FLT3 Inhibitors Are Promising Salvage Therapy for Relapsed or Refractory Acute Myeloid Leukemia (AML) in Patients with FLT3-ITD Mutations,

The FMS-like tyrosine kinase (FLT3) is a transmembrane tyrosine kinase that belongs to the class III family of receptor tyrosine kinases. Internal tandem duplication (ITD) in the juxtamembrane domain of the FLT3 is found in approximately 15–30% of AML cases and its constitutive activation of kinase cascade is considered to contribute to leukemogenesis. The prognosis for AML patients (pts) with FLT3-ITD mutation is significantly worse than that with wild-type FLT3 pts and largely a result of a high relapse rate with poor response to salvage therapy. Recently, several FLT3 inhibitors (FLT3i) have been introduced to clinical trials and some of them are exhibiting clinical efficacy. Data are lacking on whether the use of FLT3i as salvage therapy for relapsed or refractory AML pts with FLT3-ITD mutations will improve long-term outcomes and how they compare to salvage therapy with standard chemotherapy.

To determine the long-term efficacy of FLT3 inhibitors when used as first salvage therapy for refractory and relapsed AML in pts with FLT3-ITD mutations and compare it with that of conventional chemotherapy.

We conducted a retrospective study of 120 pts with AML having FLT3-ITD mutation who had relapsed after or exhibited disease refractory to front-line therapy, thus received salvage therapy in various clinical trials. The cohort was divided into two groups that received a salvage regimen consisting of 1) conventional cytotoxic chemotherapy or 2) one of several FLT3i (e.g., sorafenib, PKC-412, CEP-701, AC-220, KW-2449, AP24534) either alone or in combination with chemotherapy. Pts who had received FLT3i as part of their front-line therapy were excluded from the study. Response to salvage therapy was classified according to the International Working Group (including CR, CRp, or CRi).

Between August 1995 and June 2011, 120 pts were treated, of which 75 received conventional chemotherapy (Conventional group; 71/75 were Ara-C based) and 45 received a FLT3i (FLT3i group). Among them, 43 pts were refractory to induction (Conventional = 26 [35%] vs FLT3i = 17 [38%]) and 77 had relapsed disease (Conventional = 49 [65%] vs FLT3i = 28 [62%]). The median duration of 1st remission for the latter group was 8.9 months. The median follow-up durations in the Conventional and the FLT3i groups were 71.5 weeks and 62.3 weeks, respectively (p=0.73). Baseline characteristics, such as age, sex, ECOG performance status and other laboratory parameters were similar in both groups. The number of pts who received stem cell transplant (SCT) as part of the salvage therapy was not statistically different (Conventional = 21/75 [28%] vs FLT3i = 11/45 [24%]; p = 0.67). Of those pts, SCT was performed while they were in CR in 9/21 pts in the Conventional and 2/11 in the FLT3i group (p=0.18). SCT was performed in 1st CR only in one patient in the Conventional and none in the FLT3i group.

Response to the salvage therapy (CR, CRp and CRi) in the two groups was not statistically different (16/75 [21%] in conventional group vs 9/45 [20%] in the FLT3i group; p=0.41). The median overall survival (OS) was 41 weeks in the Conventional and 58 weeks in the FLT3i group (p=0.312). There was no significant difference in OS by treatment arm when analyzed separately for older (age above 60) and younger pts. Of the FLT3i group, 31/45 [69%] received FLT3i alone and it was combined with chemotherapy in 14/45 [31%]. The median OS was significantly better when FLT3i was combined as opposed to FLT3i monotherapy (median OS 102 weeks vs 49 weeks; p<0.05); the duration was also superior to that in Conventional group (41 weeks; p<0.05). In the pts whose initial CR duration was shorter than 12 months or who never had a CR with front-line therapy (N=88), the median OS was significantly better in FLT3i group (N=25) than that in the Conventional group (N=63) (58 weeks vs 33 weeks; p<0.01).

Salvage therapy including a FLT3 inhibitor appears to be beneficial for relapsed or refractory AML pts with FLT3-ITD mutation, especially when combined with cytotoxic chemotherapy. Pts who never experienced a CR to front-line therapy or whose CR duration was less than 12 months benefited the most from FLT3 inhibitor therapy. Although further prospective studies are necessary to confirm these results, they suggest that a FLT3 inhibitor should be included in salvage regimens for relapsed or refractory AML pts with FLT3-ITD mutation.

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