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Targeting of FLT3 AML
Table 1. Important characteristics of FLT3 kinase inhibitor therapy in acute myeloid leukemia.
FLT3-ITD IC50 [nM] (MV4-11 cellular proliferation inhibition)20,21
Midostaurin (PKC-412) 12
Sorafenib 3.2
Crenolanib 2.1
Quizartinib 0.56
Gilteritinib (ASP2215) 0.92
Relevant off target activity22
Multikinase inhibitor (PKN1, TBK1, JAK3 etc.)
Approval(s) by FDA/EMA
First-line FLT3-mutated AML and ASM
Renal cancer
liver cancer None
None
r/r-FLT3-mutated AML
Current clinical development
Maintenance post HCT
Maintenance
post HCT
Maintenance
Maintenance
Efficacy (level 1 evidence)
OS benefit
PFS and OS
benefit n.a.
OS benefit
OS benefit
Multikinase inhibitor
(VEGFR, PDGFRβ, BRAF etc.) Selective TKI
(PDGFRa/β) Selective TKI
(KIT) Selective TKI
(AXL)
AXL: AXL receptor tyrosine kinase; ASM: aggressive systemic mastocytosis; EMA: European Medicines Agency; FDA: US Food and Drug Administration; n.a.: not available; OS: over- all survival; KIT (CD117): stem cell factor receptor; PFS: progression-free survival; r/r: relapsed / refractory; TKI: tyrosine kinase inhibitor; HCT: hematopoietic allogeneic stem cell transplantation.
a clinical benefit in vivo, especially in the monotherapy setting. For example, the first-generation FLT3 and multi- kinase inhibitor midostaurin failed to induce complete remissions (CR) or even partial remissions (PR) in relapsed or refractory (r/r)-FLT3-mutated AML.23,24 Likewise, lestaurtinib, another multitargeted FLT3 TKI, kills FLT3-ITD+ AML cells in vitro and reduces bone mar- row blasts in 5 out of 17 r/r-FLT3-ITD+ AML patients. However, PR or CR are not achieved with lestaurtinib as monotherapy.25,26 In elderly relapsed FLT3-mutated AML patients, lestaurtinib given after chemotherapy did not improve response rates or survival.27 In newly diagnosed younger AML with FLT3-activating mutations, lestaur- tinib given after first-line induction and consolidation chemotherapy failed to improve either relapse-free sur- vival (RFS) or overall survival (OS).28
Sorafenib is a multitargeted TKI that was originally developed as a B-RAF and multi-kinase inhibitor in renal/hepatocellular cancer. However, the compound also shows potent FLT3-ITD inhibitory activity. Intriguingly, in a phase I trial recruiting FLT3-ITD mutated r/r-AML patients,29 sorafenib monotherapy induced PR and CR. A case series later confirmed activity of sorafenib in r/r- FLT3-ITD and also in FLT3-wild-type AML.30-32 However, no randomized sorafenib monotherapy trial was ever launched in AML. Intriguingly, when sorafenib monotherapy was given to FLT3-ITD+ AML patients relapsing after HCT, some cases achieved durable remis- sions, suggesting a remarkable synergism between pro- apoptotic FLT3-kinase inhibition and anti-AML immunity through the allogeneic immune system.32,33
The Quantum-R and ADMIRAL trials were the first randomized, placebo-controlled trials to provide evidence that second-generation, FLT3-selective inhibitors (quizar- tinib and gilteritinib) improved OS (by 2 to 4 months) in r/r-FLT3-mutated AML.34,35
Although the potential for clinical efficacy of FLT3-TKI in AML has been clearly demonstrated, in the r/r-AML setting, responses to FLT3-inhibitor monotherapy are usually only temporary. Treatment-emergent FLT3-TKI resistance restricts efficacy regardless of the type of inhibitor used.17,25,32,35-41 To address this problem, and find synergistic therapeutic modalities, TKI were integrated into available first-line AML treatments. For example, in the SORMAL trial42 and the RATIFY study,43 FLT3-TKI
were combined with chemotherapy followed by a TKI maintenance phase with either sorafenib or midostaurin. In SORAML, sorafenib led to reduced rates of relapse, progression or death.42 In the double blind, randomized RATIFY study, the addition of midostaurin to convention- al induction/consolidation chemotherapy followed by 12 months of midostaurin maintenance improved OS in FLT3-mutated AML.43
FLT3-TKI maintenance outside the context of allogeneic hematopoietic stem cell transplantation
Although BCR-ABL and FLT3-ITD drive oncogene dependence, they fail to induce leukemic self-renewal,44,45 which explains why FLT3-ITD inhibition alone fails to eliminate leukemic stem cells. In several studies, FLT3- TKI were combined with intensive chemotherapy or hypomethylating agents (HMA).28,42,43,46-54 Three of these combination therapy trials (which were randomized and placebo-controlled: RATIFY,43 SORAML,42 and clinicaltri- als.gov identifier NCT0037337346) included a TKI mainte- nance therapy after first-line chemotherapy/TKI induc- tion and consolidation.42,43,46 In all three trials, TKI mainte- nance was discontinued once patients underwent HCT. A post hoc efficacy analysis of the midostaurin-maintenance phase in the RATIFY trial suggested that midostaurin maintenance might not further reduce the probability of relapse,43 even though RATIFY was not designed to test this.55 In the SORAML study, RFS curves further separat- ed over time, including during the maintenance phase of the trial.42 However, once again, the trial could not deter- mine to what extent the sorafenib maintenance phase in particular contributed to the improved RFS.
FLT3-TKI maintenance after allogeneic stem cell transplantation
With a probability of disease recurrence of 50% or over, AML relapse remains the most frequent type of treatment failure after HCT, especially in high-risk patients with FLT3-ITD+ AML.56,57 Prognosis of relapsed AML after HCT is generally poor due to a lack of effective treatments.
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