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During an oral abstract session at the Virtual Edition of the 25th European Hematology Association (EHA) Annual Congress, Frank G. Rücker presented on the molecular landscape and prognostic impact of the FLT3-internal tandem duplication (ITD) insertion site in acute myeloid leukemia (AML),1 from an exploratory analysis of the phase III RATIFY trial (NCT00651261).
FLT3-ITD mutations are present in approximately 25% of adult patients with newly diagnosed AML and are associated with a worse prognosis, especially for patients with a high mutant to wild-type allelic ratio or those with insertions in the β1-sheet of tyrosine kinase domain 1 (TKD1). Other studies have previously shown that FLT3-ITDs in the non-juxtamembrane domain (JMD) confer resistance to a number of FLT3 inhibitors, including midostaurin, a multi-targeted protein kinase inhibitor.1
The AML Hub has previously reported on the results of the RATIFY study, which led to the approval of midostaurin for patients with FLT3-mutated AML by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) in 2017. Briefly, the results of this study show a significant improvement in the 4-year overall survival (OS) with midostaurin plus intensive chemotherapy compared with intensive chemotherapy alone (51% vs 44%, respectively). The aims of this analysis were to assess the number and structure of FLT3-ITDs in patients enrolled in the study and evaluate the prognostic impact of these insertion sites for the response to midostaurin treatment.
Table 1. Next-generation sequencing results1
bp, base pair; cAR, calculated allelic ratio; ITD, internal tandem duplication; NGS, next-generation sequencing; VAF, variant allele frequency |
|
NGS result |
Median (range) |
---|---|
Coverage |
3,119 (482–11,616) |
Counts |
96 (2–5,234) |
VAF, % |
3.32 (0.03–89.49) |
Length, bp |
45 (6–246) |
cAR/ITD |
0.04 (0.0003–8.51) |
cAR/patient |
0.27 (0.0006–10.75) |
Figure 1. Distribution of FLT3-ITD duplications1
A The number of ITDs per patient. B The location of the ITDs.
aa, amino acid; FLT3, Fms-like tyrosine kinase 3; ITD, internal tandem duplication; JM, juxtamembrane; JMD, juxtamembrane domain; TKD1, tyrosine kinase domain 1
Table 2. Correlation of FLT3-ITD insertion site with clinical characteristics and NPM1 mutation status1
BM, bone marrow; JMD, juxtamembrane domain; NPM1, nucleophosmin 1; TKD1, tyrosine kinase domain 1; WBC, white blood cells |
||||
Characteristic |
JMD only (n = 251) |
TKD1 only (n = 117) |
JMD and TKD1 (n = 84) |
p value |
---|---|---|---|---|
Median age, years |
48.3 |
46.3 |
48.1 |
0.171 |
Male, % |
40.1 |
54.8 |
48.7 |
0.067 |
Median WBC, × 109/L (range) |
40.1 (0.8–329.8) |
53.9 (1.2–144.8) |
39.9 (0.9–205.4) |
0.254 |
Median BM blasts, % |
79.5 |
80.0 |
76.0 |
0.489 |
NPM1 mutation status, % |
63.1 |
47.9 |
50.0 |
0.029 |
Impact of insertion site on outcome:
Table 3. Multivariable analysis for overall survival and cumulative incidence of relapse1
cAR, calculated allelic ratio; CR1, first complete remission; FLT3, Fms like tyrosine kinase 3; HSCT, hematopoietic stem cell transplantation; HR, hazard ratio; ITD, internal tandem duplication; JMD, juxtamembrane domain; NPM1, nucleophosmin 1; TKD1, tyrosine kinase domain 1; WBC, white blood cells |
||||
Variable |
Overall survival (n = 358) |
Cumulative incidence of relapse (n = 252) |
||
---|---|---|---|---|
|
HR (95% CI) |
p value |
HR (95% CI) |
p value |
TKD1 only (vs JMD only) |
1.61 (1.10–2.35) |
0.014 |
2.20 (1.36–3.56) |
0.001 |
TKD1 only (vs JMD/TKD1) |
2.09 (1.24–3.52) |
0.005 |
1.28 (0.78–2.09) |
0.329 |
JMD only (vs JMD/TKD1) |
1.30 (0.83–2.05) |
0.254 |
0.58 (0.38–0.88) |
0.010 |
Midostaurin treatment |
0.76 (0.57–1.01) |
0.057 |
0.76 (0.53–1.09) |
0.135 |
FLT3-ITD cAR (log2) |
1.07 (0.99–1.15) |
0.104 |
1.15 (1.04–1.28) |
0.008 |
No. of ITDs |
1.11 (0.80–1.54) |
0.530 |
1.06 (0.90–1.26) |
0.463 |
WBC (log2) |
1.03 (0.58–1.81) |
0.930 |
1.06 (0.50–2.22) |
0.879 |
Age |
1.02 (1.00–1.03) |
0.033 |
1.00 (0.98–1.02) |
0.976 |
NPM1 mutation |
0.57 (0.42–0.78) |
<0.001 |
0.73 (0.50–1.07) |
0.105 |
HSCT in CR1 |
0.38 (0.24–0.58) |
<0.001 |
0.47 (0.29–0.74) |
0.001 |
The number and location of ITDs as well as NPM1 mutations were predictive of outcome. NPM1 mutations and HSCT in CR1 were associated with improved outcome. ITDs in TKD1 only were unfavorable for OS and cumulative incidence of relapse. Patients with ITDs in TKD1 only had significantly inferior outcomes compared with those with ITDs in JMD-only or both domains. Patients with ITDs in JMD only benefited significantly from midostaurin treatment, whereas no benefit was seen in those with ITDs in TKD1 only, which confirms findings from earlier preclinical studies. However, it is important to note that there was a smaller number of patients in the TKD1-only group.
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