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Targeting of FLT3 AML
to an IDH inhibitor improves outcomes in this population is not yet known, and the question may be difficult to answer given the relative rarity of this circumstance.
Targeting non-canonical FLT3 mutations and wild-type FLT3
Trials of FLT3 inhibitors have been restricted to patients with ITD and D835 TKD mutations; however, there are a number of other less common FLT3-activating mutations. Table 2 provides an overview of non-canonical mutations of clinical significance. These mutations occur at sites within the extracellular domain, the JMD, the ATP bind- ing pocket of the TKD1, and the activation loop of the TKD2. They are often quite close to or within sites affect- ed by canonical mutations. For example, a series of acti- vating point-mutations and small insertions/deletions have been identified within exon 14 of the JMD between codons Y579 and F594, the same site in which ITD are frequently inserted. Mutations adjacent to D835 have also been identified, including point mutations affecting codons R834, I836, S840, N841 and Y842. Finally, a series of mutations within the TKD 1 have been documented in the setting of acquired resistance to FLT3 inhibitors. While each of these mutations are rare, the increased use of NGS is going to increase their detection and their col- lective prevalence may be significant. Many of these mutations impart sensitivity or resistance to FLT3 inhibitors, emphasizing the need for better recognition and familiarity with them.
There may also be a role for FLT3 inhibitors in the treat- ment of WT-FLT3 AML, especially in cases where FLT3 is overexpressed. In a mouse model of myeloproliferative disease (MPD) driven by wild-type FLT3, the administra- tion of quizartinib moderated the myeloproliferative phe- notype.80 This notion is further supported by the observa- tion that some patients with WT-FLT3 enrolled in the phase II studies of quizartinib and gilteritinib had clinical responses.64,81 The success of this strategy is likely to depend on the potency of the FLT3 inhibitor to WT FLT3 and its capacity to compete with endogenous FLT3 lig- and. A phase II study of chemotherapy plus quizartinib versus chemotherapy/placebo in patients with WT FLT3 is underway (clinicaltrials.gov identifier: NCT04107727).
Tailoring therapy to minimal residual disease
In addition to improving the rates of first remission and transplant, FLT3 inhibitors may have a role in reducing or eliminating mFLT3 minimal residual disease (MRD). The presence of MRD portends a poor prognosis in AML, and this has been demonstrated using a variety of markers and assays.82 MRD in the pre-transplant setting has also been shown to correlate with higher rates of post-trans- plant relapse. The incorporation of MRD testing into the clinical management of AML has lagged behind that of other leukemic diseases such as chronic myleoid leukemia and acute lymphoblastic leukemia due to the heterogeneous nature of AML. MRD assays have been developed in a piecemeal fashion for specific subsets of the disease, but even these have suffered from lack of standardization across laboratories, limiting their clinical utility. Nonetheless, progress has been made in the meas- urement of residual mFLT3.83-86 These assays have demon- strated prognostic relevance and are poised to assume a role as road markers to guide the effective use of FLT3 inhibitors and the management of mFLT3 AML more broadly.
The potential use of FLT3-ITD as a marker of residual disease is controversial because it can be non-detectable at relapse, or, alternatively, a previously undetected ITD mutation can emerge at relapse. However, a FLT3-ITD mutation is an appealing MRD marker for several rea- sons: first, FLT3 is almost always the final mutation in the leukemogenic sequence and therefore is associated almost exclusively with the leukemic clone and not a pre- leukemic clone. Second, each individual patient’s unique ITD sequence length serves as a longitudinal signature that reduces the likelihood of a false positive. Taken together, these indicate that the presence of residual FLT3-ITD of the same length as the initial FLT3-ITD mutation are indicative of residual leukemia. Third, the ability to target mFLT3 with FLT3 inhibitors and to meas- ure the response in mFLT3 allelic burden may make quan- titative FLT3 testing predictive, not just prognostic.63
With further prospective validation and standardiza- tion, FLT3-ITD MRD may be used to inform the decision to modulate our targeting of mFLT3. For example, given the higher rates of post-transplant relapse amongst patients with FLT3 MRD prior to transplant, clinicians might choose to deepen remissions with an additional cycle of treatment or by combining a FLT3 inhibitor with another agent prior to transplant. In MRD negative patients, surveillance for the re-emergence of FLT3-ITD MRD in the post-treatment or post-transplant setting may be used to guide the decision to re-initiate a FLT3 inhibitor to stave off clinical relapse. FLT3-ITD MRD may also serve as a valuable surrogate endpoint in trials testing new strategies to target mFLT3.
Post-transplant maintenance
The SORMAIN study is a landmark study in that it was the first to demonstrate a survival benefit to post-trans- plant maintenance with a FLT3 inhibitor. However, the rel- evance of this finding has depreciated with the rapid evo- lution of mFLT AML management. On one hand, the majority of patients enrolled in the study had no prior exposure to FLT3 inhibitors, and on the other, we now have far more potent FLT3 inhibitors. Therefore, the role of FLT3 inhibitors in the post-transplant setting remains uncertain and is actively being investigated. The largest of these studies is the international, phase III BMT-CTN 1506 (clinicaltrials.gov identifier: NCT02997202) study, which enrolled patients with mFLT3-ITD AML undergoing alloHSCT after first remission and randomized them to post-transplant maintenance with gilteritinib or placebo. The study has reached full accrual, and is now in follow up with preliminary results expected in 2021.
The importance of this study reflects the equipoise regarding the risks and benefits of FLT3 inhibitors in this setting. Second generation FLT3 inhibitors are well-toler- ated, but long-term FLT3 inhibition may not be risk free given their role in maintenance of healthy dendritic cell. Nonetheless, there are instances in which we advocate for the off-label use of FLT3 inhibitors in the post-trans- plant setting. These include patients with a high risk of post-transplant relapse such as those with high FLT3- ITD mutant allelic ratios and patients with FLT3-ITD MRD by flow or NGS prior to transplant. Our preference is to use gilteritinib in this setting because of its potency and tolerability compared to other FLT3 inhibitors in clinical use.
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