The combination continues to enroll. The addition of sorafenib significantly improved the event-free survival (EFS; 21 months vs 9 months; P=0.013) and RFS (56% vs 38%), but not OS28, although a recent update suggested an emerging trend toward improved OS29. Relapse-free survival (RFS) was calculated from the date of achieving CR/CRi until the date of relapse (death without relapse or relapse were consideredevents)8. FLT3-ITD is a constitutively activated variant of the FLT3 tyrosine kinase receptor. Gilteritinib or chemotherapy for relapsed or refractory FLT3-mutated AML. The median OS was 1.0years [CI not calculable (NC)], 2.3years (CI: 1.23.5), 1.6years (CI: 0.62.6) and 1.0years (CI: 0.81.2), respectively (P=0.9). All samples investigated in this study were obtained at the time of diagnosis. Schneider F, Hoster E, Schneider S, Dufour A, Benthaus T, Kakadia PM, et al. Lymphoma 59 2273 2286, S Schnittger 2002 Analysis of FLT3 length mutations in 1003 patients with acute myeloid leukemia: Correlation to cytogenetics, FAB subtype, and prognosis in the AMLCG study and usefulness as a marker for the detection of minimal residual disease Blood 100 59 66, M Levis 2013 FLT3 mutations in acute myeloid leukemia: what is the best approach in 2013? Furthermore, ten patients with mutated WT1 showed a median ITD length of 77bp,and 58 patients with non-mutated WT1 showed a median ITD length of 42bp (P=0.021). FMS-like tyrosine kinase 3 (FLT3) is one of the most frequently mutated genes in acute myeloid leukemia and is associated with worse clinical outcome. The main patient and disease characteristics were collected retrospectively, including demographic characteristics (age, sex), cytomorphologic assessments confirming the AML diagnosis (according to routine site practice), cytogenetics, molecular studies, first-line treatment approach, disease response assessment and disease follow-up. Efficacy and Safety of Venetoclax in Combination with Gilteritinib for Relapsed/refractory FLT3-mutated Acute Myeloid Leukemia in the Expansion Cohort of a Phase 1b Study (ASH, 2020). Low relapse rate in younger patients 60 years old with newly diagnosed FLT3-mutated acute myeloid leukemia (AML) treated with crenolanib and cytarabine/anthracycline chemotherapy. Am. Information regarding the ITD insertion site and mutational status of another 38 genes recurrently mutated in myeloid neoplasms was available in 106 and 118 patients, respectively. The median age of this group was 55.1years (range 17.185.3years); 76 males and 85 females. Prognostication refinement in NPM1-mutated acute myeloid leukemia stratified by FLT3-ITD status with different induction doses of cytarabine. Google Scholar. Blood Cancer Discov. Oncol. contracts here. Venetoclax Added to Cladribine, Idarubicin, and Cytarabine with or without a FLT3 Inhibitor in Newly Diagnosed Acute Myeloid Leukemia (EHA, 2020). Cortes, J. et al. J. Clinl. After post-remission therapy with either consolidation (high-dose cytarabine-based) or allogeneic stem cell transplant (ASCT), AR 0.51 and FLT3-ITD insertion site in TKD1 were associated with an unfavorable RFS (P=0.0008) and OS (P=0.004)15. Quizartinib, a second-generation, type I FLT3i is active against FLT3, KIT, CSF1R, PDGFR, and RET kinase34. Encouragingly, the response rate was maintained among patients previously exposed to other FLT3 TKIs. Tallman, M. S. et al. S1. Naval Daver. We further compared the survival of patients with FLT3-ITD and those with FLT3-D835 mutation in the Positive/Positive and Negative/Positive groups (Figure 3). Nevertheless, we also performed an analysis with the median ITD length of our cohort (48bp). CAS Google Scholar. Ann Hematol. Updated results from long-term follow-up of the randomized-controlled SORAML trial. We studied theFLT3-ITD length of 362 adult AML patients included in the PETHEMA AML registry. It should be noted that MDS-MLD and -EB-1 patients with low and intermediate risk in IPSS-R were included in FLT3-ITD mutation group, and showed poor prognosis. Libura, M. et al. PubMed In a single-arm phase II trial of quizartinib (90 or 135mg), the CRc rates were between 46 and 56% in ~250 R/R FLT3-ITDmut patients treated across two cohorts. Multivariate analysis showed that age < 65 years, FLT3-ITD and CEBPA bZIP in-frame mutation were independent prognostic factors. 21, 12011212 (2020). In patients with relapsed or refractory FLT3mut AML (Fig. FLT3-ITD has been strongly associated with a bad prognosis, leukocytosis, high blast counts, increased risk of relapse and shorter overall survival. These data highlight the potent anti-leukemic activity of the triplet approach in FLT3mut AML. In the frontline setting, there was a sequential decrease in CRc rates (77%31%25%) and OS (16.76.01.4 months). J. Hematol. Although poor prognosis in AML is only associated with FLT3-ITD, all activating FLT3 mutations can contribute to leukemogenesis and are thus potential targets for therapeutic interventions. FLT3-ITD length was compared between mutation and wild-type groups for each of the 39 genes using a MannWhitney test. More recently, the emergence of BCR-ABL1-positive clone was shown as a resistance mechanism to multiple FLT3is72. However, in addition to QTcF prolongation, quizartinib is also more myelosuppressive than many other FLT3 inhibitors likely due to the inhibition of KIT. Provided by the Springer Nature SharedIt content-sharing initiative. We analyzed 118 patients (median age at diagnosis 58.3, range 14.3&ndash . and JM.A. Clinical outcome stratified according to the FLT3-ITD length (cutoff 39bp) for all patients treated with intensive chemotherapy. A phase 1 study of gilteritinib in combination with induction and consolidation chemotherapy in patients with newly diagnosed AML: final results. Maiti et al. This model of initiatory and progression mutation as FLT3 is well described 37, 38. We stop the venetoclax and the FLT3i after Day 14 in patients who achieve marrow remission (<5% blasts) and/or marrow aplasia/hypoplasia/insufficiency (<5% cellularity). 2, 125 (2020). 2B). Wang, E. S. et al. We administer a second-generation FLT3i (ideally gilteritinib) continuously with HMA from cycle 1 Day 1. Among 16 patients with newly diagnosed FLT3mut AML not eligible for intensive induction, the CRc rate was 88% with FLT3-PCR negativity in 100% of responders and a projected 2-year OS of >80%. Type I FLT3is are active against both the FLT3-ITD or TKD, type II inhibitors are only active against FLT3-ITD, not TKD. It's the most common genetic change in acute myeloid leukemia (AML), a type of leukemia that starts in the bone marrow and. Seventeen patients underwent autologous hematopoietic progenitor transplantation, and forty-four patients underwent allogeneic hematopoietic progenitor transplantation (Table 1). The CRc rate was 67% (n=10/15) in the combination arm in the safety cohort prior to commencement of randomization45. Higher daunorubicin exposure benefits FLT3 mutated acute myeloid leukemia. Oncol. Larger studies of ITD size, although they did not employ these cutoffs, did not find prognostic power of this measure, which corroborates our results. In order to improve the clinical condition of FLT3-ITD-positive patients, several FLT3 inhibitors have been developed showing variable results. is a PhD candidate at Universidad Autnoma de Madrid (UAM). Get the most important science stories of the day, free in your inbox. Blood 134, 2564 (2019). A stratified analysis of FLT3-ITD length on the basis of the AR was performed in 140 patients (AR<0.5 and ITD<70bp, n=43; AR<0.5 and ITD70bp, n=15; AR>0.5 and ITD<70bp, n=61; AR>0.5 and ITD70bp, n=21). Therefore, there is a lack of consensus regarding the prognostic importance of the ITD IS and the subdomains that confer this adverse outcome. More studies will be necessary to confirm these results and to shed light on the possible physiopathologic relationship. In subsequent cycles: FLT3i is continued for the entire duration of the cycle and the venetoclax duration is reduced to 14 days or lower to mitigate cumulative prolonged cytopenias. Although poor prognosis in AML is only associated with FLT3-ITD, all activating FLT3 mutations can contribute to leukemogenesis and are thus potential targets for therapeutic interventions. Oran, B. et al. Daver, N. et al. FLT3 plays a role in cell survival, proliferation and differentiation of hematopoietic progenitor cells. 13, 139 (2020). 1,2 Real-time pCR, which has . PubMed In patients 55 years, this regimen appeared to overcome the negative impact of FLT3-ITDmut in NPM1 co-mutated patients, regardless of the FLT3 AR, with comparable 3-year OS rates of 64% and 68% in FLT3-ITDmut NPM1mut and FLT3-ITDWT NPM1mut patients, respectively (P>0.05). All four patients with ITD insertions in TKD1 had mutations in DNTM3A, compared with 39 out of 96 patients (41%) with ITD insertions in the JMD domain (P=0.031). To test the prognostic significance of the ITD length and its clinical applicability, we used recurrent previously published cutoffs, which were analyzed in series ranging from 28 to 100 intensively treated patients. The FLT3-ITD allelic ratio has clear prognostic value. (A) Overall survival. Swaminathan, M. et al. Tamaoki, T. et al. In the treatment-naive setting, the median time to neutrophil and platelet recovery among responders was 45 and 30 days, respectively, suggesting cumulative myelosuppression is to be expected and further optimization of triplets schedules is ongoing55. Interestingly, all patients with an FLT3-ITD inserted in the TKD1 domain showed DNMT3A mutations. 61, 72337239 (2001). Unfortunately, in our study, information on the site of insertion was not available in the whole cohort, and few patients harbored a TKD1 insertion.We did not carry out a statistical analysis of the insertion site given the heterogeneity in the treatment of patients analyzed and the small number of patients with an ITD inserted in the TKD1 domain. evaluated quizartinib (60mg daily) combined with either azacitidine or low-dose cytarabine in patients with newly diagnosed or R/R FLT3mut AML not eligible for intensive chemotherapy. Cancer 125, 37553766 (2019). Google Scholar. Complete response (CR) or complete responses with incomplete hematologic recovery (CRi) were defined according to current 2017 ELN guidelines8. Gale, R. E. et al. The FLT3-ITD AR was available in 140 intensively treated patients. Mead, A. J. et al. Anyone you share the following link with will be able to read this content: Sorry, a shareable link is not currently available for this article. Approximately 30% of patients with newly diagnosed acute myeloid leukemia (AML) harbor mutations in the fms-like tyrosine kinase 3 (FLT3) gene. Blood 124, 273276 (2014). The on-target mechanism of resistance includes emergence of secondary TKD mutations in patients treated with type II inhibitors like quizartinib or sorafenib69,70. . Variant allele frequency (VAF) is the ratio of ITD-mutated alleles to ITD-mutated+wild-type alleles (FLT3ITD/FLT3ITD+FLT3 wild-type)14. ISSN 2045-2322 (online). Kadia, T. et al. PubMed Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukaemia. Cortes, J. E. et al. Perl, A. E. et al. S2) in PETHEMA centralized diagnostic laboratories as previously described33. Provided by the Springer Nature SharedIt content-sharing initiative, Current Hematologic Malignancy Reports (2022), Current Treatment Options in Oncology (2022), Blood Cancer Journal (Blood Cancer J.) 4), diligent effort must be made to refer the patient to large academic centers with clinical trial options as the outcomes remain dismal with a median OS<10 months with almost any approach. Moreover, we performed an analysis of the correlation of FLT3-ITD length and insertion sites with the mutational landscape of AML, which has not been carried out thus far. Strati, P. et al. An alternate option would be to consider sequencing with alternate cycles of HMA with venetoclax and HMA with FLT3i. Netw. We introduce venetoclax with a ramp-up when the WBC is <10,000/L to decrease the risk of tumor lysis syndrome. We currently recommend the incorporation of FLT3is and ASCT in CR1 in all ASCT eligible patients with a FLT3-ITDmut AML, irrespective of the AR and/or NPM1 co-mutation status. N. Engl. However, in a recently released planned interim analysis, the study did not meet its primary endpoint of overall survival and may be terminated for futility46. Lancet Oncol. Among the FLT3mut patients, response rates were numerically higher (33%) and remission duration was longer (31 versus 16 weeks, P=0.09) in those who were naive to treatment with FLT3 inhibitors compared with those who had been exposed to prior FLT3 inhibitors. Type I FLT3is like gilteritinib are less prone to develop secondary mutations in the TKD, although the gatekeeper F691M can confer resistance to gilteritinib71. We retrospectively reviewed 3555 acute myeloid leukemia patients, who have been assessed for FLT3 mutation at our institution . These data suggests that although responses may still be achieved with gilteritinib in patients refractory to prior first-generation FLT3i-based therapies, optimization with doublet or triplet combinations with second-generation FLT3i is likely needed to significantly improve OS with prior TKI exposure. 10 1 10, K Dhner 2020 Impact of NPM1/FLT3-ITD genotypes defined by the 2017 European LeukemiaNet in patients with acute myeloid leukemia Blood 135 371 380, C Thiede 2002 Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: Association with FAB subtypes and identification of subgroups with poor prognosis Blood 99 4326 4335, KM Murphy 2003 Detection of FLT3 Internal tandem duplication and D835 mutations by a multiplex polymerase chain reaction and capillary electrophoresis assay J. Mol. FLT3 tyrosine kinase domain mutations are biologically distinct from and have a significantly more favorable prognosis than FLT3 internal tandem duplications in patients with acute myeloid leukemia.