Edited by: Lindsay Wilde, Sidney Kimmel Cancer Center, United States
Reviewed by: Alice Mims, The Ohio State University, United States
*Correspondence: Gina Keiffer,
This article was submitted to Hematologic Malignancies, a section of the journal Frontiers in Oncology
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In April 2017, following the results of the RATIFY trial (
With two FLT3 inhibitors now approved by the FDA—that is, the more selective gilteritinib and the less selective midostaurin—the question of which FLT3 inhibitor to use in combination with chemotherapy in the upfront setting has become the subject of much debate (
FLT3 is mutated in approximately 25–35% of patients with AML (
The European Leukemia Net (ELN) classifies the prognostic import of FLT3-ITD mutation status based on the presence of co-occurring mutation in nucleophosmin 1 (NPM1) and the FLT3-ITD allelic ratio (AR). The FLT3-ITD AR is determined using DNA fragment analysis as the ratio of the area under the curve “FLT3-ITD” divided by the area under the curve “FLT3-wild type”. A low AR (FLT3-ITDlow) is defined as <0.5 and a high AR (FLT3-ITDhigh) is defined as ≥0.5. Patients with FLT3-ITD mutation are characterized as favorable risk if they are FLT3-ITDlow and have a co-occurring NPM1 mutation. Patients with FLT3-ITD mutation are characterized as intermediate risk if they are FLT3-ITDlow and are NPM1 wild type (without other high-risk genetic lesions) or if they are FLT3-ITDhigh and have a co-occurring NPM1 mutation. Patients with FLT3-ITD mutation are characterized as adverse risk if they are FLT3-ITDhigh and are NPM1 wild type (
FLT3 inhibitors are classified both by selectivity of RTK binding (multikinase inhibitors vs. selective FLT3 inhibitors) and by site of binding FLT3 (type I vs. type II inhibitors). First generation FLT3 inhibitors, such as sorafenib, sunitinib and midostaurin, are unselective and bind multiple type III RTKs [e.g., platelet derived growth factors alpha and beta, stem cell factor receptor (KIT) and colony stimulating factor 1 receptor] and are therefore referred to as multikinase inhibitors. Second generation inhibitors, such as quizartinib, crenolanib and gilteritinib, are more selective and bind FLT3 only or a small number of additional RTKs (
Type I inhibitors bind FLT3 at the ATP-binding site in either the active or inactive conformation and therefore have activity in both ITD- and TKD-mutated patients. Type II inhibitors, conversely, bind the hydrophobic region adjacent to the ATP-binding site which is only accessible in the inactive conformation, thereby preventing FLT3 activation. TKD mutations, most notably D835 mutations, cause the FLT3 receptor to favor the active conformation thereby precluding binding of type II inhibitors (
Summary of classification of FLT3 Inhibitors.
Multikinase Inhibitors | Selective FLT3 Inhibitors | |
---|---|---|
MidostaurinLestauritinib**Sunitinib** | CrenolanibGilteritinib | |
SorafenibPonatinib | Quizartinib |
**No longer under clinical investigation for treatment of FLTmut+ AML.
Two FLT3 inhibitors have been approved for the treatment of FLT3-mutated AML: midostaurin and gilteritinib. Based on the results of the RATIFY trial, midostaurin was approved in combination with cytotoxic chemotherapy for the upfront treatment of FLTmut+ AML (
The promising nature of these results prompted us to raise the question of whether upfront combination treatment with a multikinase inhibitor, such as midostaurin, or a selective FLT3 inhibitor, such as gilteritinib, is a more logical approach. While it may be argued that this debate is premature, particularly since a clinical trial is currently ongoing to address this exact question (NCT03836209) (
The RATIFY trial (
Seven hundred and seventeen patients with a median age of 47.9 years were randomized to midostaurin + chemotherapy (n=360) vs. placebo + chemotherapy (n=357). The types of FLT3 mutations were equally distributed between the placebo and midostaurin groups (overall, 47.6% ITDlow, 29.8% ITDhigh, 22.6% TKD). Despite very similar complete response (CR) rates between the midostaurin (58.9%) and placebo (53.5%) groups, the median OS in the midostaurin group was 74.7 months vs. 25.6 months with placebo, and 4-year OS was 51.4 vs. 44.2%, respectively. The authors noted that the large difference in median OS was likely due to the tail of the survival curves for midostaurin + chemotherapy vs. placebo + chemotherapy falling just above and just below the 50% mark, respectively, and that a hazard ratio (HR) of 0.78 (95% CI 0.66–0.93) was more reflective of the clinical benefit of the addition of midostaurin to standard combination chemotherapy. Secondary endpoints of event free survival (EFS) and disease free survival (DFS) also favored the midostaurin group (8.2 months vs. 3.0 months and 26.7 months vs. 15.5 months, respectively).
The type of FLT3 mutation did not clearly impact overall survival [HR 0.65 FLT3-TKD (CI 0.39 – 1.08) vs. 0.81 FLT3-ITDlow (CI 0.6–1.11) vs. 0.80 FLT3-ITDhigh (CI 0.57–1.12)] but when analyzed for EFS, the benefit of midostaurin was primarily seen in the TKD group.
Adverse effects were as expected for patients receiving induction and consolidation chemotherapy. Rates of anemia and rash were higher in the midostaurin group. More patients in the placebo group experienced nausea.
These data clearly support the addition of midostaurin to standard induction and consolidation therapy in FLTmut+ AML. No other FLT3 inhibitor has shown this degree of benefit in a phase III randomized clinical trial. The benefit of midostaurin on overall survival was seen across mutation type. Thus, the answer of which FLT3 inhibitor to use in the upfront setting is simple: midostaurin.
Beyond the support for upfront use of midostaurin observed in the RATIFY trial, it has been suggested (
As the authors of RATIFY note, the observed benefit of midostaurin in FLT3-ITDlow patients, where mutations other than FLT3 may function as drivers, may be due to the multitarget effects of midostaurin
The rates of CR in the midostaurin and placebo groups were equivalent. Despite this, patients who received midostaurin experienced improved EFS, DFS and OS. Although, the survival curves overlap completely until approximately 9 months. This suggests that the benefit of midostuarin is not that it caused more remissions than placebo, but it caused deeper remissions. Furthermore, while FLT3 mutation type did not seem to impact response to midostaurin in terms of OS, the EFS benefit was primarily seen in the FLT3-TKD patients, indicating that the benefit in FLT3-TKD may overestimate the benefit in FLT3-ITD patients. Whether FLT3-ITD patients also benefit from midostuarin is not clearly demonstrated in RATIFY.
Additionally, the authors of RATIFY argue that the benefit of midostaurin persisted when accounting for patients undergoing allo-SCT. While there was a trend toward increased 4-year overall survival in patients who received midostaurin and underwent transplant in 1st CR (CR1) vs. those who received placebo and underwent transplant in CR1, this was not a statistically significant (63.7 vs. 55.7%, p=0.08). In fact, the benefit of midostaurin in transplanted patients was more influenced by timing of transplant. Those patients who received midostaurin and underwent transplant outside of CR1 had a median OS equal to those who received placebo and underwent transplant outside of CR1 (14.8 months vs. 14.4 months). More patients in the midostaurin group underwent transplant in CR1 (28%) than in the placebo group (23%). Thus, the observed benefit of midostaurin may be explained by the fact patients in the midostaurin group underwent transplant earlier.
Trials evaluating selective FLT3 inhibitors crenolanib, quizartinib, and gilteritinib in combination with traditional cytotoxic chemotherapy in the upfront setting have shown promising results. In June, 2019, updated results from a phase I/II study evaluating gilteritinib combined with 7 + 3 and consolidation treatment were presented at the annual meeting of the European Hematology Association (EHA) (
High CR rates have also been observed with 7 + 3 combined with crenolanib (72%) (
During analysis of the ADMIRAL trial, samples from patients who relapsed on gilteritinib were evaluated with next generation sequencing (NGS) for new mutations acquired at relapse (
The next most common mutations occurring in 6 patients (15%) were mutations in FLT3 itself with the majority (5/6) being FLT3 F691L, or the so called “gatekeeper mutations.” In an
Midostaurin remains the only FLT3 inhibitor FDA approved for the upfront treatment of FLT3 mutated AML. The data for use of newer, more selective inhibitors in treatment-naïve patients is rapidly evolving, and soon we may be forced to choose between several FLT3 inhibitors without randomized data directly comparing their clinical efficacy. Here, we have discussed the merits of these two approaches and the data to support them. At our institution, we are currently using midostaurin in addition to 7 + 3 for upfront management of FLT3-ITD AML. We look forward to the release of the final phase II date with gilteritinib in this setting. Further investigation is needed to determine the optimal sequencing of therapies for these complex patients.
GK and KLA wrote and edited the manuscript. NDP reviewed and edited the manuscript. All authors contributed to the article and approved the submitted version.
The authors confirm that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
The handling editor is currently organizing a Research Topic with one of the authors NDP.