Archives of Hematology and Blood Transfusion (AHBT)
Vol. 3, Issue 01, 2021

Prognostic Weight of FLT3-ITD Allelic Ratio in Newly Diagnosed Acute Myeloid Leukemia

Ferdinand Gregor1, A. Ivanic2, S. Ilavsky3

1Department of Laboratory Hematology, Iskar Institute of Clinical Coagulation Medicine
2Department of Cellular Therapy and Transplantation, Loire Center for Coagulation and Hemostasis Research
3Department of Transfusion Medicine and Blood Banking, Osam Institute of Applied Hematology
DOI: 10.5281/zenodo.22818745 | Published: 2021-11-25 | Article page and PDF

Abstract

Background: FLT3 internal tandem duplication (ITD) is among the most common and prognostically consequential mutations in newly diagnosed acute myeloid leukemia (AML), but its clinical impact is not uniform across patients.

Objective: To synthesize the published evidence on how the FLT3-ITD mutant-to-wild-type allelic ratio, rather than mutation presence alone, shapes prognosis, interacts with NPM1 co-mutation status, and informs the use of FLT3 inhibitors and allogeneic transplantation.

Methods: Narrative review of landmark cohort studies, European LeukemiaNet risk-classification updates, and randomized phase 3 trials of midostaurin, gilteritinib, quizartinib, and sorafenib in FLT3-mutated AML.

Findings: High allelic ratio (>=0.5) confers markedly worse relapse-free and overall survival than low-ratio disease, an effect layered onto NPM1 mutation status; FLT3 inhibitors improve survival across the newly diagnosed and relapsed/refractory settings, and inhibitor-era trials have generally not shown ratio to modify drug benefit, prompting the 2022 ELN revision that removed the ratio-based split for NPM1-mutated, FLT3-ITD-positive disease.

Conclusions: Allelic ratio remains a useful marker of FLT3 dependency and relapse risk that should inform transplant referral and maintenance decisions, but its role is increasingly one input among measurable residual disease and co-mutation data rather than a standalone risk cutoff.

Keywords: FLT3-ITD; allelic ratio; acute myeloid leukemia; NPM1; FLT3 inhibitors

1. Introduction

FLT3 internal tandem duplication was first described three decades ago as an in-frame insertion within the juxtamembrane domain of the FLT3 receptor tyrosine kinase, identified in a subset of acute myeloid leukemia samples by Nakao and colleagues using a simple genomic PCR assay [1]. What began as a curiosity of exon 14/15 length polymorphism turned out to be one of the two or three most consequential single lesions in adult AML. Kiyoi and colleagues linked the duplication to leukocytosis and, in a cohort large enough to matter, to shortened survival [2], and within a few years the UK Medical Research Council group confirmed the finding at scale: among 854 patients enrolled on the AML10 and AML12 trials, FLT3-ITD was present in roughly 27% of cases and independently predicted both relapse and overall survival after adjustment for cytogenetic risk group [3]. Thiede and colleagues, working through 979 patients treated on German multicenter protocols, reported an ITD frequency close to 23% and confirmed the adverse association across FAB subtypes [4]. By the early 2000s, FLT3-ITD positivity itself was accepted as bad news, and it had already become the mutation most consistently invoked when clinicians discussed molecularly targeted approaches to AML risk assessment [5].

What took longer to appreciate was that "FLT3-ITD positive" is not a single biological state. Duplications vary in length from a few base pairs to over 100, insert at different points within the juxtamembrane and adjacent tyrosine kinase domain 1, and — critically — occupy a variable fraction of the leukemic allele pool. Whitman and colleagues showed that loss of the wild-type FLT3 allele, leaving leukemic cells effectively hemizygous for the mutant, tracked with a particularly poor outcome in cytogenetically normal AML, an observation that reframed FLT3-ITD as a dosage phenomenon rather than a binary mutation call [6]. That reframing is the subject of this review: how the allelic ratio of mutant to wild-type FLT3, now measured routinely by fragment-length PCR or targeted next-generation sequencing at diagnosis, has become a continuous prognostic variable that reshapes European LeukemiaNet risk stratification, transplant referral, and the interpretation of trials testing FLT3 inhibitors in both the frontline and relapsed settings.

2. FLT3-ITD biology and detection methods

FLT3 is a class III receptor tyrosine kinase expressed on early myeloid and lymphoid progenitors; ligand binding drives receptor dimerization and downstream activation of RAS-MAPK, PI3K-AKT, and STAT5 signaling. The internal tandem duplication disrupts the autoinhibitory function of the juxtamembrane domain, producing constitutive, ligand-independent kinase activity. Because the duplicated sequence is an in-frame insertion of variable length rather than a substitution, it can be resolved by capillary fragment-length analysis of a PCR product spanning exons 14 and 15, a method that also yields the relative peak-area ratio of mutant to wild-type product — the basis for the allelic ratio measurement used in most published cohorts [4,7]. Schnittger and colleagues catalogued the diversity of insertion sites and lengths across a large diagnostic series and showed that both length and location within the juxtamembrane-TKD1 region correlate with mutant burden and, independently, with outcome [7]. Insertions that extend into the first beta-strand of the tyrosine kinase domain rather than remaining confined to the juxtamembrane region carry a distinctly worse prognosis, a finding first quantified by Kayser and colleagues in an analysis in which TKD1-inserted ITD conferred resistance to induction chemotherapy and inferior relapse-free survival compared with juxtamembrane-only insertions [8]. Next-generation sequencing panels have since largely supplanted fragment analysis for detecting co-mutations but are only gradually replacing it for ITD quantification, because short-read assemblers handle long, GC-rich duplications poorly; most allelic-ratio data guiding clinical decisions today still derive from the fragment-analysis platform that Kottaridis, Thiede, and Gale used to build the original evidence base [3,9].

3. Allelic ratio as a continuous prognostic variable

The single most influential demonstration that ratio, not presence or absence, drives risk came from Gale and colleagues, who reanalyzed a large cohort of young adults with AML using quantitative measurement of ITD mutant-to-wild-type signal [9]. Patients with a high allelic ratio, conventionally defined at or above 0.5, had roughly a three-fold increase in relapse risk compared with those with a low ratio, and five-year overall survival diverged sharply — in the range of 15% for high-ratio disease versus close to half for low-ratio disease within the same cytogenetically normal, NPM1-unmutated stratum [9]. That paper also showed that ITD length and number of duplicated clones added little once ratio was accounted for, which is part of why allelic ratio, rather than length or insertion count, became the parameter written into subsequent risk-classification schemes. Kayser and colleagues' TKD1-insertion data reinforced the same conclusion from a different angle: insertion site correlated with ratio and with resistance to the first cycle of induction, and multivariable models that included ratio retained it as an independent predictor of both event-free and overall survival [8]. In pediatric AML, Meshinchi and colleagues found essentially the same gradient — high-ratio FLT3-ITD was associated with markedly worse event-free survival than low-ratio disease, with the low-ratio group behaving closer to FLT3-wild-type patients than to their high-ratio ITD-positive counterparts [10]. The practical consequence is that a diagnostic FLT3 assay reporting only "ITD detected" without a quantitative ratio now under-informs the treating physician; the ratio, not the mutation call, is what most contemporary risk algorithms actually consume.

4. Interaction with NPM1 and co-mutation context

FLT3-ITD rarely occurs alone, and its prognostic weight is not separable from the mutation landscape it sits within. Roughly a third of adult AML carries a mutation in NPM1, first shown by Falini and colleagues to produce aberrant cytoplasmic localization of nucleophosmin and to define a molecularly distinct, generally favorable-risk subgroup within cytogenetically normal AML [11]. Schlenk and colleagues, studying patients enrolled on German AML Study Group protocols, showed that NPM1 mutation without FLT3-ITD carried a good prognosis that allogeneic transplantation in first remission did not improve, whereas the presence of FLT3-ITD — particularly at high allelic ratio — eroded that favorable effect and identified patients for whom transplant in first complete remission produced a clear survival benefit [12]. Thiede and colleagues' companion analysis of NPM1 mutation prevalence and prognostic impact across nearly 1,500 adults reinforced the same interaction: NPM1-mutated, FLT3-ITD-negative disease had the best outcomes, NPM1-wild-type, FLT3-ITD-positive disease the worst, and the NPM1-mutated/FLT3-ITD-positive group fell in between, with allelic ratio determining where within that middle group a given patient actually sat [13]. Broader genomic profiling has since placed this three-way interaction inside a larger mutational context. Patel and colleagues, analyzing patients from the ECOG E1900 trial with integrated sequencing, found that FLT3-ITD's prognostic effect was modulated by co-occurring DNMT3A and NPM1 status and, unexpectedly, by anthracycline dose during induction [14]. Papaemmanuil and colleagues, sequencing over five thousand AML cases, formalized AML genomics into class-defining subgroups and confirmed that FLT3-ITD, when it co-occurs with NPM1 mutation and no adverse-risk cytogenetic lesion, drives a genomically coherent subgroup whose outcome is disproportionately sensitive to ITD allelic burden rather than to the NPM1 mutation itself [15]. This is the mechanistic basis for the 2017 European LeukemiaNet recommendation to split NPM1-mutated, FLT3-ITD-positive AML by allelic ratio, assigning low-ratio disease to the favorable-risk category and high-ratio disease to intermediate risk [16].

Table 1: How FLT3-ITD allelic ratio modifies NPM1-based risk stratification under the 2017 European LeukemiaNet framework, reflecting the outcome gradient first described across these cohorts [11,12,13,9,16].
Table 1: How FLT3-ITD allelic ratio modifies NPM1-based risk stratification under the 2017 European LeukemiaNet framework, reflecting the outcome gradient first described across these cohorts [11,12,13,9,16].
Figure 1: Five-year overall survival diverges sharply by FLT3-ITD allelic ratio, at roughly 50% for low-ratio (<0.5) versus roughly 15% for high-ratio (>=0.5) disease in young adult AML [9], while addition of midostaurin to chemotherapy narrows a comparable gap in the
Figure 1: Five-year overall survival diverges sharply by FLT3-ITD allelic ratio, at roughly 50% for low-ratio (<0.5) versus roughly 15% for high-ratio (>=0.5) disease in young adult AML [9], while addition of midostaurin to chemotherapy narrows a comparable gap in the

unselected FLT3-mutated RATIFY population, with 4-year overall survival of 51.4% versus 44.3% for placebo [17].

5. FLT3 inhibitors and how they change the calculus

The clinical relevance of allelic ratio did not stay static once small-molecule FLT3 inhibitors entered practice, because the drugs both improve outcomes across ratio strata and complicate the biological argument for why ratio mattered in the first place. The RATIFY trial, led by Stone and colleagues, randomized newly diagnosed FLT3-mutated (ITD or TKD) AML patients aged 18-60 to induction and consolidation chemotherapy with or without the multikinase inhibitor midostaurin; four-year overall survival was 51.4% with midostaurin versus 44.3% with placebo, a statistically significant improvement that held across FLT3-ITD allelic-ratio subgroups in prespecified analysis [17]. A subsequent Alliance analysis of the same cohort, focused on relapse rather than overall survival, confirmed that midostaurin's principal effect was a reduction in relapse incidence rather than a change in complete remission rate, consistent with a drug acting on residual FLT3-driven clones after induction [18]. Pratz and colleagues had earlier shown, using an ex vivo phospho-flow assay, that the degree of FLT3 mutant allelic burden correlated with in vitro sensitivity to FLT3 inhibition, providing a mechanistic rationale for why high-ratio disease — biologically more dependent on FLT3 signaling — might derive proportionally more benefit from inhibitor therapy even though it starts from a

Figure 2: Median overall survival with FLT3 inhibitors versus control across three randomized phase 3 trials: gilteritinib 9.3 months versus chemotherapy 5.6 months in relapsed/refractory disease (ADMIRAL) [21]; quizartinib 6.2 months versus chemotherapy 4.7 months in
Figure 2: Median overall survival with FLT3 inhibitors versus control across three randomized phase 3 trials: gilteritinib 9.3 months versus chemotherapy 5.6 months in relapsed/refractory disease (ADMIRAL) [21]; quizartinib 6.2 months versus chemotherapy 4.7 months in

relapsed/refractory FLT3-ITD disease (QuANTUM-R) [20]; and quizartinib plus chemotherapy 31.9 months versus placebo plus chemotherapy 15.1 months in newly diagnosed FLT3-ITD disease (QuANTUM-First) [24].

In the relapsed and refractory setting, allelic ratio again shaped both trial design and result. Cortes and colleagues' QuANTUM-R trial restricted enrollment to FLT3-ITD-positive relapsed or refractory AML and randomized patients to the selective inhibitor quizartinib versus salvage chemotherapy; median overall survival was 6.2 months with quizartinib against 4.7 months with chemotherapy, a modest but statistically significant gain in a population selected specifically for ITD positivity rather than for ratio [20]. Perl and colleagues' ADMIRAL trial tested the type I inhibitor gilteritinib against salvage chemotherapy in relapsed or refractory FLT3-mutated AML (ITD or TKD) and reported a median overall survival of 9.3 months versus 5.6 months, with the survival curves separating early and persisting on longer follow-up [21,22]. Neither trial reported allelic ratio as a major effect modifier of inhibitor benefit, an observation that, taken together with the 2022 European LeukemiaNet revision removing the allelic-ratio split for NPM1-mutated, FLT3-ITD-positive disease, reflects a genuine shift in the field: once an effective FLT3-directed drug is available for essentially every ITD-positive patient, the biological argument for a ratio-based prognostic cutoff weakens, even though the underlying disease biology that produced the original cutoff has not changed [23]. Most recently, Erba and colleagues extended FLT3 inhibition to the frontline setting in QuANTUM-First, combining quizartinib with standard induction and consolidation in newly diagnosed FLT3-ITD AML; median overall survival was 31.9 months with quizartinib versus 15.1 months with placebo, again in a trial that enrolled by ITD positivity without an allelic-ratio threshold [24]. Sorafenib, an earlier and less selective FLT3 inhibitor, showed a more modest and cytogenetics-independent benefit in the SORAML trial conducted by Röllig and colleagues in an unselected younger AML population, improving event-free survival without a clear overall survival advantage [25], and its principal contemporary role is as post-transplant maintenance, where Burchert and colleagues' SORMAIN trial demonstrated a substantial reduction in relapse and improvement in relapse-free survival among FLT3-ITD-positive patients randomized to sorafenib versus placebo after allogeneic transplantation [26].

6. Transplant in first remission: who still needs it

Allogeneic hematopoietic cell transplantation in first complete remission remains the most reliable way to consolidate high-risk FLT3-ITD AML, and allelic ratio continues to inform who is referred even as inhibitor availability broadens. Schlenk and colleagues' original demonstration that transplant benefit concentrated in the FLT3-ITD-positive, particularly high-ratio, subgroup rather than in NPM1-mutated/FLT3-ITD-negative patients established the template still used in multidisciplinary planning: transplant in first remission for high-ratio or NPM1-wild-type FLT3-ITD disease, and chemotherapy consolidation alone, reserving transplant for relapse, in low-ratio NPM1-mutated disease [12]. Measurable residual disease assessment has begun to refine that binary further. Ivey and colleagues showed, in standard-risk (which in practice means largely NPM1-mutated) AML, that persistence of NPM1 transcript by quantitative PCR after induction predicted relapse far better than mutation status alone, a principle increasingly applied alongside FLT3-ITD ratio rather than in place of it, since ITD subclones can be lost or gained between diagnosis and relapse in ways that NPM1 mutation typically is not [27]. Where post-transplant FLT3-ITD status is known, Burchert and colleagues' SORMAIN data argue for FLT3-directed maintenance regardless of the diagnostic allelic ratio, since ratio at diagnosis does not reliably predict ITD clonal burden at the time of transplant [26]. The net effect of a decade of inhibitor trials has been to narrow, but not eliminate, the group of FLT3-ITD patients for whom transplant in first remission is unambiguously indicated: very high allelic ratio, adverse co-mutations such as DNMT3A or adverse-risk cytogenetics, and persistent measurable residual disease after induction remain the strongest indications, while low-ratio, NPM1-mutated, chemosensitive disease increasingly tolerates a chemotherapy-plus-inhibitor strategy with transplant held in reserve [23,14].

Table 2: Trials shaping the decision to transplant or add a FLT3 inhibitor in first remission, with reported survival or relapse endpoints [17,26,21,24]. Trial Population Intervention Reported
Table 2: Trials shaping the decision to transplant or add a FLT3 inhibitor in first remission, with reported survival or relapse endpoints [17,26,21,24]. Trial Population Intervention Reported

Trial Population Intervention Reported outcome

QuANTUM-First Newly diagnosed Quizartinib + Median OS [24] FLT3-ITD chemotherapy 31.9 vs 15.1 mo

7. Conclusion

Three decades after its discovery, FLT3-ITD has moved from a binary mutation call to a quantitative, continuous variable whose allelic ratio predicts relapse risk, modifies the prognostic weight of co-occurring NPM1 mutations, and — until recently — determined who was referred for transplant in first remission [1,6,9]. The arrival of midostaurin, gilteritinib, and quizartinib has changed the practical stakes of that measurement without eliminating it: inhibitor-era trials have generally not shown allelic ratio to modify drug benefit, which is one reason the European LeukemiaNet retired its ratio-based split for NPM1-mutated FLT3-ITD disease in 2022, even as ratio's original correlation with relapse biology remains intact [17,21,23]. What allelic ratio still does, reliably, is flag the patients whose disease is most FLT3-dependent and therefore most likely to relapse if that dependency is not directly targeted — by an inhibitor, by transplant, or, in the patients who need it most, by both [8,26,24]. The open question for the next decade is less whether ratio matters and more how to combine it with measurable residual disease and co-mutation data into a single, dynamic risk estimate that updates as a patient moves from diagnosis through induction to consolidation, rather than the static, diagnosis-only snapshot the field has relied on since Gale and colleagues first quantified the ratio effect [9,27].

References

  1. Nakao, M., Yokota, S., Iwai, T., Kaneko, H., Horiike, S., Kashima, K., et al. (1996) Internal tandem duplication of the flt3 gene found in acute myeloid leukemia. Leukemia, 10(12): 1911-1918.
  2. Kiyoi, H., Naoe, T., Nakano, Y., Yokota, S., Minami, S., Miyawaki, S., et al. (1999) Prognostic implication of FLT3 and N-RAS gene mutations in acute myeloid leukemia. Blood, 93(9): 3074-3080. DOI: 10.1182/blood.V93.9.3074
  3. Kottaridis, P.D., Gale, R.E., Frew, M.E., Harrison, G., Langabeer, S.E., Belton, A.A., et al. (2001) The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials. Blood, 98(6): 1752-1759. DOI: 10.1182/blood.V98.6.1752
  4. Thiede, C., Steudel, C., Mohr, B., Schaich, M., Schakel, U., Platzbecker, U., et al. (2002) Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood, 99(12): 4326-4335. DOI: 10.1182/blood.V99.12.4326
  5. Levis, M. (2013) FLT3 mutations in acute myeloid leukemia: what is the best approach in 2013? Hematology American Society of Hematology Education Program, 2013(1): 220-226. DOI: 10.1182/asheducation-2013.1.220
  6. Whitman, S.P., Archer, K.J., Feng, L., Baldus, C., Theil, K.S., Kucera, P., et al. (2001) Absence of the wild-type allele predicts poor prognosis in adult de novo acute myeloid leukemia with normal cytogenetics and the internal tandem duplication of FLT3: a cancer and leukemia group B study. Cancer Research, 61(19): 7233-7239.
  7. Schnittger, S., Bacher, U., Haferlach, C., Alpermann, T., Kern, W., Haferlach, T. (2012) Diversity of the juxtamembrane and TKD1 mutations (exons 13-15) in the FLT3 gene with regards to mutant load, sequence, length, localization, and correlation with biological data. Genes, Chromosomes and Cancer, 51(10): 910-924.
  8. Kayser, S., Schlenk, R.F., Londono, M.C., Breitenbuecher, F., Wittke, K., Du, J., et al. (2009) Insertion of FLT3 internal tandem duplication in the tyrosine kinase domain-1 is associated with resistance to chemotherapy and inferior outcome. Blood, 114(12): 2386-2392. DOI: 10.1182/blood-2009-03-209999
  9. Gale, R.E., Green, C., Allen, C., Mead, A.J., Burnett, A.K., Hills, R.K., et al. (2008) The impact of FLT3 internal tandem duplication mutant level, number, size, and interaction with NPM1 mutations in a large cohort of young adult patients with acute myeloid leukemia. Blood, 111(5): 2776-2784. DOI: 10.1182/blood-2007-08-109090
  10. Meshinchi, S., Alonzo, T.A., Stirewalt, D.L., Zwaan, M., Zehnder, J.L., Adlard, J., et al. (2006) Clinical implications of FLT3 mutations in pediatric AML. Blood, 108(12): 3654-3661. DOI: 10.1182/blood-2006-03-009233
  11. Falini, B., Mecucci, C., Tiacci, E., Alcalay, M., Rosati, R., Pasqualucci, L., et al. (2005) Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. New England Journal of Medicine, 352(3): 254-266. DOI: 10.1056/NEJMoa041974
  12. Schlenk, R.F., Dohner, K., Krauter, J., Frohling, S., Corbacioglu, A., Bullinger, L., et al. (2008) Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. New England Journal of Medicine, 358(18): 1909-1918. DOI: 10.1056/NEJMoa074306
  13. Thiede, C., Koch, S., Creutzig, E., Steudel, C., Illmer, T., Schaich, M., et al. (2006) Prevalence and prognostic impact of NPM1 mutations in 1485 adult patients with acute myeloid leukemia (AML). Blood, 107(10): 4011-4020. DOI: 10.1182/blood-2005-08-3167
  14. Patel, J.P., Gonen, M., Figueroa, M.E., Fernandez, H., Sun, Z., Racevskis, J., et al. (2012) Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. New England Journal of Medicine, 366(12): 1079-1089. DOI: 10.1056/NEJMoa1112304
  15. Papaemmanuil, E., Gerstung, M., Bullinger, L., Gaidzik, V.I., Paschka, P., Roberts, N.D., et al. (2016) Genomic classification and prognosis in acute myeloid leukemia. New England Journal of Medicine, 374(23): 2209-2221. DOI: 10.1056/NEJMoa1516192
  16. Dohner, H., Estey, E., Grimwade, D., Amadori, S., Appelbaum, F.R., Buchner, T., et al. (2017) Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood, 129(4): 424-447. DOI: 10.1182/blood-2016-08-733196
  17. Stone, R.M., Mandrekar, S.J., Sanford, B.L., Laumann, K., Geyer, S., Bloomfield, C.D., et al. (2017) Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. New England Journal of Medicine, 377(5): 454-464. DOI: 10.1056/NEJMoa1614359
  18. Larson, R.A., Mandrekar, S.J., Huebner, L.J., Sanford, B.L., Laumann, K., Geyer, S., et al. (2021) Midostaurin reduces relapse in FLT3-mutant acute myeloid leukemia: the Alliance CALGB 10603/RATIFY trial. Leukemia, 35(9): 2539-2551. DOI: 10.1038/s41375-021-01179-4
  19. Pratz, K.W., Sato, T., Murphy, K.M., Stine, A., Rajkhowa, T., Levis, M. (2010) FLT3-mutant allelic burden and clinical status are predictive of response to FLT3 inhibitors in AML. Blood, 115(7): 1425-1432. DOI: 10.1182/blood-2009-09-242859
  20. Cortes, J.E., Khaled, S., Martinelli, G., Perl, A.E., Ganguly, S., Russell, N., et al. (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. The Lancet Oncology, 20(7): 984-997. DOI: 10.1016/S1470-2045(19)30150-0
  21. Perl, A.E., Martinelli, G., Cortes, J.E., Neubauer, A., Berman, E., Paolini, S., et al. (2019) Gilteritinib or chemotherapy for relapsed or refractory FLT3-mutated AML. New England Journal of Medicine, 381(18): 1728-1740. DOI: 10.1056/NEJMoa1902688
  22. Perl, A.E., Larson, R.A., Podoltsev, N.A., Strickland, S., Wang, E.S., Atallah, E., et al. (2022) Follow-up of patients with R/R FLT3-mutation-positive AML treated with gilteritinib in the phase 3 ADMIRAL trial. Blood, 139(23): 3366-3375. DOI: 10.1182/blood.2021011583
  23. Dohner, H., Wei, A.H., Appelbaum, F.R., Craddock, C., DiNardo, C.D., Dombret, H., et al. (2022) Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel, on behalf of the ELN. Blood, 140(12): 1345-1377. DOI: 10.1182/blood.2022016867
  24. Erba, H.P., Montesinos, P., Kim, H.J., Patkowska, E., Vrhovac, R., Zak, P., et al. (2023) Quizartinib plus chemotherapy in newly diagnosed patients with FLT3-ITD-positive acute myeloid leukaemia (QuANTUM-First): a randomised, double-blind, placebo-controlled, phase 3 trial. The Lancet, 401(10388): 1571-1583. DOI: 10.1016/S0140-6736(23)00464-6
  25. Rollig, C., Serve, H., Huttmann, A., Noppeney, R., Muller-Tidow, C., Krug, U., et al. (2015) Addition of sorafenib versus placebo to standard therapy in patients aged 60 years or younger with newly diagnosed acute myeloid leukaemia (SORAML): a multicentre, phase 2, randomised controlled trial. The Lancet Oncology, 16(16): 1691-1699. DOI: 10.1016/S1470-2045(15)00362-9
  26. Burchert, A., Bug, G., Fritz, L.V., Finke, J., Stelljes, M., Rollig, C., et al. (2020) Sorafenib maintenance after allogeneic hematopoietic stem cell transplantation for FLT3-ITD-positive AML: results from the randomized, double-blind, placebo-controlled multicenter SORMAIN trial. Journal of Clinical Oncology, 38(26): 2993-3002. DOI: 10.1200/JCO.19.03345
  27. Ivey, A., Hills, R.K., Simpson, M.A., Jovanovic, J.V., Gilkes, A., Grech, A., et al. (2016) Assessment of minimal residual disease in standard-risk AML. New England Journal of Medicine, 374(5): 422-433. DOI: 10.1056/NEJMoa1507471