flt3 itd mutation prognosis

has received research funding from Astellas, and Novartis and has served as a member of advisory board in Astellas and Novartis. Patterns of resistance differ in patients with acute myeloid leukemia treated with type I versus type II FLT3-inhibitors. In particular, high (>0.5) mutant-to-wild-type (WT) allelic ratios (AR) in the FLT3-ITD gene are associated with inferior prognosis ( 6, 7 ). A phase 1 study of gilteritinib in combination with induction and consolidation chemotherapy in patients with newly diagnosed AML: final results. Article In 40 patients (87%), the prognosis based on the ELN 2017 risk stratification algorithm did not change due to AR, whereas, in 6 patients (13%), the FLT3-ITD mutation burden was <0.5 in DNA and 0.5 in cDNA, which changed their risk stratification. Prognostic significance of FLT3-ITD length in AML patients treated with intensive regimens. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. 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 . AR is defined as the ratio of ITD-mutated alleles to wild-type allele (FLT3ITD/FLT3 wild-type)13. Differential impact of allelic ratio and insertion site in FLT3-ITDpositive AML with respect to allogeneic transplantation. Clinical trial enrollment (if available) is always the first option, in both frontline and R/R FLT3mut AML. Blood 132, 3944 (2018). Perl, A. E. et al. Hematology Department, Hospital Universitario Fundacin Jimnez Daz, Avenida Reyes Catlicos, 2, 28040, Madrid, Spain, Tamara Castao-Bonilla,Juan M. Alonso-Dominguez,Carlos Blas&Jose L. Lpez-Lorenzo, Instituto de Investigacin Sanitaria (IIS-FJD), Hospital Universitario Fundacin Jimnez Daz, Madrid, Spain, Tamara Castao-Bonilla,Juan M. Alonso-Dominguez,Carlos Blas,Jose L. Lpez-Lorenzo,Daniel Lainez-Gonzalez&Juana Serrano, Hematology Department, Hospital Universitario La Fe de Valencia, Valencia, Spain, Eva Barragn,Rebeca Rodrguez-Veiga,Claudia Sargas,David Martnez-Cuadrn,Miguel A. Sanz&Pau Montesinos, Hematology Department, Hospital General de Alicante, Alicante, Spain, Hematology Department, Hospital Universitario de Salamanca, Salamanca, Spain, Hematology Department, Hospital General de Castelln, Castelln, Spain, Hematology Department, Hospital Universitario Doce de Octubre, Complutense University, CNIO, Madrid, Spain, Molecular Biology Department, Cimalab Diagnosis, Clnica Universitaria de Navarra, Navarra, Spain, Hematology Department, Hospital Universitario Clnico San Carlos, Medicine Department, UCM, Madrid, Spain, Hematology Department, Hospital Universitario de Valladolid, Valladolid, Spain, Hematology Department, Hospital Universitario Ro Hortega, Valladolid, Spain, Hematology Department, Hospital Universitario Virgen del Roco, Instituto de Biomedicina de Sevilla (IBIS/CISC/CIBERON), Sevilla, Spain, Hematology Department, Hospital Universitario de Burgos, Burgos, Spain, Hematology Department, Hospital Ntra. 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. Rydapt Prescribing Information. FLT3 -ITD is located within exon 14, corresponding to JMD,. The FLT3-ITD AR was available in 140 intensively treated patients. 135, 397402 (1986). 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. Remember me on this computer. Article 2012;91(1):9-18. In patients with FLT3mut AML who relapsed after first ASCT, sorafenib was found to be tolerable with long-lasting remissions in 7 of 29 patients treated, suggesting a potential synergy with post-ASCT alloimmune effects41. You are using a browser version with limited support for CSS. (B) Relapse-free survival. Studies have reported that a higher mutant allelic burden is associated with a worse prognosis. . We believe that triplets may be the optimal way to use FLT3i to improve long-term survival and cure rates in older patients, able to tolerate this approach. ABSTRACT. 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). The LACEWING phase III randomized trial evaluated gilteritinib with azacitidine vs azacitidine monotherapy (NCT02752035) in patients with newly diagnosed FLT3mut AML not eligible for intensive induction chemotherapy. Hematology. The FLT3-ITD patient had trisomy 8. We continue the venetoclax and FLT3i until Day 21 if the Day 14 bone marrow shows >5% blasts with >/=5% cellularity. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. No significant difference was found between acute myeloid leukemia patients with these Hematol. In patients with ongoing cytopenias (ANC0.5 and ITD<70bp, n=61; AR>0.5 and ITD70bp, n=21). Google Scholar. Additionally, different subdomains of TKD1 (HR or beta1-sheet) have been highlighted as those conferring an adverse outcome10. As in previous works, we analyzed the clinical significance of FLT3-ITD length among fit patients treated with intensive regimens15,16. 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. 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 . We tried to validate the thresholds of ITD length previously published (i.e., 39bp and 70bp) in intensivelytreated AML patients (n=161). 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. Flow diagram showing all AML patients with FLT3-ITD mutations in the study period between 2003 and 2019 on the basis of genetic data and treatment administered. Blood 130, 723 (2017). Phase 1 study of quizartinib in combination with induction and consolidation chemotherapy in patients with newly diagnosed acute myeloid leukemia. Among 161 intensively treated patients, 123 had the cytogenetic and molecular information required to calculate the 2010 ELN classification21. Additionally, the area under the ROC curve, which serves as an indicator of the diagnostic capacity of the ITD length as a whole, was 0.504. 2013 220 226, H Dhner 2017 Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel Blood 129 424 447, F Breitenbuecher 2009 Identification of a novel type of ITD mutations located in nonjuxtamembrane domains of the FLT3 tyrosine kinase receptor Blood 113 4074 4077, S Liu 2018 Pattern and prognostic value of FLT3-ITD mutations in Chinese de novo adult acute myeloid leukemia Cancer Sci. The mutation rate of FLT3/ITD in DEK/CAN-positive AML patients is as high as 70% (8,9). Google Scholar, MR ODonnell 2017 Acute myeloid leukemia, version 3.2017, NCCN clinical practice guidelines in oncology J. Natl. Such sequential approaches need to be formally evaluated in the context of prospective clinical trials. Among 729 AML patients with FLT3-ITD mutations included in the PETHEMA AML epidemiologic registry between 2003 and 2019, FLT3-ITD length was available in 362: 188 males and 174 females; median age of 60.8years (range 17.191.4years). Nevertheless, there are numerous manuscripts with contradictory results regarding the prognostic relevance of the length and insertion site (IS) of the FLT3-ITD fragment. Encouragingly, the response rate was maintained among patients previously exposed to other FLT3 TKIs. Two cases with an NPM1 mut missense each occurred concomitant with type-A mutation. These data highlight the potent anti-leukemic activity of the triplet approach in FLT3mut AML. In order to improve the clinical condition of FLT3-ITD-positive patients, several FLT3 inhibitors have been developed showing variable results. Wang, E. S. et al. 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). Publishers note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. 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. We studied theFLT3-ITD length of 362 adult AML patients included in the PETHEMA AML registry. Xuan, L. et al. Fishers exact test was employed to correlate the ITD insertion site and mutational status. 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.) A detailed analysis of all patients showed ITD integrations in the JMD-B, amino acids 572 to 578, in six patients; the JMD-S, amino acids 579 to 592, in 42 patients; the JMD-Z, amino acids 593 to 603, in 43 patients; the HR, amino acids 604 to 609, in seven patients; the B1 of TKD1, amino acids 610 to 615, in one patient; the NBL, amino acids 616 to 623, in two patients; and the B2, amino acids 624 to 630, in one patient. 2, 125 (2020). Cancer Res. Alotaibi, A. S. et al. Nakao, M. et al. Haematologica (2021). Adult patients with FLT3- ITD mutated AML treated at our institution were identified. . FLT3 -ITD mutations occur in the form of a replicated sequence in the juxtamembrane domain (JMD) and/or TKD1 of the FLT3 gene. Biochem. Using the same response criteria, the CRc rate was 85.4% (n=35/41) which compared favorably to 52% with gilteritinib alone in the ADMIRAL study. A subsequent randomized phase IIb trial evaluated lower doses, 30 or 60mg of quizartinib daily, in patients with R/R FLT3-ITDmut AML. The favorable prognostic molecular mutations, such as NPM-1 and CEBPA, are uncommon in elderly AML . 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. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate. Both mutations lead to the activation of downstream proliferation cascades [ 19, 20 ]. Tallman, M. S. et al. J. Med. Oncol. Blood 110, 12621270 (2007). 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). Despite the encouraging development of FLT3i, resistance to FLT3i is not uncommon and it can be either primary or secondary. 4). Our results, alongside previous publications, confirm that FLT3-ITD length lacks prognostic value and clinical applicability. An analysis of OS censoring at the time of allo-HSCT did not yield significant results (data not shown). 10, 588876- (2020). 377, 454464 (2017). Identification of novel FLT3 Asp835 mutations in adult acute myeloid leukaemia. On the other hand, we obtained a value (0.52) that was close to significant in the analysis of the prognostic impact of the FLT3-ITD AR according to the 2017 ELN cutoff8. 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. 5 96 102, C Sargas 2020 Networking for advanced molecular diagnosis in acute myeloid leukemia patients is possible: The PETHEMA NGS-AML project Haematologica https://doi.org/10.3324/haematol.2020.263806, Article An FLT3/ITD mutation was present in 27% of the patients and was associated with leukocytosis and a high percentage of bone marrow blast cells (P <.001 for both). https://doi.org/10.1038/s41598-021-00050-x. Samples from 118 of the 362 AML patients with FLT3-ITDmutations were analyzed with an NGS panel of 39 genes (see Supplementary Fig. 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. However, emerging data does suggest that patients with FLT3-ITDmut AR<0.5 and NPM1 co-mutation without concurrent high-risk mutations such as DNMT3A, TP53, TET2, or high-risk cytogenetics may be a more favorable subset, who may be considered for induction, consolidation followed by maintenance therapy without ASCT on a case by case basis if they achieve early MRD negativity using a highly sensitive MRD assay. Oncol. J. Clin. Wang, E. S. et al. In the QuANTUM-R and ADMIRAL trials, only 4% and 12% of patients had received prior FLT3i therapy with induction, making it difficult to draw conclusions regarding the outcomes of contemporary patients, most of whom will have received a FLT3i (commonly midostaurin) with induction36,40. Am. Upon achieving CR, the decision for ASCT is based on the risk-benefit assessment for ASCT. In patients with concurrent NPM1mut, the OS and relapse risk were comparable between FLT3 wild-type and FLT3-ITDmut AR <0.5, but worse when AR 0.5. Clonal selection with RAS pathway activation mediates secondary clinical resistance to selective FLT3 inhibition in acute myeloid leukemia. Fms-like tyrosine kinase 3 (FLT3) is a recurrent genetic abnormality in AML (~30%)1,2,3. Ravandi, F. et al. J. Hematol. Phase I/II study of combination therapy with sorafenib, idarubicin, and cytarabine in younger patients with acute myeloid leukemia. In general, AML patients with intermediate-risk cytogenetics and with a FLT3-ITD mutation have a significantly poorer prognosis with an increased relapse risk and decreased . 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. FLT3 -ITD was a poor prognostic factor in both age groups, but the favorable prognostic impact of NPM1 was more evident in patients aged 65 years or more. G Nagel 2017 Epidemiological, genetic, and clinical characterization by age of newly diagnosed acute myeloid leukemia based on an academic population-based registry study (AMLSG BiO) Ann. Upregulation of Bcl-2 confers resistance to FLT3 inhibition in FLT3-ITD AML with secondary acquired mutations. 95, 218223 (1996). Emergence of BCR-ABL1 fusion in AML post-FLT3 inhibitor-based therapy: a potentially targetable mechanism of resistancea case series. J. Med. Due to this, the development of tyrosine kinase inhibitors (TKI) blocking FLT3-ITD became a rational therapeutic concept. Mounting evidence suggests that FLT3mut can emerge at any timepoint in the disease spectrum emphasizing the need for repetitive mutational testing not only at diagnosis but also at each relapse. J. Natl Compr. We have no explanation regarding the reduced number of patients with an FLT3-ITD inserted in TKD1 found in our cohort. Am. Nevertheless, some thresholds have been applied in more than one study [i.e., 39bp and 70bp]11,15,16,17. Prognostic impact analyses of FLT3-ITD length were performed among patients treated with upfront IC regimens. Perl, A. E. et al. fms3flt3-itdaml molm13baf3-flt3-itd p-erkp-akt . Phase 2 study of azacytidine plus sorafenib in patients with acute myeloid leukemia and FLT-3 internal tandem duplication mutation. Perl, A. E. et al. Phase I/II trial of the combination of midostaurin (PKC412) and 5-azacytidine for patients with acute myeloid leukemia and myelodysplastic syndrome. Educ. 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. (D) OS according to the FLT3-ITD length and 2010 ELN genetic risk. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Article These observations have made FLT3 an attractive drug target. Mead, A. J. et al. Patients with an ITD fragment39bp or70bp had a significant reduction in OS and RFS in some of these studies, but we were unable to validate these findings11,15,16,17. **If the C1 D14 bone marrow show >5% blastscontinue venetoclax, FLT3i till D21. J. Med. DNA quantification was performed with a Nanodrop (Thermo Fisher Scientific, Waltham,MA) or Qubitfluorometer (Thermo Fisher Scientific, Waltham, MA). Alotaibi, A. S. et al. 96 1993 2003, Article DiNardo, C. D. et al. evaluated midostaurin with azacitidine in patients with both newly diagnosed and R/R AML regardless of FLT3 mutational status. Blood 136, 1617 (2020). We used the 0.5 cutoff of the AR as recommended by the 2017 ELN guidelines8.These patients were divided on the basis of the FLT3-ITD AR into an FLT3-ITDLOWgroup (41%; n=58) and an FLT3-ITDHIGHgroup (59%; n=82). (A) Overall survival. The authors declare no competing interests. In patients with newly diagnosed AML, FLT3-ITDmut is a poor prognostic factor in terms of relapse-free (RFS) and overall survival (OS)7,8,9,10. This study shows that the size of FLT3-ITD mutations has no prognostic impact in terms of survival, relapse or CR rate among newly diagnosed AML patients treated with first-line intensive regimens. 120.000 new AML cases and over . 11, 104 (2021). The combination of quizartinib with azacitidine or low dose cytarabine is highly active in patients (Pts) with FLT3-ITD mutated myeloid leukemias: interim report of a phase I/II trial. Cladribine combined with idarubicin and Ara-C (CLIA) as a frontline and salvage treatment for young patients (65 yrs) with acute myeloid leukemia. Besides FLT3-ITD MRD, only a high white blood cell count and late CR appeared to be independently associated with relapse and OS. Statistical analyses were performed with SPSS 19.0 (IBM, Armonk, NY). We aimed to shed light on the prognostic importance of theFLT3-ITD length and site of insertion by validating previously suggested sites of insertion and thresholds of ITD length. Blood 124, 34413449 (2014). Among 38 patients with FLT3mut AML who received gilteritinib 120mg daily, the CRc rate was 81.6% (n=31) including 39.5% CR and median OS was not reached at a median follow-up of 35.8 months. Blood 111, 27762784 (2008). Schlenk et al. 61, 72337239 (2001). Schneider F, Hoster E, Schneider S, Dufour A, Benthaus T, Kakadia PM, et al. and P.M.; Formal analysis, J.M.A., Investigation,T.C., J.M.A. Secondary resistance to FLT3i could be either on-target (changes in the FLT3) or off-target (constitutive activation of non-FLT3-dependent oncogenic pathways). Weisberg, E. et al. Cancer Cell 1, 433443 (2002). Naval Daver. Strati et al. Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults. CR+CRi rates between groups were compared with a chi-square test. (5) No data regarding minimal residual disease (MRD) were available in our cohort, and MRD data could be interesting to analyze in future studies. The origin and evolution of mutations in acute myeloid leukemia. 94, 984991 (2019). Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1-2 study. Prognostic implication of FLT3 and N-RAS gene mutations in acute myeloid leukemia. 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). Leukemia 26, 23532359 (2012). We aimed to assess the prognostic impact of these variables on the complete remission (CR) rates, overall survival (OS) and relapse-free survival (RFS) of AML patients withFLT3-ITDmutations. Pulmonary infiltration and acute pneumonitis-like picture are rare (<1%) but noted side effects of midostaurin that treating physicians should be aware of. Similarly, a stratified analysis of FLT3-ITD length on the basis of 2010 ELN genetic risk was performed in 123 patients (intermediate-I group, ITD<39bp, n=31 and ITD39bp, n=68; intermediate-II group, ITD<39bp, n=5 and ITD39bp, n=10; and adverse group, ITD<39bp, n=2 and ITD39bp, n=7). F fludarabine, I idarubicin, CL cladribine, A cytarabine 1.52g/m2, HMA hypomethylating agent, CR complete remission, ECOG PS Eastern Cooperative Oncology Group Performance Status, CG cytogenetics, MRD measurable residual disease, SCT stem cell transplant, HiDAC high-dose cytarabine, CBC complete blood count. Cancer 51 910 924, AT Cohen S Goto K Schreiber C Torp-Pedersen 2015 Why do we need observational studies of everyday patients in the real-life setting? In the frontline setting, there was a sequential decrease in CRc rates (77%31%25%) and OS (16.76.01.4 months). (C) OS according to the FLT3-ITD length and allelic ratio. AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML). Given the heterogeneity of treatments received and the scarce number of ISs in TKD1, we did not perform statistical analysis. 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. prospectively evaluated decitabine and quizartinib (doublet) with or without venetoclax (triplet) in patients with newly diagnosed and R/R FLT3-ITDmut AML. Zhang, W. et al.