FLT3 inhibitors and hematopoietic cell transplantation prolong survival in patients with FLT3-ITD-positive AML

FLT3 inhibitors and hematopoietic cell transplantation prolong survival in patients with FLT3-ITD-positive AML | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article FLT3 inhibitors and hematopoietic cell transplantation prolong survival in patients with FLT3-ITD-positive AML Toshihiro Matsukawa, Masahiro Onozawa, Takeshi Kondo, Minoru Kanaya, and 26 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4767599/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 30 Nov, 2024 Read the published version in Annals of Hematology → Version 1 posted 9 You are reading this latest preprint version Abstract Acute myeloid leukemia (AML) is an aggressive hematological malignancy with genetic alterations. The FMS-like tyrosine kinase 3 (FLT3) gene is frequently mutated in adult de novo AML, with two types of mutations: internal tandem duplication (ITD) and point mutations in the tyrosine kinase domain. This study aimed to investigate the impact of FLT3 inhibitors and hematopoietic cell transplantation (HCT) on survival outcomes in patients with FLT3 -ITD AML in a real-world setting. We retrospectively analyzed 139 patients with FLT3 -ITD-positive AML between 2012 and 2021. The median age was 63 years. In the propensity score-matched cohort, FLT3 inhibitors improved overall survival (OS) compared with patients treated without FLT3 inhibitors (3-year OS: 33.7% vs. 25.8%, p = 0.021). Patients who underwent HCT had superior outcomes to those without HCT (3-year OS: 45.3% vs. 2.2%, p < 0.0001). The combination of FLT3 inhibitors and HCT resulted in the highest OS and relapse-free survival (RFS) rates (3-year OS: 62.4%; 3-year RFS: 67.2%). Disease status before transplantation did not predict the prognosis, but use of FLT3 inhibitors increased survival in patients without complete remission before HCT. These results demonstrate the clinical impact of FLT3 inhibitors on survival outcomes in patients with FLT3 -ITD-positive AML, particularly when combined with HCT. FLT3 inhibitor can improve the prognosis of AML with FLT3 mutations, especially in patients who undergo HCT. acute myeloid leukemia FLT3-ITD FLT3 inhibitor Figures Figure 1 Figure 2 Introduction Acute myeloid leukemia (AML) is an aggressive hematological malignancy characterized by karyotype abnormalities and gene mutations in hematopoietic stem cells and progenitor cells [ 1 – 3 ]. Genetic alterations in AML affect the prognosis, and FMS-like tyrosine kinase 3 (FLT3) mutations are frequently detected in patients with de novo AML. Internal tandem duplication (ITD) at the juxta membrane domain and point mutations in the tyrosine kinase domain (TKD) occur in approximately 25% and 5% of cases of adult AML, respectively [ 1 ]. The FLT3 gene plays a pivotal role in the proliferation, differentiation, and survival of hematopoietic cells [ 4 ] FLT3 mutations constitutively activate multiple downstream signaling pathways, including phosphoinositide 3-kinase/Akt and Ras/mitogen-activated protein kinase, which promote cell growth and induce anti-apoptosis [ 4 ]. FLT3 -ITD AML is associated with a poor prognosis, although emerging FLT3 inhibitors, such as midostaurin, quizartinib, and gilteritinib, have improved survival outcomes in these cases [ 5 ]. FLT3 inhibitors are classified as type 1 and 2. Type 1 inhibitors, such as gilteritinib, bind to FLT3 and inactivate FLT3 signaling pathways in both FLT3 -ITD and FLT3 -TKD, whereas type 2 inhibitors, such as quizartinib, show increased binding compared with type 1 inhibitors and decrease phosphorylation of FLT3 via FLT3 -ITD [ 6 , 7 ]. FLT3 inhibitors are thus expected to increase survival and prevent relapse; however, their clinical impact in a real-world setting is still unclear. In Japan, the type 1 inhibitor, gilteritinib, was approved in December 2018, followed by the type 2 inhibitor, quizartinib, in October 2019. This study aimed to evaluate the impact of FLT3 inhibitors on survival in patients with FLT3 -ITD-positive AML in a real-world setting. Patients and methods Patient eligibility We conducted a multicenter retrospective questionnaire-based study including patients with FLT3 -ITD AML at 22 institutes in Hokkaido from January 2012 to December 2021. Patients diagnosed with acute promyelocytic leukemia, patients who died within 14 days from diagnosis, and patients with only FLT3 -TKD mutations were excluded. We defined patients who received FLT3 inhibitors for ≥ 14 days as “administration of FLT3 inhibitors” because a shorter usage of FLT3 inhibitors might not impact survival. FLT3 -ITD was detected by companion diagnostics LeukoStrat CDx FLT3 or in-house analysis. Endpoints The primary endpoint in this study was overall survival (OS). The secondary endpoints were relapse-free survival (RFS) and rate of induction failure. OS was defined from the day of diagnosis with AML to death. RFS was defined from the day of diagnosis with AML to death, relapse, or progression in patients who achieved complete remission (CR) or CR with incomplete recovery [ 8 ]. Propensity score (PS) matching To avoid potential confounding in patient characteristics, we calculated the propensity scores (PS), and caliper-matched cases with or without FLT3 inhibitors in a 1:1 ratio using the nearest-neighbor matching method with multivariable logistic regression analysis. The covariates were sex (female or male), age (≥ 65 or < 65 years), Eastern Cooperative Oncology Group (ECOG) performance status (0–2 or ≥ 3), and patients who underwent HCT (yes or no), as factors that might affect survival outcomes. Statistical analysis The patients’ characteristics were tested by χ 2 and Fisher’s exact tests for categorical data or the Mann–Whitney U test for quantitative data. OS and RFS were calculated using the Kaplan–Meier method. All statistical tests were two-sided, and a p value < 0.05 was considered significant. All statistical analyses were performed using the EZR software package in R commander for macOS version 1.61 (Saitama Medical Center, Jichi Medical University; http://www.jichi.ac.jp/saitama-sct/SaitamaHP.files/statmedEN.html ). Results Patient characteristics A total of 171 patients were registered, of whom 17 patients with acute promyelocytic leukemia, 11 patients who died within 14 days from diagnosis, and 4 patients with only FLT3 -TKD mutations were excluded. A total of 139 patients met the eligibility criteria. The median age was 63 years (range 7–95 years) and there were 56 (40.3%) women and 83 (59.7%) men (Supplementary Fig. 1). The median ECOG performance status was 1 (range, 0–4), the median white blood cell count (WBC) at diagnosis was 52,630/L (range, 680–496,000), and the median serum lactate dehydrogenase (LDH) level was 544.5 U/L (range, 20–11,937). One hundred patients (71.9%) received intensive chemotherapy (idarubicin + cytarabine, n = 76; daunorubicin + cytarabine, n = 24). The rest of the patients received non-intensive treatment, including a low-dose cytarabine regimen (n = 18), azacytidine alone (n = 6), venetoclax + azacytidine (n = 3), hydroxyurea (n = 6), or best supportive care (n = 6). Among the 100 patients who underwent intensive chemotherapy, 67 (67.0%) achieved CR after first induction therapy. Among all 139 eligible cases, a normal karyotype was detected in 104 (74.8%). HCT was conducted in 65 cases (46.8%), with 52 and 13 patients receiving myeloablative conditioning and reduced-intensity conditioning regimens, respectively. FLT3 -ITD mutations alone occurred in 134 (96.4%) patients and FLT3 -ITD plus FLT -TKD mutations occurred in 5 patients (3.6%). FLT3 inhibitors were administered in 59 cases (42.4%) based on the study criteria for the indication of primary refractory/relapse (n = 40) or maintenance (n = 19). There was no significant difference in patient age between patients treated with and without FLT3 inhibitors (median 65 years, range 7–90; median 60.5 years, range 9–95, respectively) (p = 0.76). There were also no significant differences between the two groups in terms of sex (male: 59.3% vs. 60.0%, p > 0.95), median WBC at diagnosis (61,280/µL vs. 40,520/µL, p = 0.55), median serum LDH level (585 U/L vs. 522 U/L, p = 0.64), CR after one course of induction therapy (50.8% vs. 46.2%, p = 0.72), cases who underwent HCT (47.5% vs. 46.3%, p > 0.95), and FLT3 -ITD alone (94.9% vs. 97.5%, p = 0.73) (Supplementary Table 1). We next compared the patient characteristics in the PS-matched cohort (n = 56 per group). There were no significant differences between the two groups in terms of age (median 64 years vs. 63 years, p = 0.63), sex (male: 57.2% vs. 55.4%, p > 0.95), ECOG performance status (1 vs. 1, p > 0.95), median WBC (62,150/µL vs. 51,770/µL, p = 0.56), serum LDH level (609.5 U/L vs. 524 U/L, p = 0.49), number of cases with intensive chemotherapy (42 vs. 38 cases, p = 0.59), CR rate after one course of induction therapy (64.3% vs. 68.4%, p = 0.70), patients who underwent HCT (50% vs. 50%, p > 0.95), and FLT3 -ITD alone (98.2% vs. 96.4%, p > 0.95) (Table 2 ). Among patients who underwent HCT, FLT3 inhibitors were administered only before HCT (n = 5, 17.9%), only after HCT (n = 9, 32.1%), both before and after HCT for maintenance (n = 10, 35.7%), and at relapse after HCT (n = 4, 14.3%). The FLT3 inhibitor was gilteritinib alone in 44, quizartinib alone in one, sorafenib alone in one, and sequential gilteritinib and quizartinib in 10 patients. FLT3 inhibitors were administered without transplantation for relapsed or refractory disease, not for induction, because upfront FLT3 inhibitors were only approved as induction therapy in Japan in May 2023, after this study period. Table 1 Patient characteristics of the whole cohort Total (n = 139) age, y median (range) < 65, n (%) 63 (7–95) 75 (54.0) Sex male/female, n (%) 83 (59.7)/56 (40.3) ECOG PS, median (range) 0–2/3–4, n (%) 1 (0–4) 127 (91.4)/12 (8.6) WBC, µL median (range) 52630 (680 − 496,000) LDH, U/L median (range) 544.5 (20 − 11,937) Karyotype CN/others, n (%) 104 (74.8)/35 (25.2) CR to induction therapy, n (%) 67 (48.2) HCT, n (%) MAC/RIC, n (%) 65 (46.8) 52 (80)/13 (20) FLT3 -ITD/ITD + TKD, n (%) 134 (96.4)/5 (3.6) FLT3 inhibitors, n (%) 59 (42.4) ECOG PS, Eastern Cooperative Oncology Group performance status; WBC, white blood cell; LDH, lactate dehydrogenase; CN, cytogenetically normal; CR, complete remission; HCT, hematopoietic cell transplantation; MAC, myeloablative conditioning; RIC, reduced-intensity conditioning; ITD, internal tandem duplication; TKD, tyrosine kinase domain Table 2 Patient characteristics of propensity score matched cohort FLT3i (+) (n = 56) FLT3 (-) (n = 56) P value age, y median (range) < 65, n (%) 64 (7–90) 29 (51.8) 63 (9–95) 29 (51.8) 0.63 1 Sex male/female, n (%) 32 (57.1)/24 (42.9) 31 (55.4)/25 (44.6) 1 ECOG PS, median (range) 0–2/3–4, n (%) 1 (0–4) 53 (94.6)/3 (5.4) 1 (0–4) 53 (94.6)/3 (5.4) 0.48 1 WBC, µL median (range) 62165 (1310 − 496,000) 51770 (1100 − 337,900) 0.55 LDH, U/L median (range) 609.5 (20 − 11,937) 524 (154-3,973) 0.71 CR to induction therapy, n (%) 28 (50) 27 (48.2) 1 Karyotype NK/others, n (%) 44 (78.6)/12 (21.4) 38 (67.9)/18 (32.1) 0.29 HCT, n (%) MAC/RIC 28 (50) 22 (78.6)/6 (21.4) 28 (50) 23 (82.1)/5 (17.9) 1 1 ITD/ITD + TKD, n (%) 55 (98.2)/1 (1.8) 54 (96.4)/2 (3.6) 1 The type of FLT3i, n (%) gilteritinib quizartinib sorafenib gilteritinib ◊ quizartinib 44 (78.6) 1 (1.8) 1 (1.8) 10 (17.6) FLT3i, FLT3 inhibitor; ECOG PS, Eastern Cooperative Oncology Group performance status; WBC, white blood cell; LDH, lactate dehydrogenase; CN, cytogenetically normal; CR, complete remission; HCT, hematopoietic cell transplantation; MAC, myeloablative conditioning; RIC, reduced-intensity conditioning; ITD, internal tandem duplication; TKD, tyrosine kinase domain Survival outcomes The 3-year OS and RFS in the whole study cohort were 27.4% (95% confidence interval [CI], 19.6–35.7%) and 23.0% (95% CI, 16.1–30.7%), respectively (Fig. 1A, B). We compared survival according to age: 70 years. There were only five patients aged < 18 years, but these limited cases showed favorable OS (3-year OS: 60% [95% CI, 12.6–88.2%]). Patients in the 18–40 and 41–70 year groups demonstrated 3-year OS rates of 51.8% (95% CI, 26.2–72.4%) and 30.2% (95% CI, 19.5–41.6%), respectively. However, patients aged > 70 years showed poor OS (4.7% [95% CI, 0.4–18.6%]) (Fig. 1C). The 3-year RFS rates in patients aged 70 years were 40% (95% CI, 5.2–75.3%), 51.8% (95% CI, 26.2–72.4%), 23.8% (95% CI, 14.7–34.1%), and not reached, respectively (Fig. 1D). The use of FLT3 inhibitors divided the prognosis, with patients receiving FLT3 inhibitors having better OS than those without FLT inhibitors (3-year OS: 32.4% vs. 23.4%, p = 0.0068) (Supplementary Fig. 2A). RFS in the group treated with FLT3 inhibitors in the whole cohort was similar to the group without FLT3 inhibitors (3-year RFS: 28.3% vs. 19.4%, p = 0.21) (Supplementary Fig. 2B). OS and RFS were improved in patients with HCT compared with those without HCT (3-year OS: 45.3% vs. 2.2%, p < 0.0001; 3-year RFS: 40.2% vs. 4.9%, p < 0.0001) (Supplementary Fig. 2C, D). OS and RFS were highest among patients treated with FLT3 inhibitors and HCT compared with the other groups (both p < 0.0001) (Supplementary Fig. 2E, F). The hazard ratios for OS according to use of FLT3 inhibitors and HCT in all eligible cases were 0.57 (95% CI, 0.38–0.86, p = 0.0076) and 0.31 (95% CI, 0.21–0.48, p < 0.0001), respectively. The 3-year OS and RFS rates in the PS-matched cohort were 29.7% (95% CI, 20.9–39.1%) and 25.0% (95% CI, 17.0–33.8%), respectively (Fig. 2A, B). FLT3 inhibitors improved OS in the PS-matched cohort compared with the group without FLT3 inhibitors (3-year OS: 33.7% vs. 25.8%, p = 0.021), but had no effect on RFS (28.1% vs. 21.9%, p = 0.48) (Fig. 2C, D). HCT improved OS and RFS in the PS-matched cohort compared with patients without HCT (3-year OS: 47.9% vs. 6.8%, p < 0.0001; 3-year RFS: 43.2% vs. not reached, p < 0.0001, respectively) (Fig. 2E, F). In the PS-matched cohort, FLT3 inhibitors plus HCT also improved OS (3-year OS: FLT3 inhibitors + HCT, 62.4%; HCT alone, 34.8%; FLT inhibitors alone, not reached; no FLT3 inhibitors or HCT, 17.4%; p < 0.0001) and RFS (3-year RFS: FLT3 inhibitors + HCT, 67.2%; HCT alone, 14.4%; FLT inhibitors alone, not reached; no FLT3 inhibitors or HCT, not reached; p < 0.0001) (Fig. 2G, H). Among patients who underwent HCT, hematological CR did not affect survival compared with non-CR (3-year OS: 50.5% vs. 40.0%, p = 0.44) (Supplementary Fig. 3A). Patients without CR receiving FLT3 inhibitors demonstrated superior survival outcomes compared with patients without CR and without FLT3 inhibitors (3-year OS: 62.5% vs. 16.7%, p = 0.022), (Supplementary Fig. 3B), although the comparison was limited by the small number of cases. The use of FLT inhibitors did not affect survival among patients with CR before HCT (3-year OS: with inhibitors 62.9% vs. without inhibitors 40.0%, p = 0.15). Discussion We retrospectively analyzed patients with FLT3 -mutated AML in a regional multicenter cohort in Japan. The results showed that FLT3 inhibitors and HCT improved survival outcomes among patients with FLT3 -ITD AML, while the combination of FLT3 inhibitors and HCT led to superior outcomes compared with the other treatment groups. FLT3 inhibitor administration improved outcomes among patients without HCT, but HCT had a more significant impact than FLT3 inhibitors. Among patients undergoing HCT, FLT3 inhibitors had no impact in patients with hematological CR before HCT, but improved survival in patients without CR before HCT, compared with patients without FLT3 inhibitors. Gilteritinib was approved for relapsed/refractory FLT3 -ITD/-TKD mutated AML and quizartinib was approved for newly diagnosed and relapsed/refractory FLT3 -ITD AML in Japan, but quizartinib was not approved for newly diagnosed AML during the study period. Upfront FLT3 inhibitors combined with conventional 7 + 3 induction might enhance the impact of FLT3 inhibitors. Midostaurin, a first-generation type 1 tyrosine kinase inhibitor for FLT3 -mutated AML, inhibits multi-kinases such as FLT3, KIT, and platelet-derived growth factor receptor. In the randomized phase 3 RATIFY trial, midostaurin with conventional 7 + 3 induction therapy, improved OS compared with conventional chemotherapy alone in patients with newly diagnosed FLT3 -mutated AML, but had no additional effect in patients aged ≥ 60 years [ 9 ]. First-generation FLT3 inhibitors such as midostaurin have poor specificity for FLT3 and many off-target effects, leading to side effects, including hematological adverse events [ 6 ]. Most cases (96.2%) in the current PS-matched cohort who were treated with FLT3 inhibitors initially selected gilteritinib, because this was the first-in-class agent to be approved in Japan. Gilteritinib is a second-generation type 1 FLT3 inhibitor with a high affinity for mutated FLT3 receptors that inhibits the phosphorylation of FLT3 and AXL. The randomized phase 3 ADMIRAL trial showed that gilteritinib prolonged survival in patients with relapsed or refractory FLT3 -mutated AML and induced a high incidence of CR compared with patients who received conventional salvage chemotherapy [ 10 ]. In the current study, disease status before transplantation did not affect OS, but the use of FLT3 inhibitors improved survival in patients without CR undergoing HCT. Low-dose gilteritinib after HCT also improved outcomes in initiating early post-transplantation as maintenance therapy [ 11 ]. In the ADMIRAL trial, patients who underwent HCT showed comparable outcomes between the pretransplant gilteritinib and salvage chemotherapy arms, but patients who resumed gilteritinib after HCT had better outcomes than those who did not resume gilteritinib in the gilteritinib arm [ 12 ]. Moreover, Levis et al. reported that patients with FLT3 -ITD with hematological CR of 1 × 10 − 6 or greater for FLT3 -ITD had poor OS and RFS without gilteritinib, but gilteritinib combined with HCT increased survival among these patients [ 13 ]. Maintenance therapy with FLT3 inhibitors after transplantation might prevent relapse and improve prognosis, but patients eligible for maintenance therapy after HCT need to be selected in terms of disease status pre- or post-transplantation. The second-generation type 2 FLT3 inhibitor, quizartinib, selectively inhibits FLT3 but has lower affinity to KIT, RET, colony-stimulating factor-1 receptor, and platelet-derived growth factor receptor [ 7 ]. In a phase 1 clinical trial of post-transplant maintenance therapy, four (31%) patients survived > 2 years; however, the sample size was very small, and no large randomized trials of quizartinib have been conducted for FLT3 -ITD AML after HCT [ 14 ]. A study using real-world data for 1208 patients with FLT3 -mutated AML from eight countries showed that post-transplant administration of FLT3 inhibitors (n = 219, 18.1%), including midostaurin (n = 140, 63.9%), sorafenib (n = 58, 26.5%), gilteritinib (n = 14, 6.4%), and quizartinib (n = 9, 4.1%), or other maintenance therapy (n = 224, 18.5%) improved survival [ 15 ]. In a randomized phase 3 trial, quizartinib in combination with intensive chemotherapy, improved OS, especially in cases with a higher FLT3 -ITD variant allelic frequency [ 16 ]; however, quizartinib with conventional chemotherapy still failed to improve OS in patients aged ≥ 60 years, and the study did not include patients who received FLT3 inhibitors as induction therapy. FLT3 inhibitors improved survival in patients with relapsed or refractory FLT3 -ITD AML without HCT in the current study, as reported in previous phase 3 studies of gilteritinib and quizartinib [ 10 , 17 ]. The current study had several limitations. First, the study retrospectively analyzed a small number of cases. Second, genetic alterations other than FLT3 mutations could not be assessed because a comprehensive panel for genetic mutations has not been approved in Japan. Third, FLT3 inhibitors were administered for many purposes in the patients who underwent HCT, including maintenance before transplantation and relapse after transplantation. Finally, the disease status before HCT was only assessed by morphological evaluation. In conclusion, this retrospective multicenter study revealed that FLT3 inhibitors and HCT improved survival in patients with FLT3 -ITD AML in a real-world setting. HCT had a more significant impact on survival among these patients, and intensive chemotherapy plus FLT3 inhibitors with HCT for fit patients with FLT3 -ITD AML might lead to better outcomes. Further studies are needed to determine which patients are suitable for FLT3 inhibitors as maintenance therapy after HCT. Declarations Acknowledgments We thank Susan Furness, PhD, from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript. We would like to thank all the physicians, the nursing and medical staff for their contributions and dedicated care of the patients. Funding The authors received no specific funding for this work. Conflict-of-interest disclosure The authors declare that they have no conflicts of interest. Ethical approval All procedures involving human participants were in accordance with the ethical standards of institutional research committees, national guidelines, and with the Declaration of Helsinki. This study was approved by the institutional review board of Hokkaido University Hospital (#022-0085). Authorship contributions T. Matsukawa and T.K. designed this study. T. Matsukawa, M.O., T.K., M.K., D. Hidaka, S.O., A.M., A.S., T. Miyagishima, Y. Kakinoki, J.H., S.Y., M.Y., K.W., M.T., T. Ishihara, Y.H., A.F., T. Igarashi, T.S., S.I., R.K., H.S., K.F., J.I., Y. 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Am J Hematol 93(2):222–231. 10.1002/ajh.24959 Griffin JD, Song Y, Yang H, Freimark J, Shah MV (2021) Post-transplant maintenance therapy in patients with FLT3-mutated acute myeloid leukemia: Real-world treatment patterns and outcomes. Eur J Haematol 107(5):553–565. 10.1111/ejh.13692 Erba HP, Montesinos P, Kim HJ, Patkowska E, Vrhovac R, Žák P, Wang PN, Mitov T, Hanyok J, Kamel YM, Rohrbach JEC, Liu L, Benzohra A, Lesegretain A, Cortes J, Perl AE, Sekeres MA, Dombret H, Amadori S, Wang J, Levis MJ, Schlenk RF (2023) Quizartinib plus chemotherapy in newly diagnosed patients with FLT3-internal-tandem-duplication-positive acute myeloid leukaemia (QuANTUM-First): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 401(10388):1571–1583. 10.1016/s0140-6736(23)00464-6 Cortes JE, Khaled S, Martinelli G, Perl AE, Ganguly S, Russell N, Krämer A, Dombret H, Hogge D, Jonas BA, Leung AY, Mehta P, Montesinos P, Radsak M, Sica S, Arunachalam M, Holmes M, Kobayashi K, Namuyinga R, Ge N, Yver A, Zhang Y, Levis MJ (2019) Quizartinib versus salvage chemotherapy in relapsed or refractory FLT3-ITD acute myeloid leukaemia (QuANTUM-R): a multicentre, randomised, controlled, open-label, phase 3 trial. Lancet Oncol 20(7):984–997. 10.1016/s1470-2045(19)30150-0 Additional Declarations No competing interests reported. Supplementary Files SuppFig1.eps Supplementary Fig. 1 Age distribution of total cohort (n = 139) showing sex (A) and patients who underwent hematopoietic cell transplantation (HCT) (B) SuppFig2.eps Supplementary Fig. 2 Overall survival (OS) and relapse-free survival (RFS) in all patients. FLT3 inhibitors (A, B), hematopoietic cell transplantation (HCT) (C, D), and FLT3 inhibitors plus HCT (E, F) improved survival outcomes SuppFig3.eps Supplementary Fig. 3 Overall survival (OS) in propensity score-matched patients with hematopoietic cell transplantation (HCT). A. Disease status before hematopoietic complete remission (CR) did not affect OS compared with patients without CR (p = 0.44). B. FLT3 inhibitors improved OS in patients without CR SuppTable.docx Cite Share Download PDF Status: Published Journal Publication published 30 Nov, 2024 Read the published version in Annals of Hematology → Version 1 posted Editorial decision: Revision requested 12 Nov, 2024 Reviews received at journal 12 Nov, 2024 Reviewers agreed at journal 02 Nov, 2024 Reviewers agreed at journal 02 Nov, 2024 Reviewers agreed at journal 08 Aug, 2024 Reviewers invited by journal 24 Jul, 2024 Editor assigned by journal 24 Jul, 2024 Submission checks completed at journal 24 Jul, 2024 First submitted to journal 19 Jul, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4767599","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":342773648,"identity":"d7a0724e-c31b-4a64-859b-202d1d514540","order_by":0,"name":"Toshihiro 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1","display":"","copyAsset":false,"role":"figure","size":11526,"visible":true,"origin":"","legend":"\u003cp\u003eOverall survival (OS) and relapse-free survival (RFS) in the whole study cohort. A, B. OS and RFS. C, D. OS and RFS according to age group: \u0026lt;18, 18–40, 41–70, and \u0026gt;70 years\u003c/p\u003e","description":"","filename":"Fig1.png","url":"https://assets-eu.researchsquare.com/files/rs-4767599/v1/77c824c374eb956c52729e50.png"},{"id":63299183,"identity":"b694b9da-e3f5-44c5-917b-71597dbc6498","added_by":"auto","created_at":"2024-08-26 15:52:04","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":26505,"visible":true,"origin":"","legend":"\u003cp\u003eOverall survival (OS) and relapse-free survival (RFS) in propensity score (PS)-matched patients. A, B. OS and RFS in the whole PS-matched cohort. FLT3 inhibitors (C, D) hematopoietic cell transplantation (HCT) (E, F), and FLT3 inhibitors plus HCT (G, H) improved survival outcomes\u003c/p\u003e","description":"","filename":"Fig2.png","url":"https://assets-eu.researchsquare.com/files/rs-4767599/v1/039d58416f0f21a2febf91ef.png"},{"id":70382419,"identity":"20cb559b-cf8b-4c30-8c78-c7200c23aefd","added_by":"auto","created_at":"2024-12-02 16:26:22","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":550415,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4767599/v1/4a5d831e-0f36-4289-9a47-e8bab55a4f20.pdf"},{"id":63298078,"identity":"5ebde9db-48ac-4731-a16c-3f98855d66b4","added_by":"auto","created_at":"2024-08-26 15:44:04","extension":"eps","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":767482,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplementary Fig. 1\u003c/strong\u003e Age distribution of total cohort (n = 139) showing sex (A) and patients who underwent hematopoietic cell transplantation (HCT) (B)\u003c/p\u003e","description":"","filename":"SuppFig1.eps","url":"https://assets-eu.researchsquare.com/files/rs-4767599/v1/6055fafa4939883ad7aaa687.eps"},{"id":63298079,"identity":"af36d47c-0c6a-420c-a3e0-f95b752a3999","added_by":"auto","created_at":"2024-08-26 15:44:05","extension":"eps","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":1440218,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplementary Fig. 2\u003c/strong\u003e Overall survival (OS) and relapse-free survival (RFS) in all patients. FLT3 inhibitors (A, B), hematopoietic cell transplantation (HCT) (C, D), and FLT3 inhibitors plus HCT (E, F) improved survival outcomes\u003c/p\u003e","description":"","filename":"SuppFig2.eps","url":"https://assets-eu.researchsquare.com/files/rs-4767599/v1/65795898bb7b801325a49b11.eps"},{"id":63299184,"identity":"09ac666f-fc7c-4369-8326-ac321e731ee4","added_by":"auto","created_at":"2024-08-26 15:52:05","extension":"eps","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":879134,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplementary Fig. 3\u003c/strong\u003e Overall survival (OS) in propensity score-matched patients with hematopoietic cell transplantation (HCT). A. Disease status before hematopoietic complete remission (CR) did not affect OS compared with patients without CR (p = 0.44). B. FLT3 inhibitors improved OS in patients without CR\u003c/p\u003e","description":"","filename":"SuppFig3.eps","url":"https://assets-eu.researchsquare.com/files/rs-4767599/v1/9dabaf8d0aa367c0a0535d63.eps"},{"id":63298076,"identity":"cf18d110-f61c-43e0-b1e4-a2cdb38c6430","added_by":"auto","created_at":"2024-08-26 15:44:04","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":17868,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","description":"","filename":"SuppTable.docx","url":"https://assets-eu.researchsquare.com/files/rs-4767599/v1/2eaff22d49d4a4df0db04099.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"FLT3 inhibitors and hematopoietic cell transplantation prolong survival in patients with FLT3-ITD-positive AML","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAcute myeloid leukemia (AML) is an aggressive hematological malignancy characterized by karyotype abnormalities and gene mutations in hematopoietic stem cells and progenitor cells [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Genetic alterations in AML affect the prognosis, and FMS-like tyrosine kinase 3 (FLT3) mutations are frequently detected in patients with \u003cem\u003ede novo\u003c/em\u003e AML. Internal tandem duplication (ITD) at the juxta membrane domain and point mutations in the tyrosine kinase domain (TKD) occur in approximately 25% and 5% of cases of adult AML, respectively [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The \u003cem\u003eFLT3\u003c/em\u003e gene plays a pivotal role in the proliferation, differentiation, and survival of hematopoietic cells [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] \u003cem\u003eFLT3\u003c/em\u003e mutations constitutively activate multiple downstream signaling pathways, including phosphoinositide 3-kinase/Akt and Ras/mitogen-activated protein kinase, which promote cell growth and induce anti-apoptosis [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. \u003cem\u003eFLT3\u003c/em\u003e-ITD AML is associated with a poor prognosis, although emerging FLT3 inhibitors, such as midostaurin, quizartinib, and gilteritinib, have improved survival outcomes in these cases [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. FLT3 inhibitors are classified as type 1 and 2. Type 1 inhibitors, such as gilteritinib, bind to FLT3 and inactivate FLT3 signaling pathways in both \u003cem\u003eFLT3\u003c/em\u003e-ITD and \u003cem\u003eFLT3\u003c/em\u003e-TKD, whereas type 2 inhibitors, such as quizartinib, show increased binding compared with type 1 inhibitors and decrease phosphorylation of FLT3 via \u003cem\u003eFLT3\u003c/em\u003e-ITD [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. FLT3 inhibitors are thus expected to increase survival and prevent relapse; however, their clinical impact in a real-world setting is still unclear. In Japan, the type 1 inhibitor, gilteritinib, was approved in December 2018, followed by the type 2 inhibitor, quizartinib, in October 2019. This study aimed to evaluate the impact of FLT3 inhibitors on survival in patients with \u003cem\u003eFLT3\u003c/em\u003e-ITD-positive AML in a real-world setting.\u003c/p\u003e"},{"header":"Patients and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatient eligibility\u003c/h2\u003e \u003cp\u003eWe conducted a multicenter retrospective questionnaire-based study including patients with \u003cem\u003eFLT3\u003c/em\u003e-ITD AML at 22 institutes in Hokkaido from January 2012 to December 2021. Patients diagnosed with acute promyelocytic leukemia, patients who died within 14 days from diagnosis, and patients with only \u003cem\u003eFLT3\u003c/em\u003e-TKD mutations were excluded. We defined patients who received FLT3 inhibitors for \u0026ge;\u0026thinsp;14 days as \u0026ldquo;administration of FLT3 inhibitors\u0026rdquo; because a shorter usage of FLT3 inhibitors might not impact survival. \u003cem\u003eFLT3\u003c/em\u003e-ITD was detected by companion diagnostics LeukoStrat CDx FLT3 or in-house analysis.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eEndpoints\u003c/h2\u003e \u003cp\u003eThe primary endpoint in this study was overall survival (OS). The secondary endpoints were relapse-free survival (RFS) and rate of induction failure. OS was defined from the day of diagnosis with AML to death. RFS was defined from the day of diagnosis with AML to death, relapse, or progression in patients who achieved complete remission (CR) or CR with incomplete recovery [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003ePropensity score (PS) matching\u003c/h2\u003e \u003cp\u003eTo avoid potential confounding in patient characteristics, we calculated the propensity scores (PS), and caliper-matched cases with or without FLT3 inhibitors in a 1:1 ratio using the nearest-neighbor matching method with multivariable logistic regression analysis. The covariates were sex (female or male), age (\u0026ge;\u0026thinsp;65 or \u0026lt;\u0026thinsp;65 years), Eastern Cooperative Oncology Group (ECOG) performance status (0\u0026ndash;2 or \u0026ge;\u0026thinsp;3), and patients who underwent HCT (yes or no), as factors that might affect survival outcomes.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eThe patients\u0026rsquo; characteristics were tested by χ\u003csup\u003e2\u003c/sup\u003e and Fisher\u0026rsquo;s exact tests for categorical data or the Mann\u0026ndash;Whitney U test for quantitative data. OS and RFS were calculated using the Kaplan\u0026ndash;Meier method. All statistical tests were two-sided, and a p value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered significant. All statistical analyses were performed using the EZR software package in R commander for macOS version 1.61 (Saitama Medical Center, Jichi Medical University; \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.jichi.ac.jp/saitama-sct/SaitamaHP.files/statmedEN.html\u003c/span\u003e\u003cspan address=\"http://www.jichi.ac.jp/saitama-sct/SaitamaHP.files/statmedEN.html\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003ePatient characteristics\u003c/h2\u003e \u003cp\u003eA total of 171 patients were registered, of whom 17 patients with acute promyelocytic leukemia, 11 patients who died within 14 days from diagnosis, and 4 patients with only \u003cem\u003eFLT3\u003c/em\u003e-TKD mutations were excluded. A total of 139 patients met the eligibility criteria. The median age was 63 years (range 7\u0026ndash;95 years) and there were 56 (40.3%) women and 83 (59.7%) men (Supplementary Fig.\u0026nbsp;1). The median ECOG performance status was 1 (range, 0\u0026ndash;4), the median white blood cell count (WBC) at diagnosis was 52,630/L (range, 680\u0026ndash;496,000), and the median serum lactate dehydrogenase (LDH) level was 544.5 U/L (range, 20\u0026ndash;11,937). One hundred patients (71.9%) received intensive chemotherapy (idarubicin\u0026thinsp;+\u0026thinsp;cytarabine, n\u0026thinsp;=\u0026thinsp;76; daunorubicin\u0026thinsp;+\u0026thinsp;cytarabine, n\u0026thinsp;=\u0026thinsp;24). The rest of the patients received non-intensive treatment, including a low-dose cytarabine regimen (n\u0026thinsp;=\u0026thinsp;18), azacytidine alone (n\u0026thinsp;=\u0026thinsp;6), venetoclax\u0026thinsp;+\u0026thinsp;azacytidine (n\u0026thinsp;=\u0026thinsp;3), hydroxyurea (n\u0026thinsp;=\u0026thinsp;6), or best supportive care (n\u0026thinsp;=\u0026thinsp;6). Among the 100 patients who underwent intensive chemotherapy, 67 (67.0%) achieved CR after first induction therapy. Among all 139 eligible cases, a normal karyotype was detected in 104 (74.8%). HCT was conducted in 65 cases (46.8%), with 52 and 13 patients receiving myeloablative conditioning and reduced-intensity conditioning regimens, respectively. \u003cem\u003eFLT3\u003c/em\u003e-ITD mutations alone occurred in 134 (96.4%) patients and \u003cem\u003eFLT3\u003c/em\u003e-ITD plus \u003cem\u003eFLT\u003c/em\u003e-TKD mutations occurred in 5 patients (3.6%). FLT3 inhibitors were administered in 59 cases (42.4%) based on the study criteria for the indication of primary refractory/relapse (n\u0026thinsp;=\u0026thinsp;40) or maintenance (n\u0026thinsp;=\u0026thinsp;19). There was no significant difference in patient age between patients treated with and without FLT3 inhibitors (median 65 years, range 7\u0026ndash;90; median 60.5 years, range 9\u0026ndash;95, respectively) (p\u0026thinsp;=\u0026thinsp;0.76). There were also no significant differences between the two groups in terms of sex (male: 59.3% vs. 60.0%, p\u0026thinsp;\u0026gt;\u0026thinsp;0.95), median WBC at diagnosis (61,280/\u0026micro;L vs. 40,520/\u0026micro;L, p\u0026thinsp;=\u0026thinsp;0.55), median serum LDH level (585 U/L vs. 522 U/L, p\u0026thinsp;=\u0026thinsp;0.64), CR after one course of induction therapy (50.8% vs. 46.2%, p\u0026thinsp;=\u0026thinsp;0.72), cases who underwent HCT (47.5% vs. 46.3%, p\u0026thinsp;\u0026gt;\u0026thinsp;0.95), and \u003cem\u003eFLT3\u003c/em\u003e-ITD alone (94.9% vs. 97.5%, p\u0026thinsp;=\u0026thinsp;0.73) (Supplementary Table\u0026nbsp;1).\u003c/p\u003e \u003cp\u003eWe next compared the patient characteristics in the PS-matched cohort (n\u0026thinsp;=\u0026thinsp;56 per group). There were no significant differences between the two groups in terms of age (median 64 years vs. 63 years, p\u0026thinsp;=\u0026thinsp;0.63), sex (male: 57.2% vs. 55.4%, p\u0026thinsp;\u0026gt;\u0026thinsp;0.95), ECOG performance status (1 vs. 1, p\u0026thinsp;\u0026gt;\u0026thinsp;0.95), median WBC (62,150/\u0026micro;L vs. 51,770/\u0026micro;L, p\u0026thinsp;=\u0026thinsp;0.56), serum LDH level (609.5 U/L vs. 524 U/L, p\u0026thinsp;=\u0026thinsp;0.49), number of cases with intensive chemotherapy (42 vs. 38 cases, p\u0026thinsp;=\u0026thinsp;0.59), CR rate after one course of induction therapy (64.3% vs. 68.4%, p\u0026thinsp;=\u0026thinsp;0.70), patients who underwent HCT (50% vs. 50%, p\u0026thinsp;\u0026gt;\u0026thinsp;0.95), and \u003cem\u003eFLT3\u003c/em\u003e-ITD alone (98.2% vs. 96.4%, p\u0026thinsp;\u0026gt;\u0026thinsp;0.95) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Among patients who underwent HCT, FLT3 inhibitors were administered only before HCT (n\u0026thinsp;=\u0026thinsp;5, 17.9%), only after HCT (n\u0026thinsp;=\u0026thinsp;9, 32.1%), both before and after HCT for maintenance (n\u0026thinsp;=\u0026thinsp;10, 35.7%), and at relapse after HCT (n\u0026thinsp;=\u0026thinsp;4, 14.3%). The FLT3 inhibitor was gilteritinib alone in 44, quizartinib alone in one, sorafenib alone in one, and sequential gilteritinib and quizartinib in 10 patients. FLT3 inhibitors were administered without transplantation for relapsed or refractory disease, not for induction, because upfront FLT3 inhibitors were only approved as induction therapy in Japan in May 2023, after this study period.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePatient characteristics of the whole cohort\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;139)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eage, y median (range)\u003c/p\u003e \u003cp\u003e\u0026lt;\u0026thinsp;65, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e63 (7\u0026ndash;95)\u003c/p\u003e \u003cp\u003e75 (54.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex male/female, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e83 (59.7)/56 (40.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eECOG PS, median (range)\u003c/p\u003e \u003cp\u003e0\u0026ndash;2/3\u0026ndash;4, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (0\u0026ndash;4)\u003c/p\u003e \u003cp\u003e127 (91.4)/12 (8.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWBC, \u0026micro;L median (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e52630 (680\u0026thinsp;\u0026minus;\u0026thinsp;496,000)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLDH, U/L median (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e544.5 (20\u0026thinsp;\u0026minus;\u0026thinsp;11,937)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKaryotype CN/others, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e104 (74.8)/35 (25.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCR to induction therapy, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e67 (48.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHCT, n (%)\u003c/p\u003e \u003cp\u003eMAC/RIC, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e65 (46.8)\u003c/p\u003e \u003cp\u003e52 (80)/13 (20)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eFLT3\u003c/em\u003e-ITD/ITD\u0026thinsp;+\u0026thinsp;TKD, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e134 (96.4)/5 (3.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFLT3 inhibitors, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e59 (42.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003eECOG PS, Eastern Cooperative Oncology Group performance status; WBC, white blood cell; LDH, lactate dehydrogenase; CN, cytogenetically normal; CR, complete remission; HCT, hematopoietic cell transplantation; MAC, myeloablative conditioning; RIC, reduced-intensity conditioning; ITD, internal tandem duplication; TKD, tyrosine kinase domain\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePatient characteristics of propensity score matched cohort\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFLT3i (+)\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;56)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFLT3 (-)\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;56)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eage, y median (range)\u003c/p\u003e \u003cp\u003e\u0026lt;\u0026thinsp;65, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e64 (7\u0026ndash;90)\u003c/p\u003e \u003cp\u003e29 (51.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e63 (9\u0026ndash;95)\u003c/p\u003e \u003cp\u003e29 (51.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.63\u003c/p\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex male/female, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32 (57.1)/24 (42.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31 (55.4)/25 (44.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eECOG PS, median (range)\u003c/p\u003e \u003cp\u003e0\u0026ndash;2/3\u0026ndash;4, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (0\u0026ndash;4)\u003c/p\u003e \u003cp\u003e53 (94.6)/3 (5.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (0\u0026ndash;4)\u003c/p\u003e \u003cp\u003e53 (94.6)/3 (5.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.48\u003c/p\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWBC, \u0026micro;L median\u003c/p\u003e \u003cp\u003e(range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e62165\u003c/p\u003e \u003cp\u003e(1310\u0026thinsp;\u0026minus;\u0026thinsp;496,000)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e51770\u003c/p\u003e \u003cp\u003e(1100\u0026thinsp;\u0026minus;\u0026thinsp;337,900)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.55\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLDH, U/L median\u003c/p\u003e \u003cp\u003e(range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e609.5\u003c/p\u003e \u003cp\u003e(20\u0026thinsp;\u0026minus;\u0026thinsp;11,937)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e524\u003c/p\u003e \u003cp\u003e(154-3,973)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.71\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCR to induction therapy, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28 (50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27 (48.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKaryotype NK/others, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e44 (78.6)/12 (21.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e38 (67.9)/18 (32.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.29\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHCT, n (%)\u003c/p\u003e \u003cp\u003eMAC/RIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28 (50)\u003c/p\u003e \u003cp\u003e22 (78.6)/6 (21.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28 (50)\u003c/p\u003e \u003cp\u003e23 (82.1)/5 (17.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eITD/ITD\u0026thinsp;+\u0026thinsp;TKD, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e55 (98.2)/1 (1.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e54 (96.4)/2 (3.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThe type of FLT3i, n (%)\u003c/p\u003e \u003cp\u003egilteritinib\u003c/p\u003e \u003cp\u003equizartinib\u003c/p\u003e \u003cp\u003esorafenib\u003c/p\u003e \u003cp\u003egilteritinib \u0026loz; quizartinib\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e44 (78.6)\u003c/p\u003e \u003cp\u003e1 (1.8)\u003c/p\u003e \u003cp\u003e1 (1.8)\u003c/p\u003e \u003cp\u003e10 (17.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eFLT3i, FLT3 inhibitor; ECOG PS, Eastern Cooperative Oncology Group performance status; WBC, white blood cell; LDH, lactate dehydrogenase; CN, cytogenetically normal; CR, complete remission; HCT, hematopoietic cell transplantation; MAC, myeloablative conditioning; RIC, reduced-intensity conditioning; ITD, internal tandem duplication; TKD, tyrosine kinase domain\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eSurvival outcomes\u003c/h2\u003e \u003cp\u003eThe 3-year OS and RFS in the whole study cohort were 27.4% (95% confidence interval [CI], 19.6\u0026ndash;35.7%) and 23.0% (95% CI, 16.1\u0026ndash;30.7%), respectively (Fig.\u0026nbsp;1A, B). We compared survival according to age: \u0026lt;18 years, adult/young adult (18\u0026ndash;40 years), 41\u0026ndash;70 years, and \u0026gt;\u0026thinsp;70 years. There were only five patients aged\u0026thinsp;\u0026lt;\u0026thinsp;18 years, but these limited cases showed favorable OS (3-year OS: 60% [95% CI, 12.6\u0026ndash;88.2%]). Patients in the 18\u0026ndash;40 and 41\u0026ndash;70 year groups demonstrated 3-year OS rates of 51.8% (95% CI, 26.2\u0026ndash;72.4%) and 30.2% (95% CI, 19.5\u0026ndash;41.6%), respectively. However, patients aged\u0026thinsp;\u0026gt;\u0026thinsp;70 years showed poor OS (4.7% [95% CI, 0.4\u0026ndash;18.6%]) (Fig.\u0026nbsp;1C). The 3-year RFS rates in patients aged\u0026thinsp;\u0026lt;\u0026thinsp;18, 18\u0026ndash;40, 41\u0026ndash;70, and \u0026gt;\u0026thinsp;70 years were 40% (95% CI, 5.2\u0026ndash;75.3%), 51.8% (95% CI, 26.2\u0026ndash;72.4%), 23.8% (95% CI, 14.7\u0026ndash;34.1%), and not reached, respectively (Fig.\u0026nbsp;1D). The use of FLT3 inhibitors divided the prognosis, with patients receiving FLT3 inhibitors having better OS than those without FLT inhibitors (3-year OS: 32.4% vs. 23.4%, p\u0026thinsp;=\u0026thinsp;0.0068) (Supplementary Fig.\u0026nbsp;2A). RFS in the group treated with FLT3 inhibitors in the whole cohort was similar to the group without FLT3 inhibitors (3-year RFS: 28.3% vs. 19.4%, p\u0026thinsp;=\u0026thinsp;0.21) (Supplementary Fig.\u0026nbsp;2B). OS and RFS were improved in patients with HCT compared with those without HCT (3-year OS: 45.3% vs. 2.2%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001; 3-year RFS: 40.2% vs. 4.9%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) (Supplementary Fig.\u0026nbsp;2C, D). OS and RFS were highest among patients treated with FLT3 inhibitors and HCT compared with the other groups (both p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) (Supplementary Fig.\u0026nbsp;2E, F). The hazard ratios for OS according to use of FLT3 inhibitors and HCT in all eligible cases were 0.57 (95% CI, 0.38\u0026ndash;0.86, p\u0026thinsp;=\u0026thinsp;0.0076) and 0.31 (95% CI, 0.21\u0026ndash;0.48, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), respectively.\u003c/p\u003e \u003cp\u003eThe 3-year OS and RFS rates in the PS-matched cohort were 29.7% (95% CI, 20.9\u0026ndash;39.1%) and 25.0% (95% CI, 17.0\u0026ndash;33.8%), respectively (Fig.\u0026nbsp;2A, B). FLT3 inhibitors improved OS in the PS-matched cohort compared with the group without FLT3 inhibitors (3-year OS: 33.7% vs. 25.8%, p\u0026thinsp;=\u0026thinsp;0.021), but had no effect on RFS (28.1% vs. 21.9%, p\u0026thinsp;=\u0026thinsp;0.48) (Fig.\u0026nbsp;2C, D). HCT improved OS and RFS in the PS-matched cohort compared with patients without HCT (3-year OS: 47.9% vs. 6.8%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001; 3-year RFS: 43.2% vs. not reached, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001, respectively) (Fig.\u0026nbsp;2E, F). In the PS-matched cohort, FLT3 inhibitors plus HCT also improved OS (3-year OS: FLT3 inhibitors\u0026thinsp;+\u0026thinsp;HCT, 62.4%; HCT alone, 34.8%; FLT inhibitors alone, not reached; no FLT3 inhibitors or HCT, 17.4%; p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) and RFS (3-year RFS: FLT3 inhibitors\u0026thinsp;+\u0026thinsp;HCT, 67.2%; HCT alone, 14.4%; FLT inhibitors alone, not reached; no FLT3 inhibitors or HCT, not reached; p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) (Fig.\u0026nbsp;2G, H). Among patients who underwent HCT, hematological CR did not affect survival compared with non-CR (3-year OS: 50.5% vs. 40.0%, p\u0026thinsp;=\u0026thinsp;0.44) (Supplementary Fig.\u0026nbsp;3A). Patients without CR receiving FLT3 inhibitors demonstrated superior survival outcomes compared with patients without CR and without FLT3 inhibitors (3-year OS: 62.5% vs. 16.7%, p\u0026thinsp;=\u0026thinsp;0.022), (Supplementary Fig.\u0026nbsp;3B), although the comparison was limited by the small number of cases. The use of FLT inhibitors did not affect survival among patients with CR before HCT (3-year OS: with inhibitors 62.9% vs. without inhibitors 40.0%, p\u0026thinsp;=\u0026thinsp;0.15).\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eWe retrospectively analyzed patients with \u003cem\u003eFLT3\u003c/em\u003e-mutated AML in a regional multicenter cohort in Japan. The results showed that FLT3 inhibitors and HCT improved survival outcomes among patients with \u003cem\u003eFLT3\u003c/em\u003e-ITD AML, while the combination of FLT3 inhibitors and HCT led to superior outcomes compared with the other treatment groups. FLT3 inhibitor administration improved outcomes among patients without HCT, but HCT had a more significant impact than FLT3 inhibitors. Among patients undergoing HCT, FLT3 inhibitors had no impact in patients with hematological CR before HCT, but improved survival in patients without CR before HCT, compared with patients without FLT3 inhibitors. Gilteritinib was approved for relapsed/refractory \u003cem\u003eFLT3\u003c/em\u003e-ITD/-TKD mutated AML and quizartinib was approved for newly diagnosed and relapsed/refractory \u003cem\u003eFLT3\u003c/em\u003e-ITD AML in Japan, but quizartinib was not approved for newly diagnosed AML during the study period. Upfront FLT3 inhibitors combined with conventional 7\u0026thinsp;+\u0026thinsp;3 induction might enhance the impact of FLT3 inhibitors.\u003c/p\u003e \u003cp\u003eMidostaurin, a first-generation type 1 tyrosine kinase inhibitor for \u003cem\u003eFLT3\u003c/em\u003e-mutated AML, inhibits multi-kinases such as FLT3, KIT, and platelet-derived growth factor receptor. In the randomized phase 3 RATIFY trial, midostaurin with conventional 7\u0026thinsp;+\u0026thinsp;3 induction therapy, improved OS compared with conventional chemotherapy alone in patients with newly diagnosed \u003cem\u003eFLT3\u003c/em\u003e-mutated AML, but had no additional effect in patients aged\u0026thinsp;\u0026ge;\u0026thinsp;60 years [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. First-generation FLT3 inhibitors such as midostaurin have poor specificity for FLT3 and many off-target effects, leading to side effects, including hematological adverse events [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Most cases (96.2%) in the current PS-matched cohort who were treated with FLT3 inhibitors initially selected gilteritinib, because this was the first-in-class agent to be approved in Japan. Gilteritinib is a second-generation type 1 FLT3 inhibitor with a high affinity for mutated FLT3 receptors that inhibits the phosphorylation of FLT3 and AXL. The randomized phase 3 ADMIRAL trial showed that gilteritinib prolonged survival in patients with relapsed or refractory \u003cem\u003eFLT3\u003c/em\u003e-mutated AML and induced a high incidence of CR compared with patients who received conventional salvage chemotherapy [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. In the current study, disease status before transplantation did not affect OS, but the use of FLT3 inhibitors improved survival in patients without CR undergoing HCT. Low-dose gilteritinib after HCT also improved outcomes in initiating early post-transplantation as maintenance therapy [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. In the ADMIRAL trial, patients who underwent HCT showed comparable outcomes between the pretransplant gilteritinib and salvage chemotherapy arms, but patients who resumed gilteritinib after HCT had better outcomes than those who did not resume gilteritinib in the gilteritinib arm [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Moreover, Levis et al. reported that patients with \u003cem\u003eFLT3\u003c/em\u003e-ITD with hematological CR of 1 \u0026times; 10\u003csup\u003e\u0026minus;\u0026thinsp;6\u003c/sup\u003e or greater for \u003cem\u003eFLT3\u003c/em\u003e-ITD had poor OS and RFS without gilteritinib, but gilteritinib combined with HCT increased survival among these patients [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Maintenance therapy with FLT3 inhibitors after transplantation might prevent relapse and improve prognosis, but patients eligible for maintenance therapy after HCT need to be selected in terms of disease status pre- or post-transplantation.\u003c/p\u003e \u003cp\u003eThe second-generation type 2 FLT3 inhibitor, quizartinib, selectively inhibits FLT3 but has lower affinity to KIT, RET, colony-stimulating factor-1 receptor, and platelet-derived growth factor receptor [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. In a phase 1 clinical trial of post-transplant maintenance therapy, four (31%) patients survived\u0026thinsp;\u0026gt;\u0026thinsp;2 years; however, the sample size was very small, and no large randomized trials of quizartinib have been conducted for \u003cem\u003eFLT3\u003c/em\u003e-ITD AML after HCT [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. A study using real-world data for 1208 patients with \u003cem\u003eFLT3\u003c/em\u003e-mutated AML from eight countries showed that post-transplant administration of FLT3 inhibitors (n\u0026thinsp;=\u0026thinsp;219, 18.1%), including midostaurin (n\u0026thinsp;=\u0026thinsp;140, 63.9%), sorafenib (n\u0026thinsp;=\u0026thinsp;58, 26.5%), gilteritinib (n\u0026thinsp;=\u0026thinsp;14, 6.4%), and quizartinib (n\u0026thinsp;=\u0026thinsp;9, 4.1%), or other maintenance therapy (n\u0026thinsp;=\u0026thinsp;224, 18.5%) improved survival [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. In a randomized phase 3 trial, quizartinib in combination with intensive chemotherapy, improved OS, especially in cases with a higher \u003cem\u003eFLT3\u003c/em\u003e-ITD variant allelic frequency [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]; however, quizartinib with conventional chemotherapy still failed to improve OS in patients aged\u0026thinsp;\u0026ge;\u0026thinsp;60 years, and the study did not include patients who received FLT3 inhibitors as induction therapy. FLT3 inhibitors improved survival in patients with relapsed or refractory \u003cem\u003eFLT3\u003c/em\u003e-ITD AML without HCT in the current study, as reported in previous phase 3 studies of gilteritinib and quizartinib [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe current study had several limitations. First, the study retrospectively analyzed a small number of cases. Second, genetic alterations other than \u003cem\u003eFLT3\u003c/em\u003e mutations could not be assessed because a comprehensive panel for genetic mutations has not been approved in Japan. Third, FLT3 inhibitors were administered for many purposes in the patients who underwent HCT, including maintenance before transplantation and relapse after transplantation. Finally, the disease status before HCT was only assessed by morphological evaluation.\u003c/p\u003e \u003cp\u003eIn conclusion, this retrospective multicenter study revealed that FLT3 inhibitors and HCT improved survival in patients with \u003cem\u003eFLT3\u003c/em\u003e-ITD AML in a real-world setting. HCT had a more significant impact on survival among these patients, and intensive chemotherapy plus FLT3 inhibitors with HCT for fit patients with \u003cem\u003eFLT3\u003c/em\u003e-ITD AML might lead to better outcomes. Further studies are needed to determine which patients are suitable for FLT3 inhibitors as maintenance therapy after HCT.\u003c/p\u003e "},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank Susan Furness, PhD, from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript. We would like to thank all the physicians, the nursing and medical staff for their contributions and dedicated care of the patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors received no specific funding for this work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict-of-interest disclosure\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no conflicts of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll procedures involving human participants were in accordance with the ethical standards of institutional research committees, national guidelines, and with the Declaration of Helsinki. This study was approved by the institutional review board of Hokkaido University Hospital (#022-0085).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthorship contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eT. Matsukawa and T.K. designed this study. T. Matsukawa, M.O., T.K., M.K., D. Hidaka, S.O., A.M., A.S., T. Miyagishima, Y. Kakinoki, J.H., S.Y., M.Y., K.W., M.T., T. Ishihara, Y.H., A.F., T. Igarashi, T.S., S.I., R.K., H.S., K.F., J.I., Y. Kanisawa, S.H., T.E. and D. Hashimoto performed recruitment and treatment. T. Matsukawa, T.K., M.K., D. Hidaka, S.O., A.M., A.S., T. Miyagishima, Y. Kakinoki, J.H., S.Y., M.Y., K.W., M.T., T. Ishihara, Y.H., A.F., T. Igarashi, T.S., S.I., R.K., H.S., K.F., J.I., Y. Kanisawa, S.H., and T.E. collected the data. T. Matsukawa analyzed and interpreted data. T. Matsukawa and M.O. wrote the manuscript. T.T. supervised this study. All authors provided critique of the manuscript, contributed to the final version of the manuscript, and approved it for publication.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003ePapaemmanuil E, Gerstung M, Bullinger L, Gaidzik VI, Paschka P, Roberts ND, Potter NE, Heuser M, Thol F, Bolli N, Gundem G, Van Loo P, Martincorena I, Ganly P, Mudie L, McLaren S, O'Meara S, Raine K, Jones DR, Teague JW, Butler AP, Greaves MF, Ganser A, Dohner K, Schlenk RF, Dohner H, Campbell PJ (2016) Genomic Classification and Prognosis in Acute Myeloid Leukemia. 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Lancet Oncol 20(7):984\u0026ndash;997. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/s1470-2045(19)30150-0\u003c/span\u003e\u003cspan address=\"10.1016/s1470-2045(19)30150-0\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"annals-of-hematology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"aohe","sideBox":"Learn more about [Annals of Hematology](http://link.springer.com/journal/277)","snPcode":"277","submissionUrl":"https://submission.nature.com/new-submission/277/3","title":"Annals of Hematology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"acute myeloid leukemia, FLT3-ITD, FLT3 inhibitor","lastPublishedDoi":"10.21203/rs.3.rs-4767599/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4767599/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eAcute myeloid leukemia (AML) is an aggressive hematological malignancy with genetic alterations. The FMS-like tyrosine kinase 3 (FLT3) gene is frequently mutated in adult \u003cem\u003ede novo\u003c/em\u003e AML, with two types of mutations: internal tandem duplication (ITD) and point mutations in the tyrosine kinase domain. This study aimed to investigate the impact of FLT3 inhibitors and hematopoietic cell transplantation (HCT) on survival outcomes in patients with \u003cem\u003eFLT3\u003c/em\u003e-ITD AML in a real-world setting. We retrospectively analyzed 139 patients with \u003cem\u003eFLT3\u003c/em\u003e-ITD-positive AML between 2012 and 2021. The median age was 63 years. In the propensity score-matched cohort, FLT3 inhibitors improved overall survival (OS) compared with patients treated without FLT3 inhibitors (3-year OS: 33.7% vs. 25.8%, p\u0026thinsp;=\u0026thinsp;0.021). Patients who underwent HCT had superior outcomes to those without HCT (3-year OS: 45.3% vs. 2.2%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). The combination of FLT3 inhibitors and HCT resulted in the highest OS and relapse-free survival (RFS) rates (3-year OS: 62.4%; 3-year RFS: 67.2%). Disease status before transplantation did not predict the prognosis, but use of FLT3 inhibitors increased survival in patients without complete remission before HCT. These results demonstrate the clinical impact of FLT3 inhibitors on survival outcomes in patients with \u003cem\u003eFLT3\u003c/em\u003e-ITD-positive AML, particularly when combined with HCT. FLT3 inhibitor can improve the prognosis of AML with \u003cem\u003eFLT3\u003c/em\u003e mutations, especially in patients who undergo HCT.\u003c/p\u003e","manuscriptTitle":"FLT3 inhibitors and hematopoietic cell transplantation prolong survival in patients with FLT3-ITD-positive AML","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-08-26 15:44:00","doi":"10.21203/rs.3.rs-4767599/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-11-12T12:34:12+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-11-12T09:59:37+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"314933368593681149314156349780682659362","date":"2024-11-02T23:22:14+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"301645827769812992459844610385105516310","date":"2024-11-02T16:52:37+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"173187522100454977454750766708256568718","date":"2024-08-08T15:38:12+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-07-25T03:22:54+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-07-24T16:28:17+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-07-24T16:26:41+00:00","index":"","fulltext":""},{"type":"submitted","content":"Annals of Hematology","date":"2024-07-19T10:51:09+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"annals-of-hematology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"aohe","sideBox":"Learn more about [Annals of Hematology](http://link.springer.com/journal/277)","snPcode":"277","submissionUrl":"https://submission.nature.com/new-submission/277/3","title":"Annals of Hematology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"d9d54990-fdd5-4891-b568-58308ea40568","owner":[],"postedDate":"August 26th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-12-02T16:00:42+00:00","versionOfRecord":{"articleIdentity":"rs-4767599","link":"https://doi.org/10.1007/s00277-024-06125-9","journal":{"identity":"annals-of-hematology","isVorOnly":false,"title":"Annals of Hematology"},"publishedOn":"2024-11-30 15:57:15","publishedOnDateReadable":"November 30th, 2024"},"versionCreatedAt":"2024-08-26 15:44:00","video":"","vorDoi":"10.1007/s00277-024-06125-9","vorDoiUrl":"https://doi.org/10.1007/s00277-024-06125-9","workflowStages":[]},"version":"v1","identity":"rs-4767599","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4767599","identity":"rs-4767599","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}