Azacitidine and venetoclax in previously untreated acute myeloid leukemia. Patients were classified into four therapeutic groups according to the first-line approach: intensive chemotherapy (IC), n=161; non-intensive therapy, n=43; clinical trial, n=15; and best supportive care (BSC) only, n=7. A total of 164 patients diagnosed with AML-NPM1 included in 2 consecutive CETLAM protocols and with DNMT3A and FLT3 status available were studied. In the last 25years, advances in molecular techniques have allowed a greater understanding of the pathogenesis of AML and the subsequent development of targeted therapies and a more refined prognostic classification based on the genetic features of the disease2,3. Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukaemia. Studies have reported that a higher mutant allelic burden is associated with a worse prognosis. Sorafenib is a first generation, type II multi-kinase FLT3i26 that demonstrated safety and efficacy (14/15 CR) in combination with the standard anthracycline/cytarabine induction therapy in newly diagnosed FLT3mut AML27. Phase 1 study of quizartinib in combination with induction and consolidation chemotherapy in patients with newly diagnosed acute myeloid leukemia. Cancer 125, 37553766 (2019). or. Informed consent was a requisite for patients alive at the time of data lock (January 2019). Get the most important science stories of the day, free in your inbox. (C) OS according to the FLT3-ITD length and allelic ratio. We found that patients with FLT3-ITD had a poor prognosis at any age, while patients with CEBPA biallelic mutation were younger and had a better prognosis. 1,2 Real-time pCR, which has . J. Med. Among patients treated with gilteritinib, the median overall survival was similar among those with FLT3 ITD mutations alone (9.3 months) and those with FLT3 TKD mutations alone (8.0 months). Oncol. NGS, next-generation sequencing. Biochem. Quizartinib, an FLT3 inhibitor, as monotherapy in patients with relapsed or refractory acute myeloid leukaemia: an open-label, multicentre, single-arm, phase 2 trial. Gilteritinib was generally well tolerated but was associated with increased incidence of gastrointestinal side effects, most frequently diarrhea although nausea has been occasionally observed. Google Scholar. has nothing to disclose. Midostaurin is a type I FLT3i active against PDGFR, KIT, SRC, and other RTKs22,23. Blood 125, 32363245 (2015). Hematol. FLT3 -ITD mutations occur in the form of a replicated sequence in the juxtamembrane domain (JMD) and/or TKD1 of the FLT3 gene. Acute myeloid leukemia (AML) patients with FLT3/ITD mutations have a poor prognosis. Astellas Reports XOSPATA (gilteritinib) in combination with azacitidine did not meet endpoint of overall survival in newly diagnosed flt3 mutation-positive acute myeloid leukemia patients ineligible for intensive induction chemotherapy (2020). Perl, A. E. et al. In patients with relapsed or refractory FLT3mut AML (Fig. J. Haematol. Molecular clearance of FLT3 was noted in 50% of all evaluable patients. 113, 983988 (2001). Interestingly, their prognostic effect had a strong dependence on age: FLT3 ITD indicated poor survival in younger patients (<60 years; P = .00003), but had no effect in older patients (60-74 years; P = .5), whereas NPM1 mut indicated better survival in older patients ( P = .00002), but not in younger patients ( P = .95). As more potent FLT3 inhibitors are developed, additional acquired point mutations have been identified, commonly at . Mali, R. S. et al. The median RFS was 1.2years (CI: 02.4) and 0.9years (CI: 0.617.1), respectively (P=0.3). which included NPM1 mut /FLT3-ITD high AR cases. and P.M; Writingoriginal draft, T.C. Br. and P.M.; Validation, T.C., J.M.A., E.B. Prognostic impact of FLT3-ITD, NPM1 mutation and CEBPA bZIP domain Lancet Oncol. Souki Cancer Research Fund and generous philanthropic contributions to the MD Anderson Moon Shots Program. de Sonsoles de vila-Complejo Asistencial vila, vila, Spain, Hematology Department, Hospital General de Albacete, Albacete, Spain, Hematology Department, Hospital Universitario de Gran Canaria Doctor Negrn, Las Palmas de Gran Canaria, Spain, Carlos Rodrguez-Medina&Cristina Bilbao-Syeiro, Hematology Department, Hospital General Ciudad de Jan, Jan, Spain, UGC de Hematologia, Hospital U. Reina Sofia, IMIBIC, UCO, Cordoba, Crdoba, Spain, Josefina Serrano&Joaqun Snchez-Garca, Hematology Department, Hospital Comarcal del Bierzo, Len, Spain, Hematology Department, Hospital Universitario Doctor Peset, Valencia, Spain, Hematology Department, Hospital Clnico Universitario Lozano Blesa, Zaragoza, Spain, Hematology Department, Complejo Hospitalario de Navarra, Navarra, Spain, You can also search for this author in Our treatment approach for FLT3mut AML in MD Anderson Cancer Center is as follows: in newly diagnosed patients who are eligible to receive intensive chemotherapy (Fig. Blood 100, 23932398 (2002). Citation 56 The new FLT3 inhibitors, G-749 and ASP2215, have been proved to cause strong inhibition of FLT3 phosphorylation and increase the ability to overcome drug resistance in preclinical trials, but further studies are needed to evaluate their . FLT3-ITD and NPM1 mutations were correlated, and the favorable prognostic impact of being FLT3-ITD negative and NPM1 mutation positive was evident only in patients aged 65 years or more. In order to improve the clinical condition of FLT3-ITD-positive patients, several FLT3 inhibitors have been developed showing variable results. Regarding ITD length, some authors have found that patients with shorter ITD lengths have more favorable outcomes11,12 or worse prognoses13, while other researchers did not find a prognostic relationship14. Regarding the ITD insertion site, Kayseret al22,23 observed that adult AML patients with an ITD in the beta-1 sheet had significantly inferior OS and DFS compared to those with ITDs located in other regions. Sign up for the Nature Briefing newsletter what matters in science, free to your inbox daily. 16, 16911699 (2015). 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. 120.000 new AML cases and over . 368, 20592074 (2013). 21, 12011212 (2020). 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. Juan M. Alonso-Dominguez. FLT3 -ITD has a poor prognostic impact in patients with AML at diagnosis. 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). To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. has received research funding from Astellas, and Novartis and has served as a member of advisory board in Astellas and Novartis. 93, E202E205 (2018). For post-ASCT maintenance, our agent of choice has been gilteritinib 80120mg day either as a single agent or combined with low-dose azacitidine. Minetto, P. et al. . None of the studies has carried out an internal ITD length cutoff validation by dividing the patients into a training cohort and a validation cohort, which, given the arbitrary selection of the cutoffs used, would be necessary. The length of the 362 ITDs ranged from 3 to 201bp, with a median ITD length of 48bp.The distribution of ITD length can be observed in Supplementary Fig. Among those with NPM1 wild-type, all FLT3-ITDmut patients had an increased risk of relapse and inferior OS, regardless of the AR17. Type I FLT3is are active against both the FLT3-ITD or TKD, type II inhibitors are only active against FLT3-ITD, not TKD. J. Clinl. The BSC group included 7 patients receiving transfusions and other supportive measures. Gale, R. E. et al. Abhishek Maiti, M. D. et al. PubMed Article Expression and signal transduction of the FLT3 tyrosine kinase receptor. Schlenk et al. Prognostic implication of FLT3 and N-RAS gene mutations in acute myeloid leukemia. PubMed 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.) "For patients with AML, the 5-year survival rate is only about 29%," said Dr. Erba. Am. Although the presence of FLT3-ITD, as well as levels of the FLT3-ITD allelic ratio, have been described as prognostic factors in acute myeloid leukemia (AML), little is known about how the FLT3-ITD allelic ratio impacts patients&rsquo; outcomes when receiving an allogeneic hematopoietic stem cell transplantation (HSCT). 61, 72337239 (2001). Monotherapy with selective FLT3 tyrosine kinase inhibitors (TKIs) have shown transient and limited efficacy due to the development of resistance. FLT3 mutated acute myeloid leukemia: 2021 treatment algorithm volume11, Articlenumber:104 (2021) Google Scholar. Collectively, NPM1mut even with FLT3-ITDmut AR <0.5 are likely higher risk than truly favorable risk AML and we continue to consider them for ASCT in CR1. Two classes of activating FLT3 mutations occur in AML: (1) internal tandem duplication ( FLT3 -ITD) which occur in 20-25% of patients and (2) tyrosine kinase domain mutations ( FLT3 -TKD) which are seen in 5-10% of patients [48]. Therefore, these patients were not included in the analysis stratified by 2010 ELN genetic risk21. TM,transmembrane domain; JMD, juxtamembrane domain; JMD-B, binding motif; JMD-S, switch motif; JMD-Z, zipper motif; HR, hinge region; TKD1, tyrosine kinase domain 1; B1, beta1-sheet; NBL, nucleotide binding loop; B2, beta2-sheet; and TKD2, tyrosine kinase domain 2. 13 95 100. and P.M. To obtain Higher daunorubicin exposure benefits FLT3 mutated acute myeloid leukemia. Use the Previous and Next buttons to navigate the slides or the slide controller buttons at the end to navigate through each slide. J. Hematol. PDF FLT3-ITD Expression as a Potential Biomarker for the Assessment of In patients with FLT3mut AML unsuitable for intensive chemotherapy, azacitidine with venetoclax demonstrated encouraging CR/CRi rates (5570%) and a median OS of 13.3 months64 which prompted the inclusion of this combination approach as part of NCCN AML guidelines (Fig. Password. Statistical analyses were performed with SPSS 19.0 (IBM, Armonk, NY). ISSN 2045-2322 (online). 6,, - 9 In normal bone marrow, FLT3 expression is is a PhD candidate at Universidad Autnoma de Madrid (UAM). The addition of sorafenib to standard AML treatment results in a substantial reduction in relapse risk and improved survival. In the meantime, to ensure continued support, we are displaying the site without styles Intriguingly, this was the first large study to show that the FLT3i may also benefit FLT3 wild-type patients, perhaps through multi-kinase blockade or prevention of emergent FLT3 clones at relapse28. 13, 132 (2020). AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML). Studies of FLT3 mutations in paired presentation and relapse samples from patients with acute myeloid leukemia: implications for the role of FLT3 mutations in leukemogenesis, minimal residual disease detection, and possible therapy with FLT3 inhibitors. Perl, A. E. et al. ITD amplicons with a size greater than that of the wild type (3281 bases) were interpreted as positive for the FLT3-ITD mutation. The NPM1/FLT3-ITD patients had normal karyotypes. Blood 132, 3944 (2018). Enter the email address you signed up with and we'll email you a reset link. Blood 124, 34413449 (2014). An analysis of OS censoring at the time of allo-HSCT did not yield significant results (data not shown). 135, 397402 (1986). Brinton, L. T. et al. Intensive fludarabine, high dose cytarabine and idarubicin-based induction for younger NPM1-mutated AML patient: overcoming the negative prognosis of FLT3-ITD mutation. Prognostic significance of activating FLT3 mutations in younger adults (16 to 60 years) with acute myeloid leukemia and normal cytogenetics: a study of the AML Study Group Ulm. Konopleva, M. et al. We studied theFLT3-ITD length of 362 adult AML patients included in the PETHEMA AML registry. recently showed that ASCT in CR1 improved RFS and OS independent of the FLT3-ITDmut AR or NPM1mut status in patients with FLT3-ITDmut AML20. Cortes, J. E. et al. Fig. J. Hematol. Patients treated with midostaurin had higher rates of anemia and skin rash compared to placebo and these were generally manageable with supportive care without necessitating dose reductions or interruptions in the majority of cases. Although activity was seen, the response rates were overall modest with this combination and the combination of HMA with midostaurin is not one that we routinely use or recommend for frontline FLT3-mutated AML47. Minetto and colleagues retrospectively evaluated the efficacy of fludarabine, high-dose cytarabine, and idarubicin (FAI) in 149 newly diagnosed FLT3-ITDmut and/or NPM1mut AML (only FLT3-ITDmut=29; FLT3-ITDmut NPM1mut=59, only NPM1mut=61). 2, 125 (2020). A phase 1 study of gilteritinib in combination with induction and consolidation chemotherapy in patients with newly diagnosed AML: final results. Jarno Kivioja, Disha Malani, Caroline A. Heckman, Iman Abou Dalle, Ahmad Ghorab, Gautam Borthakur, Frank G. Rcker, Ling Du, Konstanze Dhner, Feng-Ming Tien, Cheng-Hong Tsai, Hwei-Fang Tien, Kun-yin Qiu, Xiong-yu Liao, Dun-hua Zhou, Nikolaus Jahn, Ekaterina Jahn, Konstanze Dhner, Scientific Reports Res. Mutations of the fms-tyrosine kinase ( FLT3) were first described in 1997 4 and account for the most frequent molecular mutations in AML. Blood 136, 3233 (2020). Synergistic effect of BCL2 and FLT3 co-inhibition in acute myeloid leukemia. Rosnet, O. et al. The CRc rate was 67% (n=10/15) in the combination arm in the safety cohort prior to commencement of randomization45. Sorafenib maintenance after allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia with FLT3internal tandem duplication mutation (SORMAIN). 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. All eligible intermediate or high-risk patients (defined as patients with FLT3-ITDmut AR>0.50 irrespective of NPM1mut status, or FLT3-ITDmut AR<0.50 without NPM1mut) are equivocally recommended to proceed to ASCT in CR1 followed by post-ASCT FLT3i maintenance for at least 2 years (although we often continue indefinite FLT3i maintenance until long-term maintenance data becomes available). PubMed DiNardo, C. D. et al. Seventeen patients underwent autologous hematopoietic progenitor transplantation, and forty-four patients underwent allogeneic hematopoietic progenitor transplantation (Table 1). Among 362 patients, NGS was performed in 118 patients using a panel of 39 genes. Clonal selection with RAS pathway activation mediates secondary clinical resistance to selective FLT3 inhibition in acute myeloid leukemia. Yilmaz, M. et al. Tallman, M. S. et al. Nakao, M. et al. The first-generation FLT3is lack specificity for FLT3 and inhibit multiple downstream RTKs that may result in more off-target toxicities. Among patients treated with azacitidine and quizartinib in the frontline setting, the CRc rate was 78% (n=7/9) with a median OS of 21.1 months. E17 mutations affect prognosis in CBF AML, as well as response to GO and TKIs; thus, clinical trials using both agents should be considered for KIT+ . FLT3 -ITD is located within exon 14, corresponding to JMD,. FLT3-TKD activating mutations also constitutively activate FLT311; however, they have not been associated with a consistent prognostic impact12. FLT3 is a gene change, or mutation, in leukemia (blood cancer) cells. Oran et al. Sorafenib maintenance in patients with FLT3-ITD acute myeloid leukaemia undergoing allogeneic haematopoietic stem-cell transplantation: an open-label, multicentre, randomised phase 3 trial. The number, area and length of mutant peaks on capillary electrophoresis were analyzed using GeneMapper analysis software (Applied Biosystems, Foster City, CA). Pratcorona, M. et al. Prognostic impact of low allelic ratio FLT3- ITD and NPM1 mutation in acute myeloid leukemia Prognostic impact of low allelic ratio FLT3- ITD and NPM1 mutation in acute myeloid leukemia Blood Adv. An analysis of OS censoring at the time of allo-HSCT did not yield significant results (data not shown).A stratified analysis of FLT3-ITD length on the basis ofthe AR was performed in 140 patients (AR<0.5 and ITD<39bp, n=17; AR<0.5 and ITD39bp, n=41; AR>0.5 and ITD<39bp, n=23; AR>0.5 and ITD39bp, n=59). In our cohort, FLT3-ITD was located in the JMD domain (JMD-B, JMD-S, JMD-Z and HR) in 98 patients and in the TKD1 domain (B1, NBL and B2) in four patients. Welch John, S. et al. 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. 100, 184198 (2008). PubMedGoogle Scholar. This is in line with the preclinical data49 and molecular profiling of pre- and post-treatment samples66 identifying FLT3-ITDmut as a putative mechanism of resistance to venetoclax based therapies67, suggesting that FLT3-ITDmut patients may need a FLT3i incorporated into the HMA with venetoclax therapy either in a triplet or sequential approach to improve OS. The current European Leukemia Net (ELN) guidelines categorize FLT3 -ITDmut AML as favorable (NPM1mut with FLT3 wild-type Or NPM1mut with FLT3-ITD AR<0.5), intermediate (NPM1mut with FLT3-ITD AR>0.5 Or NPM1WT with FLT3-ITD AR<0.5), or adverse (NPM1WT with FLT3-ITD AR>0.5)18. Prognostic impact analyses of FLT3-ITD length were performed among patients treated with upfront IC regimens. Sorafenib combined with 5-azacytidine in older patients with untreated FLT3-ITD mutated acute myeloid leukemia. and P.M.; Visualization, T.C., J.M.A., D.L., J.S. FLT3-ITD mutations occur in the form of a replicated sequence in the juxtamembrane domain (JMD) and/or TKD1 of the FLT3 gene. Tamaoki, T. et al. The insertion site was analyzed in 106 AML patients with the FLT3-ITD mutation. Prognostic analyses were performed using the 70bp cutoff in 161 AML patients with FLT3-ITD mutations treated with IC (<70bp; n=119,70bp; n=42). Google Scholar. As consolidation therapy, one hundred patients received high-intensity treatment (3+7, n=68; 3+7+gemtuzumab ozogamicin (GO), n=4; 2+5=2; IDA-FLAG, n=1; high-dose cytarabine (HDARAC), n=23; low-dose cytarabine (LDARAC), n=1; and Ara-C 100mg/m25, n=1). Accumulating evidence have shown improved outcomes in FLT3-ITDmut patients receiving induction with higher dose anthracyclines57, cladribine58, or fludarabine added to induction backbone21, and incorporating FLT3i with induction (either first or second generation) in FLT3mut AML24,44,59,60 (Fig. Taken together, utilizing baseline FLT3-ITDmut AR to guide the post-remission therapy remains controversial. These observations have made FLT3 an attractive drug target. Pulmonary infiltration and acute pneumonitis-like picture are rare (<1%) but noted side effects of midostaurin that treating physicians should be aware of. For . To obtain Ann Hematol. Oran, B. et al. Prevalence of FLT3, NPM1 and CEBPA Mutations and Correlation to QTc prolongation >500ms emerged as a significant adverse event36. Internal tandem duplication (ITD) of the fms-related tyrosine kinase-3 gene ( FLT3) confer a poor prognosis in adult AML. Weisberg, E. et al. Fms-like tyrosine kinase 3 (FLT3) is a recurrent genetic abnormality in AML (~30%)1,2,3. CR or CRi was achieved in 70% of the patients in both groups (P=0.9). Favorable relapse risk and OS were seen in NPM1mut with FLT3 wild-type; intermediate prognosis in FLT3-ITDmut with concurrent NPM1mut, and adverse prognosis in FLT3-ITDmut with NPM1 wild-type patients16. PubMed Central and P.M.; Methodology, T.C., J.M.A., E.B., R.R.V., C.S., C.G., M.C.C., M.B.V., R.G., J.M.L., R.M.A., M.J.L., E.A., R.C., A.C., E.C., E.S.S., J.L., I.R., L.A., C.R.M., C.B.S., J.A.L.L., J.S., E.C., M.J.S., M.T.O., J.S.G., M.M., C.B., J.L.L.L., D.L., J.S., D.M.C., M.A.S. 90, 276281 (2015). Inhibition of mutant FLT3 receptors in leukemia cells by the small molecule tyrosine kinase inhibitor PKC412. Increase in bilirubin and transaminase can be seen with giltertiinib but are usually self-resolving and transient. 17 D2 D8, H-S Kim S Lee JH Kim 2018 Real-world evidence versus randomized controlled trial: Clinical research based on electronic medical records J Korean Med Sci 33 e213, RF Schlenk 2014 Differential impact of allelic ratio and insertion site in FLT3-ITD-positive AML with respect to allogeneic transplantation Blood 124 3441 3449, I Abou Dalle 2020 Impact of numerical variation, allele burden, mutation length and co-occurring mutations on the efficacy of tyrosine kinase inhibitors in newly diagnosed FLT3- mutant acute myeloid leukemia Blood Cancer J. The median age of this group was 55.1years (range 17.185.3years); 76 males and 85 females. While the adverse prognostic impact of FLT3-ITDmut in AML has been clearly proven, the prognostic significance of FLT3-TKDmut remains speculative. When comparing both subgroups using a log-rank test, there was a clear trend toward a reduced OS in FLT3-ITDHIGH patients (P=0.052). It is important to acknowledge the diverse mechanisms of FLT3i resistance after different FLT3is, and it is essential to proactively evaluate for these mechanisms at the time of FLT3i failure to optimize subsequent therapy. Xuan, L. et al. As Dr. Erba explained, patients with FLT3 -ITD-positive AML represent a particularly poor prognostic group. Precision Medicine in Myeloid Malignancies: Hype or Hope? AR is defined as the ratio of ITD-mutated alleles to wild-type allele (FLT3ITD/FLT3 wild-type)13. Midostaurin has been approved and widely used in combination with induction and consolidation therapy in patients with newly diagnosed FLT3mut AML25. In the frontline setting (n=4), the CRc rate with the triplet was 100% with FLT3-PCR negativity in all four patients56. J. Hematol. Resistance Mutations Present an Ongoing Challenge in Aggressive contracts here. The phase III RATIFY study (CALGB 10603), for example, looked at the addition of the tyrosine kinase inhibitor midostaurin to intensive chemotherapy in newly-diagnosed AML with FLT3 mutations (either ITD or TKD) and showed an overall survival (OS) benefit with midostaurin compared to placebo (74.7 vs. 25.6 months, respectively) . Age-dependent frequencies of NPM1 mutations and FLT3-ITD in patients with normal karyotype AML (NK-AML). Despite the current availability of the FLT3 inhibitor midostaurin, there is an unmet need for improved treatment options. Andrew, H. et al. FLT3 mutations occur in more than 30% of patients with acute myeloid leukemia (AML) and are associated with short relapse-free and overall survival, including internal tandem duplication (ITD) and point mutations within the tyrosine kinase domain (TKD) [1, 2].To date, multiple FLT3 kinase inhibitors have been developed and some are approved for clinical use including sorafenib, Quizartinib . Elderly patients with AML have a distinct genetic landscape compared with the younger population. (4) Only five patients in our cohort received treatment with midostaurin (2 in induction and 3 in consolidation treatment); therefore, we were not able to draw conclusions regarding the prognostic impact of the length of the ITD as described in previous studies29,30. (3) Findings regarding the relationship between ITD length/site and mutational profile might be interpreted as exploratory given the high number of correlations performed. We identified 1572 adult (age 18 year) patients with NPM1-mutated AML in first complete remission (CR1:78%) or . A comparable decrease in CRc rates (45%21%10%) and OS (7.94.04.1 months) was observed with sequential FLT3i-based therapies in the R/R AML setting73. and P.M.; Resources, T.C., J.M.A., E.B., R.R.V., C.S., C.G., M.C.C., M.B.V., R.G., J.M.L., R.M.A., M.J.L., E.A., R.C., A.C., E.C., E.S.S., J.L., I.R., L.A., C.R.M., C.B.S., J.A.L.L., J.S., E.C., M.J.S., M.T.O., J.S.G., M.M., C.B., J.L.L.L., D.M.C., M.A.S.

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