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. The data described in the literature alongside the results that we have obtained regarding ITD mutation lead us to believe that future studies should focus on the functional characterization of the protein products of the mutated genes. J. Hematol. Blood 110, 12621270 (2007). 1B) we add a second generation FLT3i to the intensive induction backbone of cladribine or fludarabine with cytarabine and idarubicin (CLIA or FIA, respectively) as published previously by our group61,62. Get the most important science stories of the day, free in your inbox. J. Hematol. Pratz, K. W. et al. Overall survival (OS) was calculated from the date of the diagnosis of AML until death in all included patients. Cancer 125, 37553766 (2019). We introduce venetoclax with a ramp-up when the WBC is <10,000/L to decrease the risk of tumor lysis syndrome. Am. Request PDF | Prognostic impact of FLT3-ITD, NPM1 mutation and CEBPA bZIP domain mutation in cytogenetically normal acute myeloid leukemia: a Hokkaido Leukemia Net study | Mutation status of FLT3 . To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. 2018 Oct 23;2 (20):2744-2754. doi: 10.1182/bloodadvances.2018020305. 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 Google Scholar. Close Log In. The FMS-like tyrosine (FLT3) gene encodes a class III receptor tyrosine kinase, sharing structural and sequence homologies with family members, including c-kit, c-FMS, FLT1, and PDGF- R. FLT3 plays a key role in the control of hematopoiesis. Google Scholar. Quizartinib demonstrated an OS of 6.2 months compared with 4.7 months with salvage chemotherapy (hazard ratio 0.76 and P=0.02). Midostaurin is a type I FLT3i active against PDGFR, KIT, SRC, and other RTKs22,23. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Whitman, S. P. et al. Sorafenib combined with 5-azacytidine in older patients with untreated FLT3-ITD mutated acute myeloid leukemia. Nevertheless, there are numerous manuscripts with contradictory results regarding the prognostic relevance of the length and insertion site (IS) of the FLT3-ITD fragment. Jain, P. et al. 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). In the frontline setting (n=4), the CRc rate with the triplet was 100% with FLT3-PCR negativity in all four patients56. 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. (B) Relapse-free survival. Conceptualization, T.C., J.M.A., E.B. 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. In acute myeloid leukemia (AML) internal tandem duplications of the FLT3 gene ( FLT3- ITD) are associated with poor prognosis. Some studies showed a reduced CR rate, while others analyzing the IS in the same region found differences in OS. recently presented the first triplet combination of venetoclax, FLT3i (mainly gilteritinib or sorafenib), and decitabine from the FLT3mut subset of the prospective decitabine 10 days with venetoclax study (NCT03404193)54. Commun. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. For post-ASCT maintenance, our agent of choice has been gilteritinib 80120mg day either as a single agent or combined with low-dose azacitidine. Sci Rep 11, 20745 (2021). 93, 11361141 (2018). The median OS was 1.3years (CI: 0.71.9) and 1.4years (CI: 0.91.9), respectively (P=0.9). In order to improve the clinical condition of FLT3-ITD-positive patients, several FLT3 inhibitors have been developed showing variable results. 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. We evaluate these patients on a case by case basis and may consider maintenance with 45 consolidation cycles of CLIA or FAI with FLT3i followed by FLT3i+/HMA maintenance for two years vs ASCT based on donor availability, age, performance status, MRD negativity, and patient preference. Swaminathan et al. Mutations of the fms-tyrosine kinase ( FLT3) were first described in 1997 4 and account for the most frequent molecular mutations in AML. 19, 889903 (2018). (D) OS according to the FLT3-ITD length and 2010 ELN genetic risk. The choice of treatment backbone depends on the patients ability to successfully tolerate intensive chemotherapy. Cortes, J. et al. has received research funding from Astellas, and Novartis and has served as a member of advisory board in Astellas and Novartis. Only four out of 106 patients had ITD IS in the TKD1 domain. An alternate option would be to consider sequencing with alternate cycles of HMA with venetoclax and HMA with FLT3i. Blood Cancer Discov. Yilmaz, M. et al. In our case, 15 AML prognostic genes including FLT3/ITD gene were all negative. and P.M.; Project administration, J.M.A. The insertion site was analyzed in 106 AML patients with the FLT3-ITD mutation. Authors Cortes, J. E. et al. FLT3-ITD allelic ratio and HLF expression predict FLT3 inhibitor efficacy in adult AML, 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, Molecular landscape and prognostic impact of FLT3-ITD insertion site in acute myeloid leukemia: RATIFY study results, Distinct clinico-biological features in AML patients with low allelic ratio FLT3-ITD: role of allogeneic stem cell transplantation in first remission, Poor outcome of pediatric patients with acute myeloid leukemia harboring high FLT3/ITD allelic ratios, Mutational spectrum and prognostic stratification of intermediate-risk acute myeloid leukemia, Genomic landscape of patients with FLT3-mutated acute myeloid leukemia (AML) treated within the CALGB 10603/RATIFY trial, Impact of FLT3-ITD allele ratio and ITD length on therapeutic outcome in cytogenetically normal AML patients without NPM1 mutation, Mutational spectrum and prognosis in NRAS-mutated acute myeloid leukemia, https://doi.org/10.3324/haematol.2020.263806, http://creativecommons.org/licenses/by/4.0/. Strati et al. Acute myeloid leukemia (AML) patients with FLT3/ITD mutations have a poor prognosis. Clinical outcomes in patients with relapsed/refractory acute myeloid leukemia treated with gilteritinib who received prior midostaurin or sorafenib. For CEBPA, 86.7% of the patients with biallelic mutation and 9.1% of patients with the single allele mutation had in-frame mutations in the bZIP domain, which were strongly associated with a favorable prognosis. FLT3-TKD activating mutations also constitutively activate FLT311; however, they have not been associated with a consistent prognostic impact12. J. Med. The median OS was 2.4years (CI 05.5), 1.7years (CI: 04.4), 1.3years (CI 0.62.0), 1.5years (CI: 0.22.7), 0.9years (CI NC) and 2.3years (CI: 04.8), respectively. The origin and evolution of mutations in acute myeloid leukemia. PubMed and P.M. Fms-like tyrosine kinase 3 (FLT3) is a recurrent genetic abnormality in AML (~30%)1,2,3. Pulmonary infiltration and acute pneumonitis-like picture are rare (<1%) but noted side effects of midostaurin that treating physicians should be aware of. 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. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. Larger studies of ITD size, although they did not employ these cutoffs, did not find prognostic power of this measure, which corroborates our results. volume11, Articlenumber:20745 (2021) Current guidelines recommend rapid molecular testing for FLT3mut at diagnosis and earlier incorporation of targeted agents to achieve deeper remissions and early consideration for allogeneic stem cell transplant (ASCT). 6,, - 9 In normal bone marrow, FLT3 expression is Rosnet, O. et al. Am. Similarly, the median ITD length in three patients with EZH2mutations was 26bp vs 48bp in the wild-type group (n=65) (P=0.031). Blood 128, 449452 (2016). PubMed Central J. Med. 381, 17281740 (2019). 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). 3). 15, 17 In our cohort, the prevalence of FLT3-ITD mutation of de novo AML patients was 21.5%. Background and aims: To explore the relationship between FLT3 (encoding Fms related tyrosine kinase 3) internal tandem duplication (ITD) mutations with the prognosis of acute promyelocytic leukemia. and P.M.; Data curation, J.M.A. Gilteritinib, a second-generation type I FLT3i demonstrated tolerability with CRc rates of 4555% in patients with R/R FLT3 (ITD or TKD)mut AML38,39. Variant allele frequency (VAF) is the ratio of ITD-mutated alleles to ITD-mutated+wild-type alleles (FLT3ITD/FLT3ITD+FLT3 wild-type)14. Blood 136, 3233 (2020). Finally, a different report showed worse clinical outcomes in terms of OS and DFS in the TKD1 group. Venetoclax, FLT3 Inhibitor and Decitabine in FLT3mut Acute Myeloid Leukemia: Subgroup Analysis of a Phase II Trial (ASH, 2020). Blood 132, 3944 (2018). DiNardo, C. D. et al. 16, 16911699 (2015). is a PhD candidate at Universidad Autnoma de Madrid (UAM). Progr. 383, 617629 (2020). 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). Blood 93, 30743080 (1999). Thank you for visiting nature.com. FLT3 is a gene change, or mutation, in leukemia (blood cancer) cells. Google Scholar. 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