Treatment of FLT-3-mutated AML

FMS- like Tyrosine Kinase 3 (FLT3) is a receptor tyrosine kinase that promotes proliferation and survival upon binding to its ligand FLT3 Ligand (FL). FLT3 - mutated Acute Myeloid Leukemia (AML) is a common form of AML which poses challenges to treating physicians. In particular, the FLT3 with the Internal Tandem Duplication (FLT3-ITD) mutation which is associated with poor survival outcomes and high relapse rates. In most cases of AML, FLT3 is expressed majorly on blasts.

In an article Blood published in January 2017, Keith W. Pratz and Mark Levis from the Sidney Kimmel Comprehensive Cancer Center, John Hopkins University, Baltimore, discussed the management of four patient cases and the emergence of novel treatment options, with respect to Tyrosine Kinase Inhibitors (TKI).

Patient diagnosed with monocytic AML

• 48-year old female patient with monocytic AML, White Blood Cell Count (WBC) was 66,000; predominantly blasts
• NPM1 Wild Type (WT) and FLT3-ITD at 27bp mutation
• Patient was treated with conventional induction chemotherapy and consolidation therapy using HiDAc
• Relapse occurred and WBC count increased to 120, 000; mostly blasts
• Mutant to WT FLT3-ITD allelic ratio was 6.46:1
• Patient was relapsed/refractory to salvage therapy containing carboplatin and topotecan
• Complete Remission (CR) with incomplete count recovery (CRi) was achieved upon administration of quizartinib (Tyrosine Kinase inhibitor [TKI])
• After Allogeneic Hematopoietic Cell Transplant (allo-HCT), patient was enrolled onto protocol (NCT01578109) and received sorafenib post- transplant maintenance therapy
• Patient is alive as of August 2016, 5 years after diagnosis

Patient diagnosed with AML

• 46-year old man with WBC count of 400,000; mostly blasts
• NPM1 and FLT3-ITD mutation migrating 363bp
• Conventional induction chemotherapy was administered
• Normal peripheral blood count recovered but 1% residual AML was detected in his bone marrow
• CR was achieved after admission of HiDAC, but relapsed afterwards
• Patient was refractory to decitabine and inhibitor of exportin 1
• The allelic FLT3-ITD mutant to WT ratio was 25:1
• Stabilization achieved after administration of ASP2215 ( a FLT3 inhibitor [TKI])
• After allo-HCT, patient was put on sorafenib (off-label, non-protocol) maintenance
• Patient is in remission, 2.5 years after diagnosis

In these case studies, both patients were relapsed/refractory to standard conventional chemotherapy and in both cases disease stabilization was achieved using TKIs, thus allowing allo-HCT to be performed. However, this approach has not been approved by regulatory bodies and hence the off-label use of sorafenib.

Newly diagnosed AML patient

• 60-year old man with WBC count of 82000 with 62% blasts
• NPM1 mutation and 2 distinct FLT3-ITD mutations at 342bp and 366bp
• Mutant to WT FLT3-ITD allelic ratio at 342bp and 366bp were 0.1:1 and 1.24:1 respectively
• Patient received idarubicin and cytarabine under the protocol (NCT01802333) after which CR was achieved
• Patient was on peri-transplant maintenance using sorafenib under the protocol (NCT01578109 ) and then underwent allo-HCT
• After allo-HCT, patient was put on sorafenib maintenance
• Patient is alive and in CR, 15 months after diagnosis

Newly diagnosed AML patient

• a 68-year old woman with WBC of 178,000; 85% were monoblasts
• NPM1 mutation and FLT3-ITD mutations at 351 bp with a mutant to WT ratio of 0.59:1
• Patient was treated with conventional induction and achieved CR
• Patient was treated with HiDAc while awaiting transplantation
• Patient underwent an allogenic transplant under protocol NCT01597778
• After Allogeneic Hematopoietic Cell Transplant (allo-HCT), patient was put on sorafenib maintenance
• Patient is alive and in remission 2-years after diagnosis

The authors noted that, although in these case studies they reported, treatment of FLT3-ITD mutated patients were successful. However, they highlighted that the overall survival of FLT3-ITD AML patients is still very poor. 

In summary, the authors stated their recommendations for newly diagnosed and relapsed/refractory FLT3-mutated AML patients. For treatment of FLT3-ITD AML mutated patients, they recommend that these patients, should be initially treated with conventional cytarabine-based chemotherapy. After recovery of normal blood cell count and achievement of CR, the patient should be put in a preparative regimen for allo-HCT and transplant should occur as soon as possible. However, in cases, where a donor is not readily available, the patent should be administered HiDAc before transplant. After transplant, patients should be administered sorafenib maintenance. For patients who relapsed and were refractory to induction therapy, the authors recommend the enrolment of these group of patients in a TKI- based salvage therapy if available, if not a combination of sorafenib and azacitidine.

Conversely, the authors hope that the in the near future treatment of newly diagnosed FLT3-ITD-mutated AML would consist of the administration of midostaurin, a TKI, in combination with induction therapy and then proceeding with allo-HCT and post-transplant maintenance with selective agents (Figure 1).

The authors suggested that the benefit of FLT3 inhibition needs to be achieved in a randomized prospective study.

Figure 1: Proposed treatment for FLT3- mutated AML.

Abstract

FLT3-mutated acute myeloid leukemia (AML), despite not being recognized as a distinct entity in the World Health Organization (WHO) classification system, is readily recognized as a particular challenge by clinical specialists who treat acute leukemia. This is especially true with regards to the patients harboring the most common type of FLT3 mutation, the internal tandem duplication (FLT3-ITD) mutation. Here we present 4 patient cases from our institution and discuss how our management reflects what we have learned about this subtype of the disease. We also reflect on how we anticipate the management might change in the near future, with the emergence of clinically useful tyrosine kinase inhibitors.