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Treatment of FLT3-ITD Positive Acute Myelogenous Leukemia with Allogeneic and Autologous Stem Cell Transplantation - Results in 175 Patients



Treatment of FLT3-ITD Positive Acute Myelogenous Leukemia with Allogeneic and Autologous Stem Cell Transplantation - Results in 175 Patients



Blood 100(11): Abstract No 2957, November 16



Activating mutations of the FLT3 receptor tyrosine kinase, either by internal tandem duplication (ITD) mutations of the juxtamembrane domain or point mutations of the tyrosine kinase domain, are common alterations in adult AML. Several groups have shown that FLT3-ITD mutations are associated with inferior outcome after standard chemotherapy. The adequate treatment for these patients is still unclear. Autologous and allogeneic stem cell transplantation (SCT) are curative treatment options for patients with AML and are offered especially to patients with intermediate and high risk cytogenetics. In the current analysis we asked for the outcome of AML patients with FLT3-ITD mutations treated with SCT. Methods: 329 adult patients with de novo AML and intermediate risk cytogenetics, i.e. normal karyotype (n=234) and other non high risk or good risk cytogenetics (n=84), (unknown n =11) age 60 and younger treated in the AML96 multicenter protocol of the Sueddeutsche Haemoblastose Group were analyzed retrospectively. Of these patients 92 were treated by autologous and 83 by allogeneic (matched sibling donor: n= 66; matched unrelated donor: n=17) SCT. Analysis for FLT3-ITD mutations was performed by PCR using genomic DNA obtained at diagnosis. In addition, quantitative analysis for the mutant to wt ratio was done in FLT3-ITD pos. cases. Results: FLT3-ITD mutations were found in 85/329 cases (25.8%). Overall, the presence of a FLT3-ITD mutation was associated with an inferior outcome (median overall survival (OS) FLT3-ITD pos. vs. neg.: 14.7 vs. 26.5; p= .0961; median disease free survival (DFS): 11.6 vs. 28.9 p=0.05). When the different treatment arms were analyzed separately, no difference in OS and DFS was found in patients treated by autologous and unrelated allogeneic SCT. In patients with related donor an unsuspected difference was observed, due to an increased rate of relapse: 52.9% vs. 14.9% (p= .0017). The most prominent survival difference was found in patients treated with chemotherapy only (OS FLT-ITD pos. vs. neg.: 5 vs. 9.6 months; p= .009; DFS: 4 vs. 17 months, p= .02) due to a highly increased early relapse rate. This finding was most evident in patients with a high/mutant to wt ratio, indicating loss of the wt-FLT3 allele. Conclusions: In patients treated with autologous transplantation, FLT3-ITD mutations are not associated with an inferior outcome. The role of allogeneic transplantation remains to be defined, but relapse is a major cause of treatment failure in FLT3-ITD+ patients

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