Skip to Content


FLT3 Positive at Relapse

Leukemia Insights - Summer 2011

FLT3 plays a role in the regulation of survival and proliferation of hematopoietic progenitor cells, in particular by synergy with other RTKs and cytokine receptors. Two major types of FLT3 mutations have been identified in up to 30% of AML patients. The most common class of mutations found in approximately 15% to 25% of AML patients, with a higher frequency in the elderly, is internal tandem duplications (ITD) in the juxtamembrane (JM) domain. The second-class of mutation, present in approximately 7% of patients, are point mutations of residue 835 in the activation loop of FLT3 that also result in ligand-independent, constitutive kinase activation. The prognosis of patients with FLT3-ITD mutations is significantly worse than that for patients with wild type FLT3 when treated with standard therapy.

The following studies are currently open for salvage treatment in patients with AML who are FLT3 positive at relapse:

  1. Ph II AC220 (1st salvage Age ≥ 60)
  2. Ph I/II Sorafenib and 5-Azacitidine
  3. Ph I/II PKC412 and AZA
  4. Ph I G-CSF & Plerixafor + Sorafenib
  5. Ida + Ara-C with Vorinostat (SAHA) (Ages 15-65)
  6. Ph I/II Vidaza + Revlimid

AC220 (Cortes J, Blood, 2009, 114, Abstract 636), Sorafenib (Borthakur G, Haematologica, 2011, 96, 62-68) and PKC412 (Fischer T, J Clin Oncol., 2010, 28, 4339-45) are inhibitors of FLT3 internal tandem duplication (ITD) signaling and have single agent activity in AML with FLT3-ITD mutation.

AC220 is a novel second-generation Class III RTK inhibitor with potent and highly efficacious FLT3 activity in vitro and in vivo. Interim results from the phase I dose-escalation study CP0001 showed that AC220 was well tolerated in the 76 treated patients. The overall response (complete remission [CR] + partial remission [PR]) observed in all AC220-treated patients was 30%. Consistent with the proposed mechanism of action of AC220, the response in the FLT3-ITD positive population was the highest, with an overall response rate of 56%; however, evidence of clinical activity was also observed in FLT3-ITD negative patients, with 20% of patients responding (Cortes J, Blood, 2009, 114, Abstract 636).

Sorafenib (Nexavar) is an oral, small molecule multikinase inhibitor of several other targets including vascular endothelial growth factor receptor-2 (VEGFR-2), VEGFR-3, and platelet-derived growth factor receptor-beta (PDGFR-β). In vitro studies conducted at MD Anderson Cancer Center demonstrated that sorafenib is a potent inhibitor of FLT3 kinase (Zhang W, J Natl Cancer Institute, 2008, 100, 184-98). In a phase I dose-escalation study conducted at M D Anderson 50 patients were enrolled. Complete remissions or complete remissions with incomplete recovery of platelets (CRp) were achieved in 10% of the patients (all with fms-like tyrosine kinase 3-internal tandem duplication) (Borthakur G, Haematologica, 2011, 96, 62-8). 

Azacitidine (AZA), an analog of the pyrimidine nucleoside cytidine, has effects on cell differentiation, gene expression, and deoxyribonucleic acid (DNA) synthesis and metabolism. Results of clinical investigations demonstrated activity of azacitidine in the treatment of AML. A randomized open label, phase III trial compared the efficacy of Azacitidine to Conventional Care Regimens (CCR). Azacitidine demonstrated statistically superior overall survival compared to CCR, with a median overall survival of 24.4 months vs. 15 months for CCR (p=0.0001). Two-year survival approximately doubled in the azacitidine arm compared to CCR: 51% vs. 26% (Fenaux P, Lancet Oncol, 2009, 10, 223-232). 

Plerixafor disrupts the interaction between SDF/CXCR4, a homing mechanism for leukemia cells to survive in the bone marrow microenvironment, and thus expected to sensitize AML cells to the effects of chemotherapy (Burger J, Leukemia, 2009, 23, 43-52). This was the rationale for combining Plerixafor with Sorafenib in patients with relapsed AML. It is thought that G-CSF will further potentiate the activity of Plerixafor by promoting differentiation of latent Leukemic stem cells (LSC’s) to progenitor cells which are more susceptible to chemotherapy.

Analysis of our experience with the combination of Ida + Ara-C with Vorinostat, a histone deacetylase 3 inhibitor, showed that the subgroup of patients with AML and FLT3-ITD mutation appears to benefit from this combination. We have reported results from a phase II trial of Vorinostat, Idarubicin and Cytarabine in Previously Untreated Acute Myelogenous Leukemia (AML) or High Risk Myelodysplastic Syndrome (MDS). A total of 75 patients were enrolled with response rate as follows: CR 57 (76%), CRp 7 (10%) for an overall response (ORR) of 86%. Of note, patients with FLT3 ITD had a CR of 91% and CRp of 9% for an ORR of 100%. This was in contrast to an ORR of 85% for the wt FLT3 group (p=0.2) (Garcia-Manero G, Blood (ASH Annual Meeting Abstracts), 2010, 116, 604) and (Garcia-Manero G, Blood, 2008, 111, 1060-6). 

A recent study of Azacitidine in MDS has shown a better outcome for those patients treated with Azacitidine compared with those receiving supportive care. Lenalidomide is indicated for the treatment of patients with transfusion-dependent anemia due to low- or Intermediate-1-risk MDS associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities. Patients age >60 years with AML that refuse standard therapy but willing to receive lower intensity programs will be considered for the study combining Vidaza and Revlimid (Garcia-Manero G, Am. J. Hematol., 2011, 86, 490-8).

© 2015 The University of Texas MD Anderson Cancer Center