Inhibition of FLT3 in AML: a Focus on Sorafenib

Home , Crenolanib, Lestaurtinib, Midostaurin, Quizartinib, Sorafenib

REVIEW Inhibition of FLT3 in AML: a focus on sorafenib

A Antar1, ZK Otrock2, J El-Cheikh1, MA Kharfan-Dabaja3, G Battipaglia4,5,6, R Mahfouz7, M Mohty4,5,6 and A Bazarbachi1

FMS-like tyrosine kinase 3 (FLT3) is one of the most commonly mutated genes in AML. FLT3 is mutated in ~ 30% of patients with AML, either by internal tandem duplications (FLT3-ITD) of the juxta-membrane domain or by a point mutation, usually involving the tyrosine kinase domain. Several FLT3 tyrosine kinase inhibitors are being evaluated in multiple studies aiming at improving outcomes. The most widely used is sorafenib, a potent multikinase inhibitor approved for hepatocellular carcinoma and renal cell carcinoma. Sorafenib monotherapy or in combination with conventional chemotherapy, has been evaluated in various settings in AML, including front-line, relapsed or refractory disease including post-allograft failures and, more recently, as post-transplant maintenance therapy. Encouraging data have emerged with several other agents like lestaurtinib, midostaurin, crenolanib, gilteritinib and quizartinib. Although transient responses to FLT3 inhibitors are often observed in case of disease relapse, the most promising approach is the use of FLT3 inhibitors either in combination with induction chemotherapy or as consolidation/ maintenance therapy after allogeneic hematopoietic cell transplantation. In this review, we summarize the clinical data on sorafenib and other FLT3 inhibitors in AML.

Bone Marrow Transplantation (2017) 52, 344–351; doi:10.1038/bmt.2016.251; published online 24 October 2016

INTRODUCTION AML prognostic subgroups are mostly based on the FMS-like tyrosine kinase 3 (FLT3) is mutated in ~ 30% of patients Medical Research Council and the European LeukemiaNet 24,25 with AML, either by internal tandem duplications (FLT3-ITD) of the classifications. The Medical Research Council classification juxta-membrane domain, or by a point mutation usually involving stratifies patients into three major sub-categories based solely on the tyrosine kinase domain (FLT3-TKD).1,2 Both mutations baseline cytogenetics: favorable, intermediate and adverse 25 constitutively activate FLT3 in a ligand-independent manner. (Table 2). The European LeukemiaNet prognostic classification Patients with AML harboring FLT3-ITD mutations have a high risk further incorporated recurrent somatic mutations such as of relapse and low cure rates.3–6 Allogeneic hematopoietic cell NPM1, FLT3 and CEBPα, and proposed four prognostic categories: 24 transplantation (allo-HCT) is recommended in first CR (CR1) for favorable, intermediate-1, intermediate-2 and adverse (Table 3). AML patients harboring this mutation.7–9 However, long-term Furthermore, the Cancer Genome Atlas Research Network overall survival (OS) remains low, probably due to higher rates analyzed the genomic and epigenomic landscapes of 200 adults of early relapse10 and poor response to chemotherapy in the with de novo AML, and identified FLT3, NPM1, DNMT3a, IDH salvage setting. (IDH1 and IDH2), TET2, RUNX1, p53, NRAS, CEBPα and WT1 as 28 Several small-molecule FLT3 tyrosine kinase inhibitors (TKIs) the top 10 genes mutated at 45% frequency. Other studies are being evaluated (Table 1), namely sorafenib, lestaurtinib have highlighted the prognostic implications of each genetic 29,30 (CEP701), midostaurin (PKC412), crenolanib (CP868596), gilteritinib abnormality alone or in the context of other known mutations. (ASP2215) and quizartinib (AC220). Some studies included AML patients with or without FLT3-ITD or TKD mutations. The efficacy of these agents, as monotherapy or in combination with FLT3 MUTATIONS IN AML conventional chemotherapy, has been evaluated in various The FLT3 gene is located on chromosome 13q12. It encodes a settings, including front-line, relapsed or refractory disease, type III receptor tyrosine kinase known to play a major role in the including post-allograft failures and, more recently, as regulation of hematopoiesis. FLT3 belongs to the KIT, FMS and – maintenance therapy after allo-HCT.11 22 Preliminary results are PDGFR family. FLT3 is expressed on the surface of normal encouraging, particularly when these TKIs are used in combination hematopoietic stem cells; however, as these differentiate, they with conventional chemotherapy in the induction setting or as lose expression of this gene.31 Activation of FLT3 requires the maintenance therapy after allo-HCT. binding of its ligand to its extracellular domain, eventually resulting in dimerization and transphosphorylation of the A-loop. This ultimately activates multiple intracellular signaling pathways GENETIC CLASSIFICATION OF AML such as mitogen-activated protein kinase (MAPK) and PI3K/protein Treatment strategies for AML patients are dependent on kinase B (AKT)-signals that play important roles in the proliferation, cytogenetic abnormalities.23–25 In addition, implications of gene survival and differentiation of hematopoietic cells.1,2,32,33 mutations such as NPM1, FLT3 and CEBPα in cytogenetically FLT3 is overexpressed in most acute leukemias. It is mutated in normal AML are now becoming more established.26,27 Currently, more than one-third of AML cases, representing one of the most

1Bone Marrow Transplantation Program, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon; 2Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, USA; 3Department of Blood and Marrow Transplantation, H Lee Mofﬁtt Cancer Center, Tampa, FL, USA; 4EBMT Paris Study Ofﬁce/CEREST-TC, Paris, France; 5Department of Hematology, Saint Antoine Hospital, Paris, France; 6INSERM UMR 938, Université Pierre et Marie Curie, Paris, France and 7Department of Pathology and Laboratory Medicine, American University of Beirut Medical Center, Beirut, Lebanon. Correspondence: Professor A Bazarbachi, Bone Marrow Transplantation Program, Department of Internal Medicine, American University of Beirut Medical Center, PO Box 113-6044, Beirut 1107 2020, Lebanon. E-mail: [email protected] Received 10 May 2016; revised 16 August 2016; accepted 17 August 2016; published online 24 October 2016 Sorafenib in AML A Antar et al 345

Table 1. Most frequently used FLT3 inhibitors

Name of the drug Kinase inhibitory proﬁle Disease under evaluation Notes

Sorafenib (Nexavar) CRAF and BRAF AML Most of these kinases are involved in KIT, FLT3, VEGFR-2, VEGFR-3 Hepatocellular carcinoma angiogenesis. and PDGFR-ß Renal cell carcinoma RAF/MEK/ERK pathway47 Thyroid carcinoma Quizartinib (AC220) FLT3/STK1 AML It is the most potent in vitro FLT3 inhibitor.16 CSF1R/FMS SCFR/KIT PDGFRs Midostaurin (PKC412) FLT3 AML Inhibits FLT3 at very low doses, generally in KIT, PDGF-Rβ, VEGFR-2 MDS the nanomolar range.48 PKC Aggressive systemic mastocytosis and mast cell leukemia81 Lestaurtinib (CEP701) FLT3 AML and MPN82,83 — JAK2 TRK A/TRK B/TRK C Crenolanib (CP868596) FLT3-ITD AML — FLT3-D835 GIST PDGFR-α Glioma PDGFR-β Gilteritinib (ASP2215) FLT3 AML — AXL ALK Abbreviations: FLT3 = FMS-like tyrosine kinase 3; GIST = gastrointestinal stromal tumor; ITD = internal tandem duplications; MDS = myelodysplastic syndrome; MPN = myeloproliferative neoplasms.

Table 2. Revised Medical Research Council cytogenetic classiﬁcation Table 3. Revised European LeukemiaNet cytogenetic classiﬁcation of of AML25 AML24

Group Cytogenetic abnormality Group Cytogenetic abnormality

Favorable t(15;17)(q22;q21), t(8;21)(q22;q22), inv(16)/t(16;16) Favorable t(8;21)(q22;q22), inv(16)/t(16;16)(p13;q22), (p13;q22) NPM1(+) and FLT3 ITD WT (normal karyotype), Intermediate All cytogenetic abnormalities not classified as mutated CEBPα (normal karyotype) favorable or adverse Intermediate-1 NPM1(+) and FLT3 ITD(+) (normal karyotype), Adverse abn(3q) [excluding t(3;5)], inv(3)/t(3;3)(q21;q26) NPM1 WT and FLT3 ITD(+) (normal karyotype), add(5q), del(5q), -5, -7, add(7q)/del(7q) NPM1 WT and FLT3 ITD WT (normal karyotype) t(6;11)(q27;q23), t(10;11)(p11 ~ 13;q23), t(11q23) Intermediate-2 t(9;11)(p22;q23), those cytogenetic abnormalities [excluding t(9;11), and t(11;19)], t(9;22)(q34;q11) not classified as favorable or adverse − 17/abn(17p) Adverse inv(3)/t(3;3)(q21;q26), Complex (⩾4 unrelated abnormalities) t(6;9)(p23,q34), t(v;11)(v;23), MLL rearranged − 5 or del(5q), − 7, abnormal (17p), complex karyotype common genetic alterations. Two main types of FLT3 mutations exist. The first is the FLT3-ITD, in or near the juxta-membrane Abbreviations: ITD = internal tandem duplications; WT = wild type. domain of the receptor, found in ~ 23% of AML patients. The second is a missense point mutation resulting in single amino-acid substitutions that mostly involves the aspartic acid 835 inferior OS.3,4,29,36–39 The rate of CR in FLT3-ITD mutated AML is of the kinase domain. In addition, less frequently seen point comparable to other AML (without FLT3-ITD), but responses are mutations, deletions and insertions in the codons surrounding usually shorter and, subsequently, poorer responses to salvage D835 and constitutive activation of the tyrosine kinase receptor 38 40 34 therapies are observed. Meshinchi et al. showed an event-free independently of the ligand, as ITD mutations interfere survival (EFS) of 44% for pediatric AML cases without FLT3-ITD with the negative regulatory function of the juxta-membrane mutation, compared with 7% for those harboring such a mutation. region, and kinase domain point mutations involve the The Medical Research Council AML10 and AML12 trials analyzed activation loop, resulting in the loss of the auto-inhibitory the outcome of 1135 AML patients based on the FLT3 mutation function, with subsequent constitutive activation of FLT3 kinase 35 status. The 10-year EFS and OS were 23% and 27% in and its downstream proliferative signaling pathways. This FLT3-ITD-positive, compared with 37% and 39% in FLT3-ITD- constitutive FLT3 signaling leads to consequent activation of negative patients, respectively (Po0.001). Among the total group STAT5, PI-3-kinase/AKT and RAS/MAPK. of 311 patients who received transplant, the relapse rate at 5 years in the allograft group was 31% in the FLT3-ITD-positive patients versus 25% in FLT3-ITD-negative patients, whereas in the autograft PROGNOSTIC SIGNIFICANCE OF FLT3-ITD MUTATION group the relapse rate was 56% in the FLT3-ITD-positive The presence of FLT3-ITD leads to the constitutive activation of the patients versus 35% in FLT3-ITD-negative patients.41 In addition, tyrosine kinase receptor and downstream signaling, which results the German AML 96 trial evaluated the prognostic significance of in a high WBC count, a higher percentage of myeloblasts and an FLT3 mutations in 979 AML patients. The proportion of patients

© 2017 Macmillan Publishers Limited, part of Springer Nature. Bone Marrow Transplantation (2017) 344 – 351 Sorafenib in AML A Antar et al 346 who had FLT3 mutations was 258 of 979 (26.4%) of AML patients and mutated FLT3-ITD to 69 patients with diploid cytogenetics and (ITD: 200 (20.4%); TKD: 75 (7.7%); ITD+TKD: 17 (1.7%)). The FLT3wt in first relapse. The CR rate and OS from the time of relapse presence of the FLT3 mutation had no influence on the CR rate were inferior in patients with mutated FLT3. (CR rate was 66.8% in patients younger than 60 years, de novo AML, FLT3-ITD-negative- and intermediate-risk cytogenetics compared with 71% in patients with FLT3-ITD). However, the MECHANISMS OF RESISTANCE TO FLT3-TKIS presence of FLT3 mutations was associated with an inferior OS and There are two main mechanisms of resistance to FLT3 inhibitors. disease-free survival (DFS).5 Moreover, the Acute Leukemia The primary resistance is due to either insensitive mutations to Working Party (ALWP) of the European Society for Blood and specific TKIs or activation of alternative signaling pathways. For Marrow Transplantation (EBMT) performed a retrospective analysis instance, most of the TKIs including sorafenib have no activity on 702 adults undergoing allo-HCT in CR1, according to the against FLT3-D835 TKD mutation. Secondary resistance is the genetic alteration variants including FLT3 mutation. In this result of acquiring resistant mutations, overexpression of FLT3, analysis, the worst outcome was observed in patients autocrine FLT3 ligand stimulation or resistant mutations in the ATP harboring a FLT3-ITD (2-year OS: 66% and 54% in NPM1mut/ binding pocket.45 FLT3-ITDmut and NPM1wt/FLT3-ITDmut compared with 81% and 75% in NPM1mut/FLT3-ITDwt and NPM1wt /FLT3-ITDwt, respectively).10 Brunet et al.8 addressed the influence of FLT3-ITD SORAFENIB PLUS CHEMOTHERAPY AS FIRST-LINE INDUCTION mutation on the outcome after allo-HCT in CR1 for patients with FOR AML AML and normal karyotype. In that retrospective analysis Promising preclinical data on sorafenib activity in AML have been conducted on 206 patients, the 2-year relapse incidence was published in recent years.46,47 Thus, many clinical trials have higher (30% versus 16%, P = 0.006) and leukemia-free survival evaluated adding sorafenib to standard chemotherapy in the lower (58% versus 71%; P = 0.04) in FLT3/ITD-positive compared first-line induction therapy in AML (Table 4). with FLT3/ITD-negative patients. In FLT3-mutated AML, Uy et al.48 reported the first prospective, One particular group of patients who harbor ITD mutations, but single arm, phase 2 study combining sorafenib to the standard have lost the wild-type copy of FLT3 appear to have a first-line induction/consolidation therapy and continuing it as uniquely adverse prognosis.42 Furthermore, several studies have maintenance in elderly (460 years). All (n = 54) patients had either demonstrated that FLT3-mutant allelic burden might also affect FLT3-ITD (71%) or FLT3-TKD (29%) mutated AML. Following prognosis, but its true prognostic relevance remains to be further treatment, 37 (69%) patients achieved a CR or CR with incomplete refined.5,42 AML patients with high FLT3-mutant allelic ratio were blood count recovery (CRi).48 The 30-day induction mortality was more likely to respond to FLT3 inhibition compared with those 9% with no additional deaths occurring during consolidation or with low mutant allelic ratio, likely due to higher FLT3 signaling maintenance.48 No treatment-related deaths were documented. dependency.22 The most important factor that contributes to the With a median follow-up of 28.3 months, 1-year OS was 62% for variation in allelic ratio is the clonal dominance and heterogeneity the FLT3-ITD and 71% for the FLT3-TKD patients. Median DFS and of the mutation, as in high allelic ratio FLT3-ITD is present in the OS in the FLT3-ITD were 12.5 and 15.0 months, respectively, and majority or all of the leukemic cells; however, in low allelic ratio, 9.0 and 16.2 months for the FLT3-TKD group, respectively. FLT3-ITD is present in a minor subclone within the bulk leukemic The most commonly reported adverse events during sorafenib population.43 In addition, most of the studies did not show any maintenance were grade 1 diarrhea, fatigue, transaminitis and association of kinase domain point mutations with unfavorable grade 2 palmar-plantar erythrodysesthesia. The results of prognosis. This may be the result of signaling differences between this study suggest that the addition of sorafenib to chemotherapy the different types of mutations. FLT3 mutations have been found for FLT3-ITD AML significantly improves the survival of older to be occasionally acquired at the time of relapse in some AML adults compared with historical controls, (at least for patients patients who do not carry it at the time of initial diagnosis.44 In between 60 and 70 years). these cases, they were associated with dismal outcome. Ravandi On the other hand, other studies evaluated the addition of et al.38 compared outcomes of 34 patients with normal karyotype sorafenib to conventional chemotherapy in newly diagnosed AML

Table 4. Studies using sorafenib plus chemotherapy as ﬁrst-line induction for AML

AML type Ref Study design Patients number Median Response Survival Relapse age, yr (range)

FLT3+Uy Prospective, 54 ⩾60 CR or 2-yr OS: 28% — et al.48 phase II Cri: 69% 2-yr DFS: 27% FLT3+or Röllig RCT 267 Placebo: 18–60 CR: 60% 3-yr OS: 63% for sorafenib, 56% Relapse after 3 yr: 34% in the wild et al.49 133 Sorafenib: for placebo (NS) sorafenib group, 49% in the placebo type 134 3-yr EFS: 40% for sorafenib, 22% group for placebo (S) Ravandi Prospective, 62 53 (18–66) CR: 49 3-yr OS: 48% 65% of the responders etal.54 phase II (79%) 3-yr DFS: 34% CRp: 5 (8%) Serve RCT 197 Placebo: 95 460yr CR: 54 Median OS: Placebo:15 m for No pts in relapse et al.50 Sorafenib: 102 (27%) placebo, 13 m for sorafenib (NS) CRi: 7 Median EFS: 7 m for placebo, (3.5%) 5 m for sorafenib (NS) Abbreviations: CRi = CR with incomplete blood count recovery; CRp = CR with incomplete platelet recovery; DFS = disease-free survival; EFS = event-free survival; m = month; OS = overall survival; pts = patienys; RCT = randomized controlled trial; ref = reference; S = signiﬁcant; yr = year.

Bone Marrow Transplantation (2017) 344 – 351 © 2017 Macmillan Publishers Limited, part of Springer Nature. Sorafenib in AML A Antar et al 347 irrespective of FLT3 mutational status. Rollig et al.49 reported a Borthakur et al.62 reported the results of a phase I study that randomized, placebo-controlled trial (SORAML) that addressed assessed sorafenib monotherapy in two different schedules in addition of sorafenib to standard induction–consolidation therapy relapsed, FLT3-mutated AML (only 16% post transplant). They in 267 newly diagnosed AML patients aged 60 years or younger. showed a favorable toxicity profile and an overall response rate of Adding sorafenib resulted in improved EFS (median of 21 versus 44% (CR: 6%, CR with incomplete platelet recovery: 4% and PR: 9 months) when compared with placebo. Similarly, 3-year EFS was 34%). Sharma et al.63 described 16 patients treated for post- significantly better with sorafenib (40% versus 22%, P = 0.013), and transplant relapse with sorafenib either as monotherapy (n =8)or the relapse-free survival was 56% for the sorafenib versus 38% in combined with chemotherapy (n = 8), showing discouraging the placebo group. However, no improvement in OS was responses (19% bone marrow responses), with disease progres- observed. The 60-day mortality was 4% in both groups. A sion in all cases and a median OS of only 83 days. This dismal plausible explanation for these significant outcomes even in outcome may be explained by the advanced disease status and by FLT3 wild-type patients is the activity of sorafenib in inhibiting an interrupted sorafenib dosing schedule. Metzelder et al.19 other kinases such as RAF, PDGF and KIT. On the other hand, the described more profound and sustained remissions in 29 FLT3-ITD absence of a survival advantage with sorafenib may be due to the AML patients, when sorafenib was given after allo-HCT (CR 48% higher proportion of allo-HCT in the placebo group (79 (59%) of and CRi 21%, complete molecular remission 24%). This may be 133 versus 68 (51%) of 133, respectively). In contrast, Serve et al.50 explained by the antileukemic synergy between sorafenib and reported an increased toxicity and early mortality without alloreactive donor cells. These findings stimulated research on the improved antileukemic efficacy when adding sorafenib to use of sorafenib as a post allo-HCT maintenance. Recently, three standard chemotherapy in AML patients older than 60 years in retrospective studies have shown favorable outcomes when using comparison to placebo. The possible explanation of this finding is sorafenib in FLT3-mutated AML patients younger than 60 years, the potential ability of younger patients to tolerate sorafenib including in the pediatric age group, specifically in the post- better than older patients, as well as differences in disease biology transplant setting.64–66 Tarlock et al.64 reported the results of a with a higher proportion of secondary AML, overexpression of retrospective study on 15 pediatric patients with FLT3/ITD+ AML, multidrug-resistant phenotypes and, possibly, more epigenetic who were treated with sorafenib for post-transplant relapse (n =9) changes in older patients.51–53 Also, Ravandi et al.54 reported a or maintenance (n = 6). They showed an OS of 67% after a median high response rate in AML patients younger than 60 years who follow-up of 21 months; however, 73% of patients experienced received a sorafenib-containing induction regimen in a phase 2 medically significant toxicities. In addition, a small case series by single arm study (CR: 49 (79%), CR with incomplete platelet De Freitas et al.65 on sorafenib use for post-transplant relapse recovery: 5 (8%)), but disease relapse occurred in the majority of FLT3/ITD+ AML in 13 relatively young patients showed an OS of patients (65% of responders). 45% after 175 days follow-up. In another retrospective study by Tschan-Plessl et al.,66 sorafenib achieved high rates of durable remissions in 17 high-risk patients who underwent HCT. SORAFENIB WITH OR WITHOUT CHEMOTHERAPY FOR RELAPSED AML Several cases with relapsed FLT3-ITD AML showed extended SORAFENIB PLUS HYPOMETHYLATING AGENTS FOR AML remissions under sorafenib monotherapy.55–61 This established Ravandi et al.67 combined sorafenib with azacitidine in a phase 2 the basis to evaluate the efficacy of sorafenib as monotherapy or study on 37 patients with FLT3-mutated AML. Half of the patients combined with chemotherapy in relapsed FLT3-mutated AML had relapsed after prior therapy, and the remaining were either either in the pre- or post-transplant setting (Table 5). primarily refractory to induction or had not received any prior

Table 5. Studies using sorafenib monotherapy or with chemotherapy for relapsed AML

Reference Study design Relation to Patients number Median age, yr (range) Response Survival Relapse transplant

Tarlock et al.64 Retrospective Post SCT 15 (9 pts for relapse, 6 14 (6–21) CR: 8 10 (67%) of pts are alive 7 (46%) pts for prophylaxis) with a median follow-up of 21 m De Freitas Retrospective Post SCT 13 38 (25–65) CR: 2 OS: 6/13 pts are alive — et al.65 CRi: 3 after 175 d (43–482) BMR: 5 HR: 2 Tschan-Plessl Retrospective Pre SCT/post 17 (12 pts for relapse, 5 53 (23–68) CMR: 11 2-yr OS: 61% 5 (30%) et al.66 SCT: 7 pts for maintenance) CR: 3 2-yr PFS: 55% Post SCT HR: 1 only: 10 Metzelder Retrospective Pre SCT: 36 65 58 (14–89) CMR: 10 TTF, median: pre-SCT, — et al.19 Post SCT: 29 CR: 2 47% after 136 d; post- CRi: 13 SCT, 38% median 197 d HR: 24 (S) BMR: 5 Sharma et al.63 Retrospective Post SCT 16 34 (20–63) CR: 0 Median OS: 83 d 100% PR: 3 Borthakur Phase 1 Pre SCT/post 50 61 (21–88) CR: 3 —— et al.62 SCT CRp: 2 PR: 17 Abbreviations: BMR = bone marrow response; CMR = complete molecular remission; CRi = CR with incomplete blood count recovery; d = day; DFS = disease-free survival; HR = hematological remission; m = month; OS = overall survival; pts = patients; S = signiﬁcant; SCT = stem cell transplantation; TTF = time to treatment failure; yr = year.

© 2017 Macmillan Publishers Limited, part of Springer Nature. Bone Marrow Transplantation (2017) 344 – 351 Sorafenib in AML A Antar et al 348 therapy. Only seven patients had received a prior allo-HCT. The retrospectively, the efficacy of sorafenib maintenance (versus no overall response was 46%, including 6 (16%) CR and 10 (27%) CRi. maintenance). The study showed that patients (n = 26) who The median OS was 6.2 months. Not surprisingly, responders had received sorafenib had better OS compared with controls longer OS compared with non-responders (7.8 versus 6.2 months, (n = 54; 83% versus 58%; P = 0.019). In multivariable analysis, P = 0.01; Table 6). sorafenib maintenance significantly improved OS (hazard ratio Muppidi et al.68 combined sorafenib with decitabine in a small 0.14, P = 0.0047) and DFS (hazard ratio 0.09, P = 0.0005). Pratz series of six patients with relapsed/refractory AML and demon- et al.73 reported the results of a prospective study of pre- and strated overall responses in five (83%) cases with a median post-allogeneic transplant use of sorafenib on 28 FLT3-mutated survival of 155 days. Four of the five patients (80%) achieved CRi. AML patients. After a median post-transplant follow-up of 450 days (range, 107–1192), both median EFS and OS had not been reached. Fifteen of 28 patients were still on therapy without SORAFENIB AS MAINTENANCE THERAPY AFTER ALLO-HCT evidence of relapse at the time of publication.73 The paradigm of maintenance therapy after allo-HCT is becoming more popular.69 For instance, in patients with CML or Ph+ ALL, treatment with inhibitors of the BCR-ABL tyrosine kinase is widely OTHER FLT3 INHIBITORS used as prophylaxis or as therapy for minimal residual disease.70,71 In addition to sorafenib, other kinase inhibitors with inhibitory The incorporation of sorafenib in the maintenance setting is activity against FLT3 have been tested in AML (Table 8). supported by the observation that there appears to be an anti- Midostaurin (PKC412) was first evaluated in 20 patients with leukemia synergism between sorafenib and alloreactive donor FLT3-positive relapsed/refractory AML or MDS patients not eligible cells. In addition, chemotherapy-induced marrow aplasia leads to for chemotherapy, and resulted in 450% reduction in peripheral elevated FLT3-ligand levels that may augment on-target activity of blood myeloblasts in 14 (75%) patients.15 This finding led to the a FLT3 inhibitor.72 launching of a randomized phase 2 trial of 95 patients with similar Sorafenib as a maintenance agent has been evaluated in small disease characteristics, but including both mutated and wild-type recent studies (Table 7). Chen et al.18 published the results of the FLT3 (35 versus 60 patients). The results showed an overall first phase 1 trial of sorafenib maintenance after allo-HCT in response in 25 (71%) and 32 (56%) patients for FLT3-mutated and FLT3-ITD AML patients. The study showed that sorafenib can be wild-type, respectively.74 Recently, Stone et al.75 reported the final safely used after transplantation with a maximum tolerated dose results of a phase 3 randomized controlled trial of midostaurin in of 400 mg twice daily. Furthermore, the study demonstrated combination with daunorubicin and cytarabine as front-line a 1-year DFS of 85% and 1-year OS of 95% after SCT. We recently treatment for 717 patients with FLT3-mutated AML o60 years reported another series19 on six patients who received sorafenib of age. Treatment consisted of daunorubicin and cytarabine mostly as maintenance post-allo-HCT. All six patients were alive induction plus midostaurin or placebo, followed by consolidation and in CR after a median follow-up of 16 months (range, 10–29) with high-dose cytarabine plus midostaurin or placebo in the case since first induction, and 12 months (range, 4–20) after initiation of of CR, followed by maintenance midostaurin or placebo. After a sorafenib. median follow-up of 57 months, the median EFS and OS for the More recently, two studies on sorafenib maintenance were midostaurin versus placebo groups were 8 versus 3 months and reported in abstract form.21,73 Brunner et al.21 reported, 74.7 versus 26 months, respectively. Currently, there are two

Table 6. Studies using sorafenib plus hypomethylating agents in AML

Reference Study design, HMA used Patients number Median age, yr (range) Response Survival Relapse

Ravandi Phase 1/2 single arm, 43 64 (24–87) CR:16% Median OS: 6.2 m 9 among 16 et al.67 azacitidine CRi: 27% Median EFS: 3.8 m responders Muppidi Retrospective, decitabine 6 56 (34–70) CR/CRi: 80% Median OS: 111 d — et al.68 (59–348) Abbreviations: CRi = CR with incomplete blood count recovery; d = day; EFS = event-free survival; m = month; OS = overall survival; pts = patients; yr = year.

Table 7. Studies using sorafenib as post allo-HCT maintenance in AML

Reference Study design Patients number Median age, yr Survival Relapse (range)

Antar et al.20 Retrospective 6 50 (32–58) 6 (100%) of pts are alive with a median follow-up of 16 m 0% Pratz et al.22 Prospective 28 54 Median OS: NR 5 Median follow-up post SCT: 450 d (18%) Median EFS: NR Brunner Retrospective two 80 Sorafenib: Sorafenib: 54.5 2-yr OS: 83% for Sorafenib, 58% for control (S) — et al.21 arms 26 (20–74) 2-yr DFS: 85% for sorafenib, 52% for control (S) Control: 54 Control: 53 (25–72) Chen et al.18 Phase 1 22 54 (20–67) 1-yr OS: 95% 3 2-yr OS: 78% (14%) 1-yr PFS: 85% 2-yr PFS: 72% Abbreviations: d = day; DFS = disease-free survival; EFS = event-free survival; m = month; NR = not reached; OS = overall survival; pts = patients; S = signiﬁcant; SCT = stem cell transplantation; yr = year.

Table 8. AML studies using FLT3 inhibitors other than sorafenib

Reference FLT3 inhibitor used Study design Patients Median age, yr Response Survival number (range)

Cortes Quizartinib for relapsed/refractory Phase 1 76 60 (23–86) CR:10 (13%) Median OS: 14 w (18 w for et al.17 AML FLT3+orWT PR: 13 (17%) FLT3+10 w for WT) Levis Lestaurtinib (L) for relapsed/refractory Randomized 224 CT: 54 (21–79) CT: 23 (CR/CRp) No difference in OS et al.78 AML FLT3+ CT: 112 L L+CT: 59 (20–81) L+CT: 29 (CR/CRp) +CT: 112 Smith Lestaurtinib for relapsed/refractory Phase 1/2 14 61(18–74) 50% PB blast — et al.14 AML FLT3+ reduction: 5 (36%) Knapper Lestaurtinib for untreated older patients with Phase 2 29 FLT3+: 5 73 (67–82) BMR: 5 — et al.77 AML not fit for CT (FLT3+orWT) WT: 24 HR: 3 Stone Midostaurin (M) versus placebo (P) for first-line RCT phase 3 717 M: 48 (18–60) CR: M 59%, P 54% Median OS: M 74.7 m, P et al.75 FLT3+ AML added to ind/cons/main 360 P: 357 (NS) 26 m (S) Median EFS: M m, P 3 m (S) Fischer Midostaurin for relapsed/refractory Randomized 95 FLT3+: FLT3+: 16 (46%) ORR: FLT3+25 Median survival: FLT3 et al.74 AML FLT3+orWT phase 2 35 WT: 60 were 465 yr (71%), WT 32 (56%) +100 d, WT 159 d WT: 45 (75%) were 465 yr Stone Midostaurin for relapsed/refractory AML or MDS Phase 2 20 62 (29–78) 50% PB blast — et al.15 not candidates for CT FLT3+ reduction: 14 (75%) Randhawa Crenolanib for relapsed/refractory AML Phase 2 38 61 (30–87) ORR: 47% Median EFS: 8 weeks et al.79 Median OS: 19 weeks Levis Gilteritinib for relapsed/refractory AML Phase 1/2 166 — ORR: 57% — et al.80 Abbreviations: BMR = bone marrow response; CRp = CR with incomplete platelet recovery; CT = conventional therapy; d = day; EFS = event-free survival; HR = hematological remission; ind/cons/main = induction/consolidation/maintenance; m = month; ORR = overall response rate; OS = overall survival; PB = peripheral blood; PR = partial response; pts = patients; RCT = randomized controlled trial; S = significant; w = week; WT = wild type; yr = year.

ongoing trials studying the efficacy of midostaurin in combination CONCLUSION with azacitidine (NCT01093573) or decitabine (NCT01846624) in Until recently, the therapeutic management of AML has remained older patients with AML. unchanged for the past four decades. However, there has been Quizartinib (AC220) has been evaluated in a phase 1 study in 76 significant progress in understanding the biology and genomics relapsed/refractory FLT3-mutated or wild type AML patients. implications in AML. FLT3 TKIs are now showing encouraging Complete and PRs were observed in 10 (13%) and 13 (17%) results across a variety of AML management settings. The patients, respectively. The median OS was 14 weeks (18 weeks for combination of sorafenib or other TKI with chemotherapy during 17 76 FLT3-mutated and 10 weeks for FLT3 wild type). Levis et al. induction of AML looks very promising based on at least two 4 evaluated quizartinib monotherapy in 134 patients 60 years of randomized trials, although the positive effects were not restricted age with relapsed/refractory AML and showed 54% and 32% to FLT3-mutated cases. Use of TKI for patients with relapsed disease composite CR (CR+CRp+CRi) in FLT3-ITD-mutated and FLT3 wild-type can be helpful, but responses are relatively transient in most cases cases, respectively. A phase 1/2 trial of quizartinib in because of rapid acquisition of resistance. The most outstanding combination with 5-azacitidine or low-dose cytarabine in younger results were reported in the post allo-HCT setting using sorafenib as 4 patients with relapsed/refractory AML and in patients 60 years maintenance strategy in the setting of minimal residual disease of age with previously untreated AML is currently ongoing negative cases. In this setting, sorafenib is well tolerated, but dose (NCT01892371). adjustments are often necessary. Finally, multiple ongoing fi Lestaurtinib (CEP701) has been rst evaluated in a phase 1/2 prospective randomized trials will help to better define the place study in 14 patients with relapsed/refractory FLT3-mutated AML, of FLT3 inhibitors in the treatment algorithm of AML. leading to a 50% reduction in peripheral blood blasts in 36% of patients.14 In a phase 2 study, Knapper et al.77 used lestaurtinib in 29 untreated patients (⩾67 years) with AML FLT3+ or wild type not CONFLICT OF INTEREST considered fit for chemotherapy, and showed a bone marrow The authors declare no conflict of interest. response in five and a hematological response in three patients only. Moreover, Levis et al.78 reported a randomized trial of lestaurtinib as monotherapy or in combination with AUTHOR CONTRIBUTIONS chemotherapy in relapsed/refractory FLT3-mutated AML patients, All authors participated in writing the paper, and they reviewed and approved showing CR/CRi in 23 patients in the lestaurtinib arm and in 29 the final manuscript. AB suggested the idea of the paper. patients in the combination arm. No difference in OS was observed. Crenolanib is a potent small TKI that has activity against both REFERENCES the FLT3-ITD and the FLT3-D835 TKD mutation. A phase II study of 1 Gilliland DG, Griffin JD. The roles of FLT3 in hematopoiesis and leukemia. crenolanib on 38 relapsed/refractory AML patients (FLT3 TKI-naive: Blood 2002; 100: 1532–1542. 34%; progressed on prior FLT3 TKI: 56%) showed an overall 2 Levis M, Small D. FLT3: ITDoes matter in leukemia. Leukemia 2003; 17: 1738–1752. response rate of 47%.79 3 Kottaridis PD, Gale RE, Frew ME, Harrison G, Langabeer SE, Belton AA et al. The presence of a FLT3 internal tandem duplication in patients with acute myeloid Gilteritinib (ASP2215) is a potent inhibitor of FLT3 with activity leukemia (AML) adds important prognostic information to cytogenetic risk group against FLT3-ITD and FLT3-TKD. A phase I/II study of gilteritinib in and response to the first cycle of chemotherapy: analysis of 854 patients from the patients with relapsed/refractory AML patients showed an overall United Kingdom Medical Research Council AML 10 and 12 trials. Blood 2001; 98: 80 response rate of 57%. 1752–1759.

© 2017 Macmillan Publishers Limited, part of Springer Nature. Bone Marrow Transplantation (2017) 344 – 351 Sorafenib in AML A Antar et al 350 4 Frohling S, Schlenk RF, Breitruck J, Benner A, Kreitmeier S, Tobis K et al. Prognostic recommendations from an international expert panel, on behalf of the European significance of activating FLT3 mutations in younger adults (16 to 60 years) with LeukemiaNet. Blood 2010; 115: 453–474. acute myeloid leukemia and normal cytogenetics: a study of the AML Study 25 Grimwade D, Hills RK, Moorman AV, Walker H, Chatters S, Goldstone AH et al. Group Ulm. Blood 2002; 100: 4372–4380. Refinement of cytogenetic classification in acute myeloid leukemia: 5 Thiede C, Steudel C, Mohr B, Schaich M, Schakel U, Platzbecker U et al. Analysis of determination of prognostic significance of rare recurring chromosomal FLT3-activating mutations in 979 patients with acute myelogenous leukemia: abnormalities among 5876 younger adult patients treated in the United Kingdom association with FAB subtypes and identification of subgroups with poor Medical Research Council trials. Blood 2010; 116:354–365. prognosis. Blood 2002; 99: 4326–4335. 26 Pastore F, Dufour A, Benthaus T, Metzeler KH, Maharry KS, Schneider S et al. 6 Rombouts WJ, Blokland I, Lowenberg B, Ploemacher RE. Biological characteristics Combined molecular and clinical prognostic index for relapse and survival in and prognosis of adult acute myeloid leukemia with internal tandem duplications cytogenetically normal acute myeloid leukemia. J Clin Oncol 2014; 32: 1586–1594. in the Flt3 gene. Leukemia 2000; 14:675–683. 27 Mrozek K, Marcucci G, Paschka P, Whitman SP, Bloomfield CD. Clinical relevance 7 Bornhauser M, Illmer T, Schaich M, Soucek S, Ehninger G, Thiede C et al. Improved of mutations and gene-expression changes in adult acute myeloid leukemia with outcome after stem-cell transplantation in FLT3/ITD-positive AML. Blood 2007; normal cytogenetics: are we ready for a prognostically prioritized molecular 109: 2264–2265. classification? Blood 2007; 109:431–448. 8 Brunet S, Labopin M, Esteve J, Cornelissen J, Socie G, Iori AP et al. Impact of FLT3 28 Cancer Genome Atlas Research Network. Genomic and epigenomic landscapes of internal tandem duplication on the outcome of related and unrelated adult de novo acute myeloid leukemia. N Engl J Med 2013; 368:2059–2074. hematopoietic transplantation for adult acute myeloid leukemia in first remission: 29 Schlenk RF, Dohner K, Krauter J, Frohling S, Corbacioglu A, Bullinger L et al. a retrospective analysis. J Clin Oncol 2012; 30:735–741. Mutations and treatment outcome in cytogenetically normal acute myeloid 9 DeZern AE, Sung A, Kim S, Smith BD, Karp JE, Gore SD et al. Role of allogeneic leukemia. N Engl J Med 2008; 358: 1909–1918. transplantation for FLT3/ITD acute myeloid leukemia: outcomes from 133 30 Patel JP, Gonen M, Figueroa ME, Fernandez H, Sun Z, Racevskis J et al. Prognostic consecutive newly diagnosed patients from a single institution. Biol Blood Marrow relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med 366 – Transplant 2011; 17: 1404–1409. 2012; :1079 1089. 10 Schmid C, Labopin M, Socie G, Daguindau E, Volin L, Huynh A et al. Outcome of 31 Kayser S, Levis MJ. FLT3 tyrosine kinase inhibitors in acute myeloid leukemia: 55 – patients with distinct molecular genotypes and cytogenetically normal AML after clinical implications and limitations. Leuk Lymphoma 2014; :243 255. allogeneic transplantation. Blood 2015; 126:2062–2069. 32 Lyman SD, Jacobsen SE. c-kit ligand and Flt3 ligand: stem/progenitor cell factors 91 – 11 Galanis A, Ma H, Rajkhowa T, Ramachandran A, Small D, Cortes J et al. Crenolanib with overlapping yet distinct activities. Blood 1998; : 1101 1134. is a potent inhibitor of FLT3 with activity against resistance-conferring point 33 Stirewalt DL, Radich JP. The role of FLT3 in haematopoietic malignancies. Nat Rev 3 – mutants. Blood 2014; 123:94–100. Cancer 2003; :650 665. 12 Man CH, Fung TK, Ho C, Han HH, Chow HC, Ma AC et al. Sorafenib treatment of 34 Yamamoto Y, Kiyoi H, Nakano Y, Suzuki R, Kodera Y, Miyawaki S et al. Activating FLT3-ITD(+) acute myeloid leukemia: favorable initial outcome and mechanisms mutation of D835 within the activation loop of FLT3 in human hematologic 97 – of subsequent nonresponsiveness associated with the emergence of a D835 malignancies. Blood 2001; : 2434 2439. fi mutation. Blood 2012; 119: 5133–5143. 35 Grif th J, Black J, Faerman C, Swenson L, Wynn M, Lu F et al. The structural basis for 13 – 13 Ravandi F, Cortes JE, Jones D, Faderl S, Garcia-Manero G, Konopleva MY et al. autoinhibition of FLT3 by the juxtamembrane domain. Mol Cell 2004; :169 178. Phase I/II study of combination therapy with sorafenib, idarubicin, and cytarabine 36 Kiyoi H, Naoe T, Nakano Y, Yokota S, Minami S, Miyawaki S et al. Prognostic in younger patients with acute myeloid leukemia. J Clin Oncol 2010; 28: implication of FLT3 and N-RAS gene mutations in acute myeloid leukemia. Blood 93 – 1856–1862. 1999; : 3074 3080. 14 Smith BD, Levis M, Beran M, Giles F, Kantarjian H, Berg K et al. Single-agent 37 Wagner K, Damm F, Thol F, Gohring G, Gorlich K, Heuser M et al. FLT3-internal CEP-701, a novel FLT3 inhibitor, shows biologic and clinical activity in patients tandem duplication and age are the major prognostic factors in patients with relapsed acute myeloid leukemia with normal karyotype. Haematologica 2011; 96: with relapsed or refractory acute myeloid leukemia. Blood 2004; 103: 3669–3676. – 15 Stone RM, De Angelo J, Galinsky I, Estey E, Klimek V, Grandin W et al. PKC 412 FLT3 681 686. 38 Ravandi F, Kantarjian H, Faderl S, Garcia-Manero G, O'Brien S, Koller C et al. inhibitor therapy in AML: results of a phase II trial. Ann Hematol 2004; 83: Outcome of patients with FLT3-mutated acute myeloid leukemia in first relapse. S89–S90. Leuk Res 2010; 34: 752–756. 16 Zarrinkar PP, Gunawardane RN, Cramer MD, Gardner MF, Brigham D, Belli B et al. 39 Schnittger S, Schoch C, Dugas M, Kern W, Staib P, Wuchter C et al. Analysis of FLT3 AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of length mutations in 1003 patients with acute myeloid leukemia: correlation to acute myeloid leukemia (AML). Blood 2009; 114: 2984–2992. cytogenetics, FAB subtype, and prognosis in the AMLCG study and usefulness as a 17 Cortes JE, Kantarjian H, Foran JM, Ghirdaladze D, Zodelava M, Borthakur G et al. marker for the detection of minimal residual disease. Blood 2002; 100:59–66. Phase I study of quizartinib administered daily to patients with relapsed 40 Meshinchi S, Woods WG, Stirewalt DL, Sweetser DA, Buckley JD, Tjoa TK et al. or refractory acute myeloid leukemia irrespective of FMS-like tyrosine kinase Prevalence and prognostic significance of Flt3 internal tandem duplication in 3-internal tandem duplication status. J Clin Oncol 2013; 31: 3681–3687. pediatric acute myeloid leukemia. Blood 2001; 97:89–94. 18 Chen YB, Li S, Lane AA, Connolly C, Del Rio C, Valles B et al. Phase I trial of 41 Gale RE, Hills R, Kottaridis PD, Srirangan S, Wheatley K, Burnett AK et al. maintenance sorafenib after allogeneic hematopoietic stem cell transplantation No evidence that FLT3 status should be considered as an indicator for for fms-like tyrosine kinase 3 internal tandem duplication acute myeloid leukemia. transplantation in acute myeloid leukemia (AML): an analysis of 1135 patients, Biol Blood Marrow Transplant 2014; 20: 2042–2048. excluding acute promyelocytic leukemia, from the UK MRC AML10 and 12 trials. 19 Metzelder SK, Schroeder T, Finck A, Scholl S, Fey M, Gotze K et al. High activity of Blood 2005; 106: 3658–3665. sorafenib in FLT3-ITD-positive acute myeloid leukemia synergizes with 42 Gale RE, Green C, Allen C, Mead AJ, Burnett AK, Hills RK et al. The impact of FLT3 allo-immune effects to induce sustained responses. Leukemia 2012; 26: internal tandem duplication mutant level, number, size, and interaction with 2353–2359. NPM1 mutations in a large cohort of young adult patients with acute myeloid 20 Antar A, Kharfan-Dabaja MA, Mahfouz R, Bazarbachi A. Sorafenib maintenance leukemia. Blood 2008; 111: 2776–2784. appears safe and improves clinical outcomes in FLT3-ITD acute myeloid leukemia 43 Meshinchi S. Allelic ratio: a marker of clonal dominance. Blood 2014; 124: after allogeneic hematopoietic cell transplantation. Clin Lymphoma Myeloma Leuk 3341–3342. 15 – 2015; : 298 302. 44 Shih LY, Huang CF, Wu JH, Lin TL, Dunn P, Wang PN et al. Internal tandem 21 Brunner A, Li S, Fathi A, Ho VT, Stone RM, Soiffer RJ et al. Hematopoietic Cell duplication of FLT3 in relapsed acute myeloid leukemia: a comparative analysis of Transplantation with or without Sorafenib Maintenance for Patients with FLT3-ITD bone marrow samples from 108 adult patients at diagnosis and relapse. Blood 126 Acute Myeloid Leukemia in CR1. Blood 2015; : 864. 2002; 100:2387–2392. 22 Pratz KW, Sato T, Murphy KM, Stine A, Rajkhowa T, Levis M. FLT3-mutant allelic 45 Kindler T, Lipka DB, Fischer T. FLT3 as a therapeutic target in AML: still challenging burden and clinical status are predictive of response to FLT3 inhibitors in AML. after all these years. Blood 2010; 116: 5089–5102. 115 – Blood 2010; : 1425 1432. 46 Zhang W, Konopleva M, Ruvolo VR, McQueen T, Evans RL, Bornmann WG et al. 23 Byrd JC, Mrozek K, Dodge RK, Carroll AJ, Edwards CG, Arthur DC et al. Sorafenib induces apoptosis of AML cells via Bim-mediated activation of the Pretreatment cytogenetic abnormalities are predictive of induction success, intrinsic apoptotic pathway. Leukemia 2008; 22:808–818. cumulative incidence of relapse, and overall survival in adult patients with de 47 Zhao W, Zhang T, Qu B, Wu X, Zhu X, Meng F et al. Sorafenib induces apoptosis in novo acute myeloid leukemia: results from Cancer and Leukemia Group B HL60 cells by inhibiting Src kinase-mediated STAT3 phosphorylation. Anticancer 100 – (CALGB 8461). Blood 2002; : 4325 4336. Drugs 2011; 22:79–88. 24 Dohner H, Estey EH, Amadori S, Appelbaum FR, Buchner T, Burnett AK et al. 48 Uy GL, Mandrekar S, Laumann K, Sanford B, Marcucci G, Zhao W et al. Addition of Diagnosis and management of acute myeloid leukemia in adults: sorafenib to chemotherapy improves the overall survival of older adults with

Bone Marrow Transplantation (2017) 344 – 351 © 2017 Macmillan Publishers Limited, part of Springer Nature. Sorafenib in AML A Antar et al 351 FLT3-ITD mutated acute myeloid leukemia (AML) (Alliance C11001). Blood 68 Muppidi MR, Portwood S, Griffiths EA, Thompson JE, Ford LA, Freyer CW et al. 2015; 126. Decitabine and sorafenib therapy in FLT-3 ITD-mutant acute myeloid leukemia. 49 Rollig C, Serve H, Huttmann A, Noppeney R, Muller-Tidow C, Krug U et al. Addition Clin Lymphoma Myeloma Leuk 2015; 15:S73–S79. of sorafenib versus placebo to standard therapy in patients aged 60 years or 69 El Cheikh J, Otrock ZK, Qannus AA, Kharfan-Dabaja MA, Bazarbachi A. younger with newly diagnosed acute myeloid leukaemia (SORAML): a multicentre, Risk-adapted approach to hla-matched sibling hematopoietic cell allografting: phase 2, randomised controlled trial. Lancet Oncol 2015; 16:1691–1699. impact of adjusting conditioning intensity and integrating post-transplant 50 Serve H, Krug U, Wagner R, Sauerland MC, Heinecke A, Brunnberg U et al. therapeutic interventions. Clin Lymphoma Myeloma Leuk 2016; 16:304–310. Sorafenib in combination with intensive chemotherapy in elderly patients 70 Hess G, Bunjes D, Siegert W, Schwerdtfeger R, Ledderose G, Wassmann B et al. with acute myeloid leukemia: results from a randomized, placebo-controlled trial. Sustained complete molecular remissions after treatment with imatinib-mesylate J Clin Oncol 2013; 31: 3110–3118. in patients with failure after allogeneic stem cell transplantation for chronic 51 Rollig C, Thiede C, Gramatzki M, Aulitzky W, Bodenstein H, Bornhauser M et al. myelogenous leukemia: results of a prospective phase II open-label multicenter A novel prognostic model in elderly patients with acute myeloid leukemia: results study. J Clin Oncol 2005; 23: 7583–7593. of 909 patients entered into the prospective AML96 trial. Blood 2010; 116: 71 Pfeifer H, Wassmann B, Bethge W, Dengler J, Bornhauser M, Stadler M et al. 971–978. Randomized comparison of prophylactic and minimal residual disease-triggered 52 Leith CP, Kopecky KJ, Chen IM, Eijdems L, Slovak ML, McConnell TS et al. imatinib after allogeneic stem cell transplantation for BCR-ABL1-positive acute 27 – Frequency and clinical significance of the expression of the multidrug resistance lymphoblastic leukemia. Leukemia 2013; : 1254 1262. proteins MDR1/P-glycoprotein, MRP1, and LRP in acute myeloid leukemia: 72 Sato T, Yang X, Knapper S, White P, Smith BD, Galkin S et al. FLT3 ligand impedes fi 117 a Southwest Oncology Group Study. Blood 1999; 94: 1086–1099. the ef cacy of FLT3 inhibitors in vitro and in vivo. Blood 2011; : – 53 Thol F, Damm F, Ludeking A, Winschel C, Wagner K, Morgan M et al. Incidence 3286 3293. and prognostic influence of DNMT3A mutations in acute myeloid leukemia. 73 Pratz KW, Ivana G, Karp JE, Luznik L, Smith BD, Jones RJ et al. Prospective study of J Clin Oncol 2011; 29: 2889–2896. peri-transplant use of sorafenib as remission maintenance for FLT3-ITD patients 126 54 Ravandi F, Arana Yi C, Cortes JE, Levis M, Faderl S, Garcia-Manero G et al. Final undergoing allogeneic transplantation. Blood 2015; : 3164. report of phase II study of sorafenib, cytarabine and idarubicin for initial therapy 74 Fischer T, Stone RM, Deangelo DJ, Galinsky I, Estey E, Lanza C et al. Phase IIB trial in younger patients with acute myeloid leukemia. Leukemia 2014; 28: 1543–1545. of oral Midostaurin (PKC412), the FMS-like tyrosine kinase 3 receptor (FLT3) and 55 Metzelder S, Wang Y, Wollmer E, Wanzel M, Teichler S, Chaturvedi A et al. multi-targeted kinase inhibitor, in patients with acute myeloid leukemia and Compassionate use of sorafenib in FLT3-ITD-positive acute myeloid leukemia: high-risk myelodysplastic syndrome with either wild-type or mutated FLT3. J Clin Oncol 2010; 28: 4339–4345. sustained regression before and after allogeneic stem cell transplantation. 75 Stone RM, Mandrekar S, Sanford BL, Geyer S, Bloomfield CD, Dohner K et al. The Blood 2009; 113: 6567–6571. multi-kinase inhibitor midostaurin (M) prolongs survival compared with placebo 56 Metzelder SK, Wollmer E, Neubauer A, Burchert A. [Sorafenib in relapsed and (P) in combination with daunorubicin (D)/cytarabine (C) induction (ind), high-dose refractory FLT3-ITD positive acute myeloid leukemia: a novel treatment option]. C consolidation (consol), and as maintenance (maint) therapy in newly diagnosed Deutsche medizinische Wochenschrift 2010; 135: 1852–1856. acute myeloid leukemia (AML) patients (pts) age 18-60 with FLT3 mutations 57 Safaian NN, Czibere A, Bruns I, Fenk R, Reinecke P, Dienst A et al. Sorafenib (muts): an international prospective randomized (rand) P-controlled double-blind (Nexavar) induces molecular remission and regression of extramedullary disease trial (CALGB 10603/RATIFY [Alliance]). Blood 2015; 126:6. in a patient with FLT3-ITD+ acute myeloid leukemia. Leuk Res 2009; 33:348–350. 76 Levis MJ, Perl AE, Dombret H, Döhner H, Steffen B, Rousselot P et al. Final results 58 Lee SH, Paietta E, Racevskis J, Wiernik PH. Complete resolution of leukemia cutis of a phase 2 open-label, monotherapy efficacy and safety study of quizartinib with sorafenib in an acute myeloid leukemia patient with FLT3-ITD mutation. (AC220) in patients with FLT3-ITD positive or negative relapsed/refractory acute Am J Hematol 2009; 84: 701–702. myeloid leukemia after second-line chemotherapy or hematopoietic stem cell 59 Schroeder T, Zohren F, Saure C, Bruns I, Czibere A, Safaian NN et al. Sorafenib transplantation final results of a phase 2 open-label, monotherapy efficacy and treatment in 13 patients with acute myeloid leukemia and activating FLT3 safety study of quizartinib (AC220) in patients with FLT3-ITD positive or negative mutations in combination with chemotherapy or as monotherapy. Acta Haematol relapsed/refractory acute myeloid leukemia after second-line chemotherapy or 2010; 124: 153–159. hematopoietic stem cell transplantation. Blood 2012; 120:673. 60 Mori M, Sprague J. The successful remission induction by sorafenib and long-term 77 Knapper S, Burnett AK, Littlewood T, Kell WJ, Agrawal S, Chopra R et al. A phase 2 complete remission in a FLT3-ITD-positive patient with a refractory acute trial of the FLT3 inhibitor lestaurtinib (CEP701) as first-line treatment for older 36 – erythroid leukemia and abnormal cytogenetics. Leuk Res 2012; :e1 e3. patients with acute myeloid leukemia not considered fit for intensive 61 Mohan BP, How GF, Loh Y, Linn YC. Sorafenib monotherapy gives sustainable chemotherapy. Blood 2006; 108: 3262–3270. suppression of FLT3 clone in untreated patients with FLT3-internal tandem 78 Levis M, Ravandi F, Wang ES, Baer MR, Perl A, Coutre S et al. Results from a 157 – duplication positive acute myeloid Leukaemia. Br J Haematol 2012; :131 132. randomized trial of salvage chemotherapy followed by lestaurtinib for patients 62 Borthakur G, Kantarjian H, Ravandi F, Zhang W, Konopleva M, Wright JJ et al. with FLT3 mutant AML in first relapse. Blood 2011; 117:3294–3301. Phase I study of sorafenib in patients with refractory or relapsed acute leukemias. 79 Randhawa JK, Kantarjian HM, Borthakur G, Thompson P, Konopleva M, Daver N 96 – Haematologica 2011; :62 68. et al. Results of a phase II study of crenolanib in relapsed/refractory acute myeloid 63 Sharma M, Ravandi F, Bayraktar UD, Chiattone A, Bashir Q, Giralt S et al. Treatment leukemia patients (Pts) with activating FLT3 mutations results of a phase II study of FLT3-ITD-positive acute myeloid leukemia relapsing after allogeneic stem cell of crenolanib in relapsed/refractory acute myeloid leukemia patients (Pts) with 17 – transplantation with sorafenib. Biol Blood Marrow Transplant 2011; : 1874 1877. activating FLT3 mutations. Blood 2014; 124: 389. 64 Tarlock K, Chang B, Cooper T, Gross T, Gupta S, Neudorf S et al. Sorafenib treat- 80 Levis M, Ravandi F, Altman JK, Cortes JE, Ritchie EK, Larson RA et al. Results of a ment following hematopoietic stem cell transplant in pediatric FLT3/ITD acute first-in-human, phase I/II trial of ASP2215, a selective, potent inhibitor of FLT3/Axl myeloid leukemia. Pediatr Blood Cancer 2015; 62: 1048–1054. in patients with relapsed or refractory (R/R) acute myeloid leukemia (AML). J Clin 65 De Freitas T, Marktel S, Piemontese S, Carrabba MG, Tresoldi C, Messina C et al. Oncol 2015; 33: 7003. High rate of hematological responses to sorafenib in FLT3-ITD acute myeloid 81 Gotlib J. Tyrosine kinase inhibitors and therapeutic antibodies in advanced leukemia relapsed after allogeneic hematopoietic stem cell transplantation. eosinophilic disorders and systemic mastocytosis. Curr Hematol Malig Rep 2015; Eur J Haematol 2016; 96:629–636. 10:351–361. 66 Tschan-Plessl A, Halter JP, Heim D, Medinger M, Passweg JR, Gerull S. Synergistic 82 Hexner EO, Serdikoff C, Jan M, Swider CR, Robinson C, Yang S et al. Lestaurtinib effect of sorafenib and cGvHD in patients with high-risk FLT3-ITD+AML allows (CEP701) is a JAK2 inhibitor that suppresses JAK2/STAT5 signaling and the long-term disease control after allogeneic transplantation. Ann Hematol 2015; 94: proliferation of primary erythroid cells from patients with myeloproliferative 1899–1905. disorders. Blood 2008; 111: 5663–5671. 67 Ravandi F, Alattar ML, Grunwald MR, Rudek MA, Rajkhowa T, Richie MA et al. 83 Al-Jamal HA, Mat Jusoh SA, Hassan R, Johan MF. Enhancing SHP-1 expression with Phase 2 study of azacytidine plus sorafenib in patients with acute myeloid 5-azacytidine may inhibit STAT3 activation and confer sensitivity in lestaurtinib leukemia and FLT-3 internal tandem duplication mutation. Blood 2013; 121: (CEP-701)-resistant FLT3-ITD positive acute myeloid leukemia. BMC Cancer 2015; 4655–4662. 15: 869.