Skip Navigation LinksHome > March 2014 - Volume 21 - Issue 2 > Will FLT3 inhibitors fulfill their promise in acute myeloid...
Current Opinion in Hematology:
doi: 10.1097/MOH.0000000000000022
MYELOID DISEASE: Edited by Martin S. Tallman

Will FLT3 inhibitors fulfill their promise in acute myeloid leukemia?

Pratz, Keith W.a; Luger, Selina M.b

Free Access
Article Outline
Collapse Box

Author Information

aDepartment of Oncology, Division of Hematologic Malignancies, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland

bAbramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA

Correspondence to Keith W. Pratz, MD, Kimmel Cancer Center at Johns Hopkins, 1650 Orleans Street, Room 245, Baltimore, MD 21231, USA. E-mail: Kpratz1@jhmi.edu

Collapse Box

Abstract

Purpose of review

‘FMS’-like tyrosine kinase 3 (FLT3) mutations in acute myeloid leukemia (AML) have been brought from discovery in the early 1990s to clinical targeting in the past 10 years. Despite several promising leads in preclinical models, no agent has yet been approved for clinical use. Here we will review the development of novel therapies for AML with FLT3 mutations.

Recent findings

Initial clinical development focused on broad kinase inhibitors which were found to have limited clinical activity due to insufficient kinase inhibitory activity and high toxicity. Subsequent development has brought forth narrow-spectrum inhibitors with potent in-vivo activity and reasonable clinical tolerance, but many patients still progress with prolonged use.

Summary

The optimal role for targeting FLT3 may depend on multimodality therapy and will likely require hematopoietic transplant. The incorporation of ABL kinase inhibitors into acute lymphoblastic leukemia management should serve as a model for incorporation of FLT3-targeted agents into clinical care. Strategies incorporating FLT3-targeted agents into AML therapy are ongoing, but challenges in trial design, clinical heterogeneity and need for long-term follow-up make these investigations complicated in design and implementation.

Back to Top | Article Outline

INTRODUCTION

Following the success of small molecule inhibition of BCR/ABL in chronic myeloid leukemia (CML) [1], a large effort has been underway to identify and target activated kinases in other malignancies with the goal of improving clinical outcomes. One promising target in AML is the receptor tyrosine kinase ‘FMS’-like tyrosine kinase 3 (FLT3). FLT3 was first described in humans in 1994 [2], and is thought to play a role in early hematologic differentiation and early B and T-cell development [3]. Activating mutations of the receptor tyrosine kinase FLT3 are some of the most common molecular abnormalities in acute myeloid leukemia (AML), present in about 30% of newly diagnosed patients [4]. Internal tandem duplications (ITDs) within the juxtamembrane domain of FLT3 are found in about 23% of de-novo AML, and represent the most common activating mutation. The presence of a FLT3-ITD mutation in an AML patient portends a poor prognosis, with only 22% of younger adult patients maintaining a remission for 2 years in a recent phase III cooperative group study [5]. FLT3 kinase domain mutations (FLT3-TKDmut), which are found in about 7% of newly diagnosed AML, seem to have limited impact on clinical outcomes; therefore attention has been primarily focused on developing improved therapies for FLT3-ITD AML [6]. More than 20 different small-molecule inhibitors of FLT3 kinase activity have been described in the literature, several of which have advanced to phase II and phase III clinical trials [7]. This review will discuss the results of these studies, the issues encountered and the ongoing direction for clinical development.

Box 1
Box 1
Image Tools
Back to Top | Article Outline

FLT3-ITD ACUTE MYELOID LEUKEMIA

Clinical outcomes of patients with FLT3-ITD mutant leukemias are influenced by several leukaemia-specific factors. High ratio of the mutant FLT3-ITD allele compared to FLT3 wild-type allele (allelic burden) has been associated with inferior survival and decreased complete remission in response to conventional chemotherapy in newly diagnosed AML patients [8]. The presence of a concurrent nucleophosmin (NPM1) mutation in the setting of a FLT3-ITD mutation may abrogate the adverse effects of FLT3-ITD, particularly in patients with low FLT3-ITD allelic burden [9]. This ratio can change during the course of disease, patients with relapsed disease having a higher allelic burden [10]. The allelic burden is also predictive for in-vitro response to FLT3 inhibitors, with patients homozygous for the ITD allele being the most responsive to more selective FLT3 inhibitors [10]. Lastly, the length of the ITD is variable, and a longer ITD length has been associated with worse clinical prognosis in some [11], but not all, studies [9].

Back to Top | Article Outline

FLT3 INHIBITORS AS MONOTHERAPY

Several small-molecule inhibitors of tyrosine kinases were studied in early-phase clinical studies (Table 1). One of the most studied early agents in development is lestaurtinib (CEP-701), with a phase I/II trial of lestaurtinib in relapsed or refractory AML patients with FLT3 mutations in 2003 [13]. Correlative assays in this and a subsequent phase II study demonstrated that clinical response was more likely in patients who had in-vitro leukemic blast sensitivity to CEP-701, and if, in vivo, CEP-701 plasma level was sufficient to significantly inhibit FLT3 autophosphorylation in a sustained fashion. Partial response was achieved in 8 of 27 patients (3 of 5 FLT3-ITD; 5 of 22 wild type). All 8 responders had drug plasma levels sufficient to inhibit FLT3 phosphorylation to below 15% of baseline activity.

Table 1
Table 1
Image Tools

Midostaurin, an indolocarbazole derivative like lestaurtinib, was evaluated in a phase II trial for relapsed or refractory FLT3-mutated AML patients [27]. At a dose of 75 mg three times daily, 14/20 patients displayed at least hematologic improvement, with one complete remission. Midostaurin is tightly bound to alpha-1 acid glycoprotein (AAG), and responses correlated very well with the degree of FLT3 inhibition determined by the pharmacodynamic assessment of FLT3 inhibitory activity in the patient's plasma (PIA) [28].

The multikinase inhibitor sorafenib (bi-aryl urea), approved for use in renal cell carcinoma, has been evaluated in early-phase clinical trials. As a single agent, sorafenib has been studied on an intermittent schedule in refractory AML with or without a FLT3 mutation [29]. A clinical response was observed in 9/16 patients (56%), including all 6 patients with FLT3-ITD alone. In a separate phase I dose-escalation trial of sorafenib in relapsed/refractory acute leukemias, PIA of kinase targets ERK and FLT3-ITD demonstrated excellent target inhibition, with FLT3-ITD silencing occurring below the maximal tolerated dose (MTD) [20]. Despite encouraging correlative studies, no patient met criteria for complete or partial response in this monotherapy study. Several case reports of compassionate use of sorafenib off protocol, with complete remissions, have, however, been reported in the literature [30,31].

Quizartinib (AC220), a novel bis-aryl urea, may well be the most potent and specific inhibitor of FLT3 currently in development [23,32]. A phase I study has recently been completed, studying activity in both FLT3 wild type and ITD-relapsed and refractory AML [33]. Seventy-six patients were treated on one of two schedules: intermittent (day 1–14) or continuous (day 1–28) dosing. Pharmacokinetic studies revealed a prolonged plasma half-life of approximately 36 h and excellent ex-vivo target inhibition at dose levels above 12 mg per day. Additionally, an active metabolite was found, which likely contributes significantly to the biologic activity of AC220. The dose-limiting toxicity was QTc prolongation at 300 mg continuous dosing. The phase II study of quizartinib was preliminarily reported, evaluating 90 mg per day in females and 135 mg per day in males in a continuous dosing strategy [24]. Of the 99 FLT3-ITD-mutated patients, the rate of complete remission with or without count recovery (CRc) was 44%. Thirty-four of the 44 responding patients were able to proceed to allogeneic transplantation. The median duration of CRc was 11.3 weeks.

Ponatinib, which was clinically approved in the United States for refractory CML, has also been found to have activity in FLT3-mutant AML [26]. In a phase I study of relapsed and refractory AML patients with or without FTL3 mutations, ponatinib was found to induce complete remission with incomplete recovery of counts (CRi) in 2 of the 10 patients with documented FLT3-ITD mutations. Preclinically, ponatinib is suggested to have activity against several of the common kinase domain mutations excluding the most common acquired resistance clone with D835Y mutation [34]. Concerns regarding arterial thrombus risk in postmarketing study of CML and Philadelphia chromosome positive acute lymphoblastic leukemia (ALL) have led the US Food and Drug Administration (FDA) to remove ponatinib from the market as of 31 October 2013 (US FDA press release, 31 October 2013).

The use of these agents as monotherapy supports the concept of targeted therapy, but has not resulted in prolonged disease-free survival. These results, however, support the study of these agents in combination with chemotherapy or in the maintenance of remission setting.

Back to Top | Article Outline

COMBINATIONAL STUDIES

With limited clinical activity of early-phase agents targeting FLT3-ITD, combinational studies for newly diagnosed and relapsed refractory AML were begun.

Back to Top | Article Outline
Lestaurtinib in combination with chemotherapy

Drawing on the results of preclinical studies combining lestaurtinib with chemotherapy demonstrating sequential synergy [35], the Cephalon 204 trial began accruing patients in 2003. AML patients were eligible for this trial if they were in first relapse and they harbored a FLT3 mutation. The trial was stratified according to the duration of first remission: patients whose first remission lasted less than 6 months received mitoxantrone, etoposide and cytarabine (MEC) [36], whereas those whose first remission lasted for more than 6 months were treated with high-dose cytarabine (HiDAc) [37] (Table 2). Patients were randomized to receive lestaurtinib at a dose of 80 mg twice daily beginning with the completion of chemotherapy and continuing for up to 16 weeks. The efficacy of target inhibition was determined through the use of a PIA for FLT3 [28]. The results failed to demonstrate clinical benefit of the addition of lestaurtinib to standard salvage therapy [38]. Correlative assays demonstrated incomplete target inhibition in 42% of patients at day 15 of therapy. Those patients who were found to have sustained inhibition (>85% inhibition) were more likely to have complete remission, suggesting some association of clinical response with target activity.

Table 2
Table 2
Image Tools
Back to Top | Article Outline
Midostaurin combined with chemotherapy

In a pilot trial of newly diagnosed AML with or without FLT3 mutations, midostaurin was evaluated in different schedules in combination with induction therapy using a conventional cytarabine and daunorubicin (’7+3’) regimen followed by high-dose cytarabine consolidation. One arm was given midostaurin on days 1–7 and days 15–21, and a second arm received midostaurin on days 8–21 of chemotherapy. In general, midostaurin doses that were well tolerated when used as monotherapy (100 mg orally twice daily) were intolerable (due to nausea) when given concomitantly or following chemotherapy. This study was amended due to the high level of grade 3 nausea and vomiting with 100 mg of midostaurin [40▪▪,44]. In the amended study, midostaurin was started at a dose of 50 mg twice daily. Maintenance midostaurin was allowed on this protocol per the initial dosing randomization. At the MTD of 50 mg twice a day, complete remissions were achieved in 20 of 27 patients with wild-type FLT3 and 12 of 13 patients with FLT3-ITD. On the basis of these results, a phase III randomized trial of midostaurin combined with chemotherapy for newly diagnosed FLT3-ITD and FLT3-TKDmut AML patients under age 60 (RATIFY) was performed [45]. No results are yet available, but a presentation of enrollment data at the American Society of Clinical Oncology Annual Meeting in 2011 illustrated the complexity of performing such a study with a need to screen 2470 patients centrally to enroll 564 patients on protocol.

Back to Top | Article Outline
Sorafenib combined with chemotherapy

In a phase II single-institution study of newly diagnosed AML with or without FLT3 mutations, sorafenib was administered for 7 days at 400 mg twice a day with cytarabine and idarubicin in induction and consolidation, followed by a year of maintenance sorafenib [46,47]. The combination was tolerable, and the investigators reported a high complete remission rate in FLT3-mutated patients (14/15). Despite this high initial complete remission rate, 9/14 patients have gone on to relapse, with the other 5 in ongoing complete remission with median follow-up of 62 weeks.

In an elderly patient population, a randomized trial of chemotherapy ± sorafenib was studied in FLT3-ITD and FLT3 wild type. In the investigational arm, sorafenib was given at a dose of 400 mg twice daily continuously from day 3 until 3 days before next cycle [41▪▪]. There were more adverse events associated with inclusion of sorafenib into chemotherapy and there was no significant improvement in event-free survival (EFS) or overall survival (OS). In the 29 FLT3-ITD patients, complete remission was lower than in wild-type FLT3 (40 vs. 77%, respectively) and sorafenib did not impact on complete remission rate in this small group (57 vs. 64% without).

Back to Top | Article Outline
Quizartinib combined with chemotherapy

Quizartinib is being incorporated into conventional cytarabine/daunorubicin induction in an ongoing phase I study in newly diagnosed AML. Preliminary reports from this study suggest quizartinib is tolerated well at 40 mg twice daily when given for 14 days in induction and consolidation [48]. Plans are in development for a cooperative group phase III study to examine the efficacy of quizartinib in FLT3-mutated patients.

Back to Top | Article Outline

POST-TRANSPLANT AND OTHER MAINTENANCE STRATEGIES

Allogeneic transplantation carried out in first remission appears to be the most effective conventional strategy for curing FLT3-ITD AML [49]. Even after complete remission with induction therapy, there is high likelihood of relapse, with a short duration of remission, and relapse before a donor can be found. Therefore, challenges with these patients include maintaining remission long enough to undergo transplantation, and suppression of the growth of any leukemia clone still present after a transplant. Several case reports have documented somewhat durable remissions to sorafenib when given to patients relapsing after transplant [50,51▪▪]. Clinical trials are ongoing investigating the utility and safety of quizartinib, sorafenib and midostaurin after allogeneic transplant [51▪▪].

Back to Top | Article Outline

FACTORS AFFECTING CLINICAL FLT3 TARGETING EFFICACY AND ASSOCIATED RESISTANCE MECHANISMS

Preclinical studies evaluating small-molecule inhibitors of FLT3 were described shortly after the discovery of FLT3 mutations in AML [12]. Through these studies, it was revealed that the timing of incorporation of FLT3 inhibitors into therapy is predicted to influence clinical efficacy due to the cell cycle arresting characteristics of FLT3 inhibition [35]. The ligand of the FLT3 receptor (FL) is found at peak levels 15 days after chemotherapy [52]. This ligand surge during aplasia renders the FLT3-ITD receptors more resistant to all FLT3 inhibitors and the surge appears to increase in level with each subsequent cycle of cytotoxic chemotherapy [52]. The surge of FL with each successive cycle as a potential resistance factor is an important consideration regarding the early incorporation of transplantation in FLT3-ITD leukemia [52]. It is unclear if ITD length is associated with sensitivity to FLT3 inhibitor therapy, but there appear to be biologic changes that occur with long ITD insertions [53].

Resistance to agents targeting FLT3-ITD has been well described and can develop rapidly. The most common change associated with resistance is the acquisition of a point mutation in the kinase domain (D835Y) [54,55▪] or others [56,57]. Other mechanisms have been described including up-regulation of antiapoptotic pathways such as MCL-1 [58] or stromal response signaling cascades such as CXCR4 [59]. A retrospective study of patients receiving off-label sorafenib upon relapse, however, revealed that only few developed resistance to sorafenib when given in the post-transplant setting (47 vs. 38%; P = 0.03) [51▪▪].

Back to Top | Article Outline

COMCLUSION AND FUTURE DIRECTIONS

Clinical development of novel therapeutics in AML has been a challenging endeavor for many years. Cytarabine and anthracycline-based regimens have been the standard for more than two decades. Despite numerous novel genetic lesions having been discovered over the past two decades, individualized therapy for AML has yet to be realized for most AML patients. Although clinical activity of FLT3 inhibitors has now been well described in FLT3-ITD AML, statistical evidence of improved outcomes has yet to be documented. There are several potential explanations for this: we have yet to develop an effective inhibitor of FLT3; FLT3 inhibitory therapy begets increased FLT3 dependency and signaling, thus leading to failure of therapy due to further up-regulation or resistant mutation development; FLT3-ITD is not a founding lesion and therefore its inhibition as a sole modality is not expected to result in durable responses.

As demonstrated by several correlative studies of lestaurtinib, poor bioavailability and tolerability in early FLT3 inhibitor studies likely led to clinical failure. This does not appear to be the case with more recent studies of quizartinib and sorafenib. Clinical resistance appears to be mediated through development of point mutations in the kinase domain [25,54]. Further development of agents to specifically inhibit both point mutations and ITD mutations is ongoing. Crenolanib is a novel agent in phase I studies, with data to suggest activity against kinase domain mutations in vitro[25].

The promise of targeted therapy in oncology is to deliver high potency therapy to specific subsets of patients to improve outcomes and lessen toxicity. Kinase inhibitor therapy alone for malignancies with more than one driving lesion is unfortunately unlikely to be successful in large numbers of patients. Despite the dramatic outcome improvements in CML with single agent Abl kinase inhibitors, in Philadelphia chromosome positive ALL clinical outcomes are only dramatically improved when inhibitor therapy is incorporated into multimodality therapy such as chemotherapy with allogeneic transplant [60,61]. Clinical trials incorporating novel therapeutics into multimodality therapy are complex to design, difficult to execute, and require large numbers of patients to obtain results that are statistically significant, and this makes the uniform study of these patients extremely challenging, but it remains critical to their development and to progress in these diseases.

Back to Top | Article Outline

Acknowledgements

The work is supported by NIH core grant P30 CA006973 (K. Pratz). K. Pratz has also received clinical trial support funding from NIH for investigations into the peri-transplant use of sorafenib for FLT3-ITD AML supported by grant U01 CA070095.

Back to Top | Article Outline
Conflicts of interest

K. Pratz has received clinical trial support from Astellas/Ambit Pharmaceuticals for phase I study of quizartinib.

Back to Top | Article Outline

REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest

Back to Top | Article Outline

REFERENCES

1. Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med. 2001; 344:1031–1037.

2. Small D, Levenstein M, Kim E, et al. STK-1, the human homolog of Flk-2/Flt-3, is selectively expressed in CD34+ human bone marrow cells and is involved in the proliferation of early progenitor/stem cells. Proc Natl Acad Sci U S A. 1994; 91:459–463.

3. Schmidt-Arras D, Schwable J, Bohmer FD, Serve H. Flt3 receptor tyrosine kinase as a drug target in leukemia. Curr Pharm Des. 2004; 10:1867–1883.

4. Moreno I, Martin G, Bolufer P, et al. Incidence and prognostic value of FLT3 internal tandem duplication and D835 mutations in acute myeloid leukemia. Haematologica. 2003; 88:19–24.

5. Fernandez HF, Sun Z, Yao X, et al. Anthracycline dose intensification in acute myeloid leukemia. N Engl J Med. 2009; 361:1249–1259.

6. Bacher U, Haferlach C, Kern W, et al. Prognostic relevance of FLT3-TKD mutations in AML: the combination matters: an analysis of 3082 patients. Blood. 2008; 111:2527–2537.

7. Knapper S. FLT3 inhibition in acute myeloid leukaemia. Br J Haematol. 2007; 138:687–699.

8. Thiede C, Steudel C, Mohr B, et al. Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood. 2002; 99:4326–4335.

9. Gale RE, Green C, Allen C, et al. 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. 2008; 111:2776–2784.

10. Pratz KW, Sato T, Murphy KM, et al. FLT3-mutant allelic burden and clinical status are predictive of response to FLT3 inhibitors in AML. Blood. 2010; 115:1425–1432.

11. Stirewalt DL, Kopecky KJ, Meshinchi S, et al. Size of FLT3 internal tandem duplication has prognostic significance in patients with acute myeloid leukemia. Blood. 2006; 107:3724–3726.

12. Levis M, Allebach J, Tse KF, et al. A FLT3-targeted tyrosine kinase inhibitor is cytotoxic to leukemia cells in vitro and in vivo. Blood. 2002; 99:3885–3891.

13. Smith BD, Levis M, Beran M, et al. Single-agent CEP-701, a novel FLT3 inhibitor, shows biologic and clinical activity in patients with relapsed or refractory acute myeloid leukemia. Blood. 2004; 103:3669–3676.

14. Weisberg E, Boulton C, Kelly LM, et al. Inhibition of mutant FLT3 receptors in leukemia cells by the small molecule tyrosine kinase inhibitor PKC412. Cancer Cell. 2002; 1:433–443.

15. Fischer T, Stone RM, DeAngelo DJ, et al. Phase IIB trial of oral midostaurin (PKC412), the FMS-like tyrosine kinase 3 receptor (FLT3) and multi-targeted kinase inhibitor, in patients with acute myeloid leukemia and high-risk myelodysplastic syndrome with either wild-type or mutated FLT3. J Clin Oncol. 2010; 28:4339–4345.

16. O’Farrell AM, Abrams TJ, Yuen HA, et al. SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo. Blood. 2003; 101:3597–3605.

17. Fiedler W, Serve H, Döhner H, et al. A phase 1 study of SU11248 in the treatment of patients with refractory or resistant acute myeloid leukemia (AML) or not amenable to conventional therapy for the disease. Blood. 2005; 105:986–993.

18. Kelly LM, Yu JC, Boulton CL, et al. CT53518, a novel selective FLT3 antagonist for the treatment of acute myelogenous leukemia (AML). Cancer Cell. 2002; 1:421–432.

19. DeAngelo DJ, Stone RM, Heaney ML, et al. Phase 1 clinical results with tandutinib (MLN518), a novel FLT3 antagonist, in patients with acute myelogenous leukemia or high-risk myelodysplastic syndrome: safety, pharmacokinetics, and pharmacodynamics. Blood. 2006; 108:3674–3681.

20. Pratz KW, Cho E, Levis MJ, et al. A pharmacodynamic study of sorafenib in patients with relapsed and refractory acute leukemias. Leukemia. 2010; 24:1437–1444.

21. Pratz KW, Cortes J, Roboz GJ, et al. A pharmacodynamic study of the FLT3 inhibitor KW-2449 yields insight into the basis for clinical response. Blood. 2009; 113:3938–3946.

22. Cortes J, Roboz GJ, Kantarjian HM, et al. A phase I dose escalation study of KW-2449, an oral multi-kinase inhibitor against FLT3, Abl, FGFR1 and Aurora in patients with relapsed/refractory AML, ALL and MDS or resistant/intolerant CML [abstract]. Blood (ASH Annual Meeting Abstracts). 2008; 112:2967

23. Zarrinkar PP, Gunawardane RN, Cramer MD, et al. AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML). Blood. 2009; 114:2984–2992.

24. Levis MJ, Perl AE, Dombret H, et al. Final results of a phase 2 open-label, monotherapy efficacy and safety study of quizartinib (AC220) in patients with FLT3-ITD positive or negative relapsed/refractory acute myeloid leukemia after second-line chemotherapy or hematopoietic stem cell transplantation [abstract]. Blood (ASH Annual Meeting Abstracts). 2012; 120:673

25. Zimmerman EI, Turner DC, Buaboonnam J, et al. Crenolanib is active against models of drug-resistant FLT3-ITD-positive acute myeloid leukemia. Blood. 2013; 122:3607–3615.

26. Shah NP, Talpaz M, Deininger MWN, et al. Ponatinib in patients with refractory acute myeloid leukaemia: findings from a phase 1 study. Br J Haematol. 2013; 162:548–552.

27. Stone RM, DeAngelo DJ, Klimek V, et al. Patients with acute myeloid leukemia and an activating mutation in FLT3 respond to a small-molecule FLT3 tyrosine kinase inhibitor, PKC412. Blood. 2005; 105:54–60.

28. Levis M, Brown P, Smith BD, et al. Plasma inhibitory activity (PIA): a pharmacodynamic assay reveals insights into the basis for cytotoxic response to FLT3 inhibitors. Blood. 2006; 108:3477–3483.

29. Zhang W, Konopleva M, Shi YX, et al. Mutant FLT3: a direct target of sorafenib in acute myelogenous leukemia. J Natl Cancer Inst. 2008; 100:184–198.

30. Safaian NN, Czibere A, Bruns I, et al. Sorafenib (Nexavar®) induces molecular remission and regression of extramedullary disease in a patient with FLT3-ITD+ acute myeloid leukemia. Leuk Res. 2009; 33:348–350.

31. Metzelder S, Wang Y, Wollmer E, et al. Compassionate use of sorafenib in FLT3-ITD-positive acute myeloid leukemia: sustained regression before and after allogeneic stem cell transplantation. Blood. 2009; 113:6567–6571.

32. Cortes JE, Kantarjian H, Foran JM, et al. Phase I study of quizartinib administered daily to patients with relapsed or refractory acute myeloid leukemia irrespective of FMS-like tyrosine kinase 3: internal tandem duplication status. J Clin Oncol. 2013; 31:3681–3687.

33. Cortes J, Foran J, Ghirdaladze D, et al. AC220, a potent, selective, second generation FLT3 receptor tyrosine kinase (RTK) inhibitor, in a first-in-human (FIH) phase 1 AML study [abstract]. Blood (ASH Annual Meeting Abstracts). 2009; 114:636

34. Smith CC, Lasater EA, Zhu X, et al. Activity of ponatinib against clinically-relevant AC220-resistant kinase domain mutants of FLT3-ITD. Blood. 2013; 121:3165–3171.

35. Levis M, Pham R, Smith BD, Small D. In vitro studies of a FLT3 inhibitor combined with chemotherapy: sequence of administration is important to achieve synergistic cytotoxic effects. Blood. 2004; 104:1145–1150.

36. Amadori S, Arcese W, Isacchi G, et al. Mitoxantrone, etoposide, and intermediate-dose cytarabine: an effective and tolerable regimen for the treatment of refractory acute myeloid leukemia. J Clin Oncol. 1991; 9:1210–1214.

37. Mayer RJ, Davis RB, Schiffer CA, et al. Intensive postremission chemotherapy in adults with acute myeloid leukemia. Cancer and Leukemia Group B. N Engl J Med. 1994; 331:896–903.

38. Levis M, Ravandi F, Wang ES, et al. Results from a randomized trial of salvage chemotherapy followed by lestaurtinib for patients with FLT3 mutant AML in first relapse. Blood. 2011; 117:3294–3301.

39. Ravandi F, Cortes JE, Jones D, et al. Phase I/II study of combination therapy with sorafenib, idarubicin, and cytarabine in younger patients with acute myeloid leukemia. J Clin Oncol. 2010; 28:1856–1862.

40▪▪. Stone RM, Fischer T, Paquette R, et al. Phase IB study of the FLT3 kinase inhibitor midostaurin with chemotherapy in younger newly diagnosed adult patients with acute myeloid leukemia. Leukemia. 2012; 26:2061–2068.

Report of phase I study of midostaurin in newly diagnosed AML documenting toxicity at single agent MTD but high complete response rate in dose chosen for phase III study.


41▪▪. Serve H, Krug U, Wagner R, et al. Sorafenib in combination with intensive chemotherapy in elderly patients with acute myeloid leukemia: results from a randomized, placebo-controlled trial. J Clin Oncol. 2013; 31:3110–3118.

Report of incorporation of sorafenib into newly diagnosed AML in patients over age 60 showing no significant clinial benefit.


42. Rollig C, Muller-Tidow C, Huttmann A, et al. Sorafenib versus placebo in addition to standard therapy in adult patients <=60 years with newly diagnosed acute myeloid leukemia: results from the randomized-controlled Soraml trial [abstract]. Blood (ASH Annual Meeting Abstracts). 2012; 120:144

43. Cooper T, Sposto R, Cassar J, et al. A phase I study of AC220 in combination with cytarabine and etoposide in relapsed/refractory childhood ALL and AML: a therapeutic advances in Childhood Leukemia & Lymphoma (TACL) study [abstract]. Blood (ASH Annual Meeting Abstracts). 2012; 120:3605

44. Stone RM, Fischer T, Paquette R, et al. A phase 1b study of midostaurin (PKC412) in combination with daunorubicin and cytarabine induction and high-dose cytarabine consolidation in patients under age 61 with newly diagnosed de novo acute myeloid leukemia: overall survival of patients whose blasts have FLT3 mutations is similar to those with wild-type FLT3 [abstract]. Blood (ASH Annual Meeting Abstracts). 2009; 114:634

45. Stone RM, Dohner H, Ehninger G, et al. CALGB 10603 (RATIFY): a randomized phase III study of induction (daunorubicin/cytarabine) and consolidation (high-dose cytarabine) chemotherapy combined with midostaurin or placebo in treatment-naive patients with FLT3 mutated AML [abstract]. ASCO Meeting Abstracts. 2011; 29:(15_Suppl):TS199

46. Ravandi F, Cortes J, Faderl S, et al. Combination of sorafenib, idarubicin, and cytarabine has a high response rate in patients with newly diagnosed acute myeloid leukemia (aml) younger than 65 years [abstract]. Blood (ASH Annual Meeting Abstracts). 2008; 112:768

47. Ravandi F, Cortes JE, Jones D, et al. Phase I/II study of combination therapy with sorafenib, idarubicin, and cytarabine in younger patients with acute myeloid leukemia. J Clin Oncol. 2010; 28:1856–1862.

48. Altman JK, Foran JM, Pratz KW, et al. Results of a phase 1 study of quizartinib (AC220, ASP2689) in combination with induction and consolidation chemotherapy in younger patients with newly diagnosed acute myeloid leukemia [abstract]. Blood (ASH Annual Meeting Abstracts). 2013; 122:623

49. DeZern AE, Sung A, Kim S, et al. Role of allogeneic transplantation for FLT3/ITD acute myeloid leukemia: outcomes from 133 consecutive newly diagnosed patients from a single institution. Biol Blood Marrow Transplant. 2011; 17:1404–1409.

50. Sharma M, Ravandi F, Bayraktar UD, et al. Treatment of FLT3-ITD-positive acute myeloid leukemia relapsing after allogeneic stem cell transplantation with sorafenib. Biol Blood Marrow Transplant. 2011; 17:1874–1877.

51▪▪. Metzelder SK, Schroeder T, Finck A, et al. High activity of sorafenib in FLT3-ITD-positive acute myeloid leukemia synergizes with allo-immune effects to induce sustained responses. Leukemia. 2012; 26:2353–2359.

Reports of durable remissions with sorafenib for patients with FLT3-ITD AML in the postallogeneic transplant setting.


52. Sato T, Yang X, Knapper S, et al. FLT3 ligand impedes the efficacy of FLT3 inhibitors in vitro and in vivo. Blood. 2011; 117:3286–3293.

53. Pekova S, Ivanek R, Dvorak M, et al. Molecular variability of FLT3/ITD mutants and their impact on the differentiation program of 32D cells: implications for the biological properties of AML blasts. Leuk Res. 2009; 33:1409–1416.

54. Man CH, Fung TK, Ho C, et al. Sorafenib treatment of FLT3-ITD+ acute myeloid leukemia: favorable initial outcome and mechanisms of subsequent nonresponsiveness associated with the emergence of a D835 mutation. Blood. 2012; 119:5133–5143.

55▪. Moore AS, Faisal A, de Castro DG, et al. Selective FLT3 inhibition of FLT3-ITD(+) acute myeloid leukaemia resulting in secondary D835Y mutation: a model for emerging clinical resistance patterns. Leukemia. 2012; 26:1462–1470.

Report of selecive resistance patterns in AML treated with FLT3-ITD inhibitors.


56. Heidel F, Solem FK, Breitenbuecher F, et al. Clinical resistance to the kinase inhibitor PKC412 in acute myeloid leukemia by mutation of Asn-676 in the FLT3 tyrosine kinase domain. Blood. 2006; 107:293–300.

57. von Bubnoff N, Engh RA, Aberg E, et al. FMS-like tyrosine kinase 3-internal tandem duplication tyrosine kinase inhibitors display a nonoverlapping profile of resistance mutations in vitro. Cancer Res. 2009; 69:3032–3041.

58. Breitenbuecher F, Markova B, Kasper S, et al. A novel molecular mechanism of primary resistance to FLT3-kinase inhibitors in AML. Blood. 2009; 113:4063–4073.

59. Zeng Z, Shi YX, Samudio IJ, et al. Targeting the leukemia microenvironment by CXCR4 inhibition overcomes resistance to kinase inhibitors and chemotherapy in AML. Blood. 2009; 113:6215–6224.

60. Ottmann OG, Druker BJ, Sawyers CL, et al. A phase 2 study of imatinib in patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoid leukemias. Blood. 2002; 100:1965–1971.

61. Carpenter PA, Snyder DS, Flowers MED, et al. Prophylactic administration of imatinib after hematopoietic cell transplantation for high-risk Philadelphia chromosome positive leukemia. Blood. 2007; 109:2791–2793.

Keywords

acute myeloid leukemia; FLT3 mutations; tyrosine kinase inhibitors

© 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins

Login

Search for Similar Articles
You may search for similar articles that contain these same keywords or you may modify the keyword list to augment your search.