FLT3

ESH 2018 | Impact of FLT3-ITD allelic ratio on outcomes/ therapy for FLT3-positive AML

At the European School of Hematology (ESH) Clinical Updates in Acute Leukemia Meeting on Saturday 5th of May 2018, Mark Levis from John Hopkins Medicine, Baltimore, presented a talk titled “FLT3 inhibitors”. The speaker discussed the prognostic impact of FLT3-ITD mutant allelic ratio on remission induction and post-remission treatment and also the use of FLT3 inhibitors.

Mutations in the fms like tyrosine kinase 3 (FLT3) gene represent one of the most commonly encountered, and clinically challenging, classes of acute myeloid leukemia (AML) mutations and it is expressed in approximately 30% of patients. There are two types of FLT3 mutations, Internal Tandem Duplication (ITD) in or near the juxtamembrane domain of the receptor and point mutations resulting in single amino acid substitutions occurring within the activation loop of the Tyrosine Kinase Domain (TKD).2 Patients with FLT3-ITD mutations present with a very large disease burden and have a worse prognosis than patients with wild-type FLT3 mutations and thus a key focus for therapy development.

The speaker first discussed the prognostic role of the mutant to wild-type (WT) allelic ratio (AR) and insertion sites in FLT3-ITD on outcomes of AML patients. Moreover, it is unclear whether AR can be used as a predictive marker for allogeneic hematopoietic stem cell transplantation (HSCT). Allelic ratio can be determined using polymerase chain reaction. However, it can be associated with PCR bias, the longer the mutant the less the enzyme can amplify and the speaker noted that the allelic ratio is influenced by how it is determined and this is not carried out worldwide.

In a study published in Blood in 2014 by Richard Schlenk and colleagues, it was found that high allelic ratio and ITD insertion site in TKD1 can predict for low complete remission (CR) rates and poor survival in FLT3-ITD-positive AML patients. Moreover, the performance of HSCT in first CR outweighs the negative impact of high allelic ratio on survival in this group of patients.3 Similarly, in a study by David C. Linch and colleagues published in blood in 2014, it was observed that relapse rates did not differ markedly according to FLT3-ITD levels. Additionally, the authors suggested that if consolidation therapies are to be determined by relapse risk, then patients low-level FLT3-ITD should not be considered as good risk.4

The speaker, Mark Levis, then described previously published retrospective studies which have demonstrated a beneficial role for allogeneic transplant for FLT3-ITD AML. Based on this, the speaker made the following recommendations. He suggested that PCR-based assay should be used to diagnose for FLT3-ITD. Furthermore, FLT3-ITD AR influences the prognosis of the patient but noted that these methodologies are not standardized and requires more data from clinical trials. He further suggested that where feasible, allogeneic transplant is preferred for FLT3-ITD AML.

The speaker discussed findings from the phase III randomized RATIFY study which demonstrated that addition of midostaurin to standard chemotherapy significantly prolongs the survival of younger adult patients with FLT3-mutated AML.5 Additionally, data from a sub-analysis of this phase III study, which was presented at the 2017 American Society of Hematology Meeting, demonstrated that maintenance therapy with midostaurin was well tolerated but its value could not be established in FLT3 mutated AML patients. At present, there are other on-going studies with highly specific and potent FLT3 inhibitors such as gilteritinb, which is investigating the benefit of FLT3 inhibitors for maintenance therapy in AML.  

The speaker concluded his talk by suggesting that caution should be exercised in the interpretation of ARs for FLT3-ITD AML. Additionally, “allogeneic transplant, when feasible, is still indicated for FLT3-ITD AML, regardless of AR”. At present, there is no evidence for maintenance therapy with any FLT3 inhibitor.

References
  1. Levis M. FLT3 inhibitors. ESH Clinical Updates in Acute Leukemias. May 4–6 2018, Budapest, Hungary.
  2. Schlenk. R. F. et al. Differential impact of allelic ratio and insertion site in FLT3-ITD-positive AML with respect to allogeneic transplantation. Blood. 2014 Nov 27; 124(23): 3441–9. DOI: 10.1182/blood-2014-05-578070. Epub 2014 Sep 30.
  3. Linch D. C. et al. Impact of FLT3(ITD) mutant allele level on relapse risk in intermediate-risk acute myeloid leukemia. Blood. 2014 Jul 10; 124(2):273–6. DOI: 10.1182/blood-2014-02-554667. Epub 2014 May 22.
  4. Stone R.M. et al. Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a FLT3 Mutation. N Engl J Med. 2017 Jun 23. DOI: 10.1056/NEJMoa1614359. [Epub ahead of print].
  5. Larson R. A. et al. An Analysis of Maintenance Therapy and Post-Midostaurin Outcomes in the International Prospective Randomized, Placebo-Controlled, Double-Blind Trial (CALGB 10603/RATIFY [Alliance]) for Newly Diagnosed Acute Myeloid Leukemia (AML) Patients with FLT3 Mutations. Oral Abstract #145: 59th ASH Annual Meeting and Exposition, Atlanta, GA.
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