first protocol (AML 96) compared two different induction schedules employing different schedules of intermediate AraC and Idarubicin. The second protocol (AML 2002) studied the role of two different induction therapies in patients failing to reach CR after the first induction therapy. From the 800 patients treated within these protocols 338 pts. had a normal karyotype. Complete remissions were obtained in 277 patients after one or two induction cycles. Out of these patients 78 pts received a consolidation therapy by allogeneic HCT whereas 169 pts were further treated by conventional chemotherapy or by autologous transplantation. HCT was performed after conditioning with cytoxan and 1200 cGy total body irradiation followed by GvH-D prophylaxis with cyclosporine and methotrexate. Material at the time of diagnosis to analyse the presence of a FLT3-ITD mutation was available in 116 pts. Of those, 70 patients received conventional chemotherapy whereas 46 pts. were transplanted from an allogeneic donor as postremission therapy.

Data were analyzed on an intend-to-treat-analysis in 116/277 patients being in CR1 after induction therapy from whom a FLT3-ITD mutation analysis was available. The EFS in this cohort of 116 patients was 38% after 5 years. Within the subgroup of patients (n=46) who received a HCT from an allogeneic donor the EFS was 44% compared to 33% (p=0.19) within the subgroup of conventional treated patients(n=70). As previously described, the detection of a FLT3-ITD mutation had a negative impact on event free survival which was calculated with 25% after 5 years in contrast to 46% in FLT3-ITD negative patients (p=0.06). In a further step EFS was analyzed according to the FLT3 status and the postremission treatment given. The EFS in conventional treated patients was significantly different (FLT3-ITD negative: LFS=50% vs. FLT3-ITD positive: LFS=19%; p=0.05). But, allogeneic HCT in first complete remission equalizes this difference (FLT3-ITD negative: LFS=50% vs. FLT3-ITD positive: LFS=35%; p=0.58). Major significant differences were seen in relapse incidences (RI) between the four subgroups of patients (FLT3-ITD positive and negative, conventional postremission therapy or allogeneic HCT; p=0.003). FLT3-ITD positive patients treated with conventional chemotherapy had a RI of 80% that could be reduced to a RI of 48% in the group of HCT patients. Within the two different treatment groups of FLT3-ITD negative patients the RI in the conventional treated group was 55% compared to 26% in HCT patients.

To conclude, the worse prognostic impact of the presence FLT3-ITD mutation on the outcome of CN-AML pts. can be improved by allogeneic HCT performed in first complete remission after two courses of induction therapy. Allogeneic HCT reduces the relapse incidence in FLT3-ITD positive as well as in FLT3-ITD negative pts.