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Acute myeloid leukemia (AML) is a heterogeneous disease that manifests itself in morphology, immunology, cytogenetics, and molecular genetics, and even in the response to treatment and long-term prognosis
of AML patients.
FMS-associated tyrosine kinase 3 (FLT3) mutations are common at initial diagnosis in adults with AML, with mutation rates decreasing to 15% to 30%
with age.
About three-quarters of FLT3 mutations are internal tandem repeats (FLT3-ITD), and the remaining mutations are point mutations
that occur in the tyrosine kinase domain (FLT3-TKD).
Patients with AML with FLT3-ITD mutations have a worse
prognosis than FLT3-ITD mutations compared with FLT3 wild-type AML.
Patients with a high proportion of FLT3-ITD alleles (ARs) (AR≥0.
5) and no NPM1 mutations have a worse
prognosis.
Midostaurin is a first-generation type I multi-target kinase inhibitor with inhibitory activity
against both FLT3-ITD and FLT3-TKD mutations.
In a randomized Phase 3 pivotal CALGB 10603 (RATIFY) trial comparing placebo, patients aged 18 to 59 years with newly diagnosed AML with FLT3 mutation experienced significant improvements
in overall survival (OS) and event-free survival (EFS) after receiving midostaurin plus intensive chemotherapy sequential 1-year midostaurin maintenance therapy.
Based on this trial, Midostaurin has been approved
by the FDA and EMA.
As a result, a large single-arm Phase 2 clinical study, the AMLSG 16-10 trial (NCT01477606), was conducted to evaluate the efficacy and safety
of midostaurin in young and elderly AML patients with FLT3-ITD mutations newly diagnosed.
methods
Inclusion criteria for the AMLSG 16-10 trial: age 18 to 70 years; Newly diagnosed AML with FLT3-ITD mutation; Patients are able to receive intensive chemotherapy
.
Among them, the initial AML included new-onset AML, secondary AML secondary to myeloid tumors, and treatment-related AML, while acute promyelocytic leukemia and core binding factor (CBF) AML were not eligible
for inclusion.
The trial had two control groups, the first from five previous AMLSG trials, a historical control cohort of 415 AML patients aged 18 to 70 years who were newly diagnosed with FLT3-ITD mutations; The second control group came from 273 patients
in the placebo group of the RATIFY trial.
The primary endpoint of the AMLSG 16-10 trial was event-free survival (EFS), and the key secondary endpoint was overall survival (OS).
Results of the study results of the patient's baseline characteristics
From June 2012 to February 2018, the AMLSG 16-10 trial included a total of 451 patients, of which 440 were evaluable Data from 855 patients were used for the analysis of efficacy endpoints, including 440 in the AMLSG 16-10 trial and 415 in the AMLSG historical control
.
199 (45%) patients received allogeneic hematopoietic stem cell transplantation (allo-HSCT) after the first complete response/complete response (CR/CRi) with incomplete hematologic recovery, with 150 (48%) and 49 (38%)
in the young (18-59) and elderly (60-70) groups, respectively.
> most patients at the age of 55 years received a low-intensity conditioning regimen
.
Eighty-three patients received consolidation therapy
with high-dose cytarabine.
Of the 163 patients receiving maintenance therapy with midostaurin, 128 started after allo-HSCT and 35 after consolidation of cytarabine in large
doses.
The baseline characteristics of the patients are detailed in Table 1
.
Table 1.
Baseline characteristics of patients in the control group with AMLSG 16-10 and AMLSG history
The median follow-up time for the AMLSG 16-10 trial and the AMLSG historical control group was 40.
4 and 76.
3 months
, respectively.
The 2-year EFS rate and 2-year OS rate in the AMLSG 16-10 trial were 41% (95% CI, 0.
36-0.
46) and 55% (95% CI, 0.
50-0.
60), respectively, compared with 2-year EFS and 2-year OS rates in the AMLSG historical control group of 21% (95% CI, 0.
17-0.
25) and 38% (95% CI, 0.
33-0.
43),
respectively.
The specific EFS and OS results are shown in Table 2
.
Table 2.
Efficacy results of AMLSG 16-10 and AMLSG historical controls
In multivariate analysis, both young (18-59) and elderly (60-70) patients in the AMLSG 16-10 trial had a significant improvement in EFS (young, HR=0.
59, P<0.
001; older, HR=0.
42, P<0.
001; overall, HR=0.
55, P<0.
001)
compared with the AMLSG historical control 。 In the context of midostaurin therapy, NPM1 mutations were favorable prognostic factors (HR, 0.
48; P<0.
001), older age (10-year increase in HR, 1.
02; P<0.
001), and high WBC count (HR, 10-fold increase by 1.
21; P=0.
011) is a significant disadvantage; The trend towards event incidence was higher in patients with FLT3-ITD AR≥0.
5 (HR, 1.
21; P=0.
052).
In addition, there was a significant benefit in OS in the AMLSG 16-10 group compared with the historical control group (HR, 0.
56; P< 0.
001), and was equally significant
in younger and older patients.
The results of EFS and OS multivariate analysis are shown in Table 3
.
Table 3.
Results of multivariate analysis of the AMLSG16-10 trial and the AMLSG historical control group EFS and OS
In the sensitivity analysis of allo-HSCT as a time-dependent covariate, the efficacy of midostaurin was still significant
.
For safety outcomes, intensive chemotherapy in combination with midostaurin is also safe
in young adults and elderly patients.
Conclusions
The results of this trial provide important confirmatory data support for previous pivotal RATIFY studies, which also show that midostaurin also has good efficacy and good safety
in elderly patients with FLT3-ITD mutation AML 。 Although this trial significantly improves the efficacy of patients with FLT3-ITD mutation AML, only 50% of young and 30% of elderly patients still achieve long-term survival, so further elucidating of the mechanism of primary and secondary resistance in patients with FLT3-ITD mutation AML is needed in the future to bring better treatment options
for this patient population.
References:
Hartmut Do€hner, Daniela Weber, Julia Krzykalla, Walter Fiedler，et al.
Midostaurin plus intensive chemotherapy for younger and older patients with AML and FLT3 internal tandem duplications.
Blood Adv 2022; 6 (18): 5345–5355.
doi: https://doi.
org/10.
1182/bloodadvances.
2022007223.
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