The Role of Kinase Inhibitors in the Treatment of Patients with Acute Myeloid Leukemia

Catherine C. Smith, MD, and
Neil P. Shah, MD, PhD
Article Summary: 

American Society of Clinical Oncology Educational Book

2013 ASCO Annual Meeting

Leukemia, Myelodysplasia, and Transplantation

Targeting Activated Kinases in Acute and Chronic Leukemias


Multiple small molecule kinase inhibitors are currently undergoing development for the treatment of acute myeloid leukemia (AML). Recently, selective and potent FLT3 inhibitors such as AC220 (quizartinib) have proven clinically effective in patients with AML with FLT3 internal tandem duplication (ITD) mutations, but inhibitors of other pathologically activated kinases in AML such as c-KIT and JAK2 have achieved less clinical success. Other classes of inhibitors currently undergoing clinical development target mediators of downstream signaling pathways such as mTOR and MEK or cell cycle machinery such as aurora kinases, PLK1, or cyclin-dependent kinases. Other than FLT3 inhibitors, most inhibitors have achieved only rare bone marrow responses, and kinase inhibitor therapy in AML remains investigational. Continuing efforts to develop kinase inhibitors for the treatment of AML will require careful selection of patients for clinical trials, translational studies to characterize responders, and investigation of combination therapy that may be capable of improving response rates and duration.

The ability of the tyrosine kinase inhibitor (TKI) imatinib to effect deep and sustained remissions in chronic myeloid leukemia (CML) has sparked continuing efforts to achieve similar results in other hematologic malignancies, including acute myeloid leukemia (AML). However, the molecular heterogeneity of AML has limited the ability of kinase inhibitors to achieve broad success in this disease, despite evidence of frequent pathologic activation via mutation of kinases such as FMS-like tyrosine kinase 3 (FLT3),1-3 KIT,4,5 and other signaling molecules such as RAS.6-8 Kinase inhibitor therapy in AML has been complicated by difficulty in developing potent and selective inhibitors, as well as by the question of whether observed mutations are truly “addicting” and, therefore, represent valid therapeutic targets whose successful inhibition would be predicted to result in true disease remissions. It is also unclear whether clinical benefit will be restricted to patients harboring any mutation in the target gene, those with a specific subset of mutations, or would also include patients whose disease demonstrates overexpression of the intended target in the absence of a structural mutation. Finally, the optimal use and timing of kinase inhibitors in AML therapy is unclear—as monotherapy in remission induction and maintenance or in sequence or combination with other therapies such as traditional chemotherapy, novel pathway inhibitors, or hypomethylating agents. This article will review classes of investigational kinase inhibitors in AML and their potential role in the treatment of AML.


Among the most common genetic lesions in AML are constitutively activating mutations of the FLT3 receptor tyrosine kinase (RTK). Internal tandem duplication (ITD) mutations in FLT3 are detected in approximately 20% of AML cases and are associated with poor prognosis.9,10 Another 5% to 10% of patients with AML express constitutively activating point mutations in the tyrosine kinase domain (TKD), commonly at the activation loop (AL) residue D835.2,3 Efforts to effectively target FLT3 in AML have been fervent and longstanding, but initial attempts were largely unsuccessful, resulting in only transient reductions in peripheral blasts with few bone marrow responses.11,12 First-generation FLT3 inhibitors suffered from lack of potency, selectivity, and favorable pharmacokinetic properties.13 In addition, data has suggested that FLT3 mutations are secondary rather than initiating genetic lesions in AML, hinting that FLT3 mutations may not be critical for disease pathogenesis.14-16

The recent success of the investigational FLT3 inhibitor AC220 (quizartinib) in achieving a composite complete remission (CR) rate of approximately 50% in a phase II study in patients with relapsed/refractory FLT3-ITD-positive AML17,18 has rekindled interest in FLT3 as a therapeutic target, although most AC220-responsive patients experienced incomplete recovery of peripheral blood counts despite clearance of bone marrow blasts. The evolution of TKD mutations in eight of eight patients who experienced relapse after a bone marrow response on AC220 confirmed that clinical responses in these patients were achieved by FLT3 inhibition and that relapses were mediated by the reactivation of FLT3 kinase activity.19 Resistance mutations occurred at the “gatekeeper” residue in FLT3, F691, recurrently mutated to a leucine (3 patients) and most frequently at the activation loop residue D835 (6 patients) (including one patient who developed both an F691L and D835V mutation), suggesting that substitutions at the D835 residue may be a common problematic cause of resistance to AC220. Mutations at D835 have also been associated with clinical resistance to sorafenib, which has also been reported to be clinically active in FLT3-ITD-positive AML.20 These findings validate FLT3-ITD as a therapeutic target and further suggest that “cooperating” genetic lesions such as FLT3-ITD, which are believed to occur relatively late during evolution of the malignant clone, can remain critically important for the survival of cells in which they arise. It is not yet clear whether other FLT3 activating mutations (such as point mutations at D835 in the absence of an ITD) are equally valid therapeutic targets, as clinical experience in this population has been limited and both AC220 and sorafenib appear inactive against these mutations.19-21

The rapid emergence of resistance-conferring FLT3 TKD mutations in patients who respond to AC220 underscores the need for additional clinically effective FLT3 inhibitors with activity against AC220-resistant mutants. As stated previously, although the United States Food and Drug Administration (FDA)-approved multikinase inhibitor sorafenib has achieved remissions in FLT3-ITD-positive AML,20,22 it appears to be vulnerable to the same spectrum of KD mutations as AC220.19 The ABL/FLT3 inhibitor ponatinib, recently FDA-approved for the treatment of TKI-resistant CML, achieved CR in two of seven patients with TKI-naïve FLT3-ITD-positive AML treated on a phase I study23 and appears to have activity against AC220-resistant FLT3 gatekeeper mutations at F691.24 However, ponatinib's clinical activity and its ability to suppress the AC220-resistant F691L mutation needs to be assessed in larger clinical trial experience. Other inhibitors with in vitro activity against AC220-resistant FLT3 KD mutations are currently undergoing clinical trial evaluation in FLT3-mutant AML, including PLX3397 (which has equipotent activity against the FLT3 F691L mutant)25 and crenolanib (active against the broadly-resistant D835 mutants),26,27 but clinical evidence of activity has yet to be reported.

Although AC220 has demonstrated an impressive rate of remission induction in patients with chemotherapy-refractory FLT3-ITD-positive AML, most remissions do not meet traditional CR criteria and instead represent clearance of bone marrow blasts with incomplete recovery of blood counts (CRi). Additionally, instead of the hypocellular response associated with chemotherapy, AC220 response in many patients appears to be associated with a syndrome of terminal myeloid differentiation resulting in marrow hypercellularity associated with a neutrophil surge and inflammatory tissue infiltrates.28 These observations suggest that remissions in AML achieved with kinase inhibitor treatment may appear different from those achieved with standard chemotherapy and that response criteria may need to be adjusted accordingly. It remains to be seen if remissions associated with incomplete count recovery will translate to increased overall survival. In the case of patients who are eligible for allogeneic stem cell transplant, the best use of kinase inhibitor therapy may be as a bridge to transplant.


In contrast to the recent experience with FLT3, no other activated kinase has yet clearly proven to be an effective therapeutic target in AML. Activating mutations in c-KIT in the form of insertion or deletion mutations in exon 8 or as point mutations in the activation loop in exon 17 (commonly at residue D816) occur in about 2% of AML cases29 and are enriched in core binding factor AML, where they are reported to occur in approximately 30% of patients with inversion 16 (16% within exon 17 and 13% within exon 8) and 22% of patients with t(8;21) (18% within exon 17 and 4% within exon 8).5 No clinical trials have assessed the efficacy of KIT inhibitors in patients with AML with KIT mutations; notably, all clinically available KIT inhibitors appear to be inactive against KIT D816 mutations.30 KIT inhibitors have, however, achieved mixed success in patients with c-KIT overexpression. In case reports, KIT inhibitors SU541631 and imatinib32 induced remission in patients with c-KIT overexpression, and in one pilot phase II study, five of 21 patients with AML with c-KIT overexpression responded to imatinib, including two patients harboring a low percentage of bone marrow blasts who achieved CR when treated with imatinib shortly following chemotherapy.33 However, two other studies reported no responses in patients with AML with c-KIT expression.34,35 In the case of responders, it is unclear if responses were actually achieved via KIT inhibition. It is likely that the therapeutic potential of KIT inhibition in AML will not be truly tested until KIT inhibitors with activity against commonly found activating KIT mutations (i.e., D816V) are available and clinical trials in well-selected patient populations are performed in the setting of careful correlative studies designed to identify predictors of response.

Activating JAK2 V617F mutations, though commonly found in myeloproliferative neoplasms (MPN),36 are rare in AML37,38 and are most frequently identified in patients with a pre-existing MPN. Ruxolitinib, a JAK1/JAK2 inhibitor recently FDA-approved for the treatment of advanced myelofibrosis, has been assessed in a phase II clinical trial in relapsed/refractory leukemias.39 In this trial, three of 38 patients achieved CR (one with incomplete count recovery); all three who responded had post-MPN AML (two of three were JAK2V617F mutation positive). However, there was no significant difference in JAK2V617F allele burden in assessed responders or in any other patient; thus, it is unclear if these responses were achieved via inhibition of JAK2 or another kinase. The potential role of ruxolitinib and other JAK2 inhibitors in the treatment of post-MPN AML remains unclear.


Given the difficulty of targeting individual mutated kinases, either because of lack of inhibitors with clinical efficacy against particular mutations or the inherent difficulty of “drugging” the target (as is the case of RAS mutations, which result in isoforms with decreased enzymatic activity not amenable to “inhibition” in the traditional sense40), there has been considerable interest in developing inhibitors of signaling pathways downstream of these kinases. This strategy has yet to yield convincing evidence of clinical efficacy, a result likely partially attributable to lack of patient selection as well poor understanding of how oncogenic signaling pathways are perturbed in individual patients.

TABLE 1. Kinase Inhibitors Investigated in AML

TargetInhibitorsReported Single-Agent Composite Remission Rate (CR + CRi)AML Patient Population
SorafenibAnecdotal22; 92%20FLT3-ITD+
CrenolanibNAAny FLT3 mutation
KITImatinibAnecdotal32; *10%33KIT overexpression
SU5416Anecdotal31KIT overexpression
JAK2Ruxolitinib8%39Post-MPN AML
MEKTrametinib19%46RAS-mutant leukemia (includes other leukemias)
Aurora KinaseAZD115214%48Unselected
MLN82371 patient49Unselected

Abbreviations: AML, acute myeloid leukemia; CR, complete remission; CRi, incomplete recovery of blood counts; NA, not assessed; MPN, myeloproliferative neoplasms; CDK, cyclin dependent kinase; PLK1, polo-like kinase 1.

*Patients with less than 5% blasts at start of treatment

The mammalian target of rapamycin (mTOR) is a serine/threonine kinase involved in the regulation of cell growth and proliferation and is a downstream effector of the mitogen-activated protein kinase (MAPK) and the phosphatidylinositol 3–kinase (PI3K)/AKT pathways known to be activated by mutated FLT341 and KIT.42 In a pilot study of the mTOR inhibitor rapamycin in nine unselected patients with relapsed/refractory AML, four patients responded with 50% or more decrease in blood or bone marrow blasts, but no CRs were achieved.43 In a phase I study of the mTOR inhibitor everolimus, no responses were observed in nine patients with AML treated.44 Similarly, in a larger phase II study, deforolimus (AP23573), a novel nonprodrug rapamycin analog, had little effect in an AML population, with only one of 22 patients achieving hematologic improvement without bone marrow response.45

Mitogen-activated extracellular signal-related kinase (MEK) is a key effector of the MAPK pathway that has recently been successfully targeted in metastatic melanoma cases with the activating BRAF V600E mutation. Trametinib (GSK1120212), is an oral MEK inhibitor that has successfully extended progression-free and overall survival in a phase III open-label trial in patients with metastatic melanoma.46 Trametinib is currently undergoing phase I/II evaluation in relapsed/refractory myeloid malignancies, including AML. Recently, an overall response rate of 28% in RAS-mutant leukemias was reported, with 11 of 57 patients with N- or K-RAS mutations achieving bone marrow CR (19%; some with incomplete count recovery).47 No patient without a RAS mutation achieved a bone marrow CR, further underscoring the importance of appropriate patient selection in kinase inhibitor therapy.


With the goal of targeting additional downstream mediators and potentially expanding the population of patients who might benefit from kinase inhibitor therapy beyond those with detectable signaling mutations, recent clinical efforts have explored the therapeutic potential of inhibitors targeting kinases that are important in cell cycle progression and mitosis, such as aurora kinases, polo-like kinase 1 (PLK1), and cyclin dependent kinases (CDK).

Aurora kinases are a family of highly conserved serine–threonine protein kinases that play key roles in mitosis and have been shown to be overexpressed in human leukemias. Aurora A plays a key role in centrosome maturation, spindle assembly, meiotic maturation, and metaphase I spindle orientation. Aurora B kinase is a critical component of the chromosomal passenger complex (CPC) that mediates chromosome condensation, chromosome orientation on the mitotic spindle and the spindle-assembly checkpoint, as well as the final stages of cytokinesis.48 Several studies of aurora kinase inhibitors in AML have reported promising results. In a phase I/II study in AML, AZD1152, an inhibitor of aurora kinase B, induced responses in 25% of patients (64 patients), including nine CRs across the phase I and II portions (6 with incomplete count recovery).49 A phase II study in AML and myelodysplastic syndrome of MLN8237, an oral inhibitor of aurora kinase A, reported a 13% response rate (in 57 patients), including one CR ongoing with 1 year of follow-up at the time of the report.50

Targeting cell cycle checkpoint regulators also appears to have some favorable activity in AML. CDKs are known to play an important role in regulating cell cycle progression.51 Similarly, PLK1 also plays a role in cell cycle checkpoint control and control of mitotic progression, particularly metaphase–anaphase transition and mitotic exit.52 Recently dinaciclib, a potent and selective inhibitor of CDKs 1, 2, 5, and 9 demonstrated some ability to reduce peripheral and bone marrow blasts in patients with AML in a phase II study in advanced acute leukemias.53 Volasertib (BI 2536), an inhibitor of PLK1 has also demonstrated some activity in a phase I/II monotherapy study in elderly patients with relapsed/refractory AML, achieving one CR, one CRi, and one partial response (PR).54 In an interim analysis of an open-label, randomized study of low-dose ara-C (LDAC) with or without volasertib, volasertib appeared to potentiate the effect of chemotherapy in patients with AML ineligible for intensive therapy; a significantly greater proportion of patients receiving volasertib plus LDAC achieved a CR or CRi compared with patients who received LDAC alone (31.0% vs. 11.1%; p = 0.0277), including a trend toward improved event-free survival.55


At the present time, kinase inhibitor therapy in AML remains investigational, and in the majority of cases, bone marrow responses in the form of CR or CRi have been the exception rather than the rule with monotherapy. However, even in the case of FLT3-ITD-positive AML, where the use of the selective and potent FLT3 inhibitor AC220 has impressively achieved an approximately 50% composite CR rate in a relapsed/refractory population as a single agent, questions remain about the optimal use and timing of these inhibitors that are applicable to the use of all such inhibitors in AML treatment.

Can response rates be improved when combined with chemotherapy or with hypomethylating agents? Although the first generation FLT3 inhibitor CEP701 showed no benefit when added to salvage chemotherapy in FLT3 mutant AML,55 it may be that inhibitors with improved single agent activity such as AC220 would have additional beneficial effect in combination with chemotherapy, either to improve remission rates or to lower the likelihood of relapse. Currently, a phase I study testing the safety and tolerability of AC220 in combination with chemotherapy is ongoing. Illustrating the potential strength of a combination strategy, however, a recent study of sorafenib combined with 5-azacitadine reported a high 44% response rate in relapsed/refractory FLT3-ITD-positive AML, including 10 patients (29%) with CRi, four patients (12%) with CR, and one patient (3%) with PR (who experienced clearance of bone marrow blasts down to 6%).58 Other studies have indicated the feasibility and tolerability of kinase inhibitors when used in combination with chemotherapy.59 In the future, as more effective FLT3 inhibitors are developed, combination strategies involving FLT3 inhibitors with non-overlapping resistance profiles or of FLT3 inhibitors and other downstream inhibitors may be capable of minimizing resistance mechanisms and improving overall response rates. Finally, given the high rate of relapse in patients with FLT3-ITD-positive AML, a strategy of FLT3 inhibitor maintenance therapy either after induction chemotherapy or after stem cell transplant may be an additional strategy to maintain remission and improve outcomes.


With the clinical success of AC220 in FLT3-ITD-positive AML and clear evidence from translational studies that responses (and relapses) are mediated via FLT3 kinase activity, the therapeutic potential of kinase inhibitor therapy in AML has just begun to be realized. In the case of other kinase inhibitors, however, deep bone marrow responses have been rare, and little is known about the true mechanism of action of these agents or predictors of response. It is not yet clear whether mutations in c-KIT, JAK2, or RAS are truly “addicting” in human AML and, therefore, valid therapeutic targets. In all these cases, it will be important to develop further selective and potent inhibitors, ideally effective against all clinically relevant mutations in the target kinase, and to properly select for treatment patients whose leukemias are most likely to be dependent on the activity of the target kinase. When patients do respond, it will be important to perform rigorous molecular characterization of their disease to elucidate the mechanism of response. In the case of cell cycle inhibitors, modest response rates have been observed and may be improved if inhibitors are combined with chemotherapy. For all inhibitors, further work will be needed to define and overcome resistance mechanisms and determine whether to utilize inhibitors alone or in combination with other drugs to achieve optimal clinical outcomes.


Dr. Smith has a Leukemia & Lymphoma Society Career Development Award for Special Fellows; Dr. Shah is a Leukemia & Lymphoma Society Scholar in Clinical Research.

Key Points

  • AML is molecularly heterogeneous, and it is unlikely that any single class of small molecule inhibitor will be broadly clinically effective.
  • Selective and potent FLT3 inhibitors such as AC220 are highly active in patients with AML who have FLT3-ITD mutations, but most responders with bone marrow remissions have incomplete recovery of blood counts; rapid relapse is common and associated with reactivation of FLT3 kinase activity via drug resistant kinase domain mutations.
  • Anecdotal remissions have been reported with inhibitors of KIT and JAK2, but it is unclear if responses have been achieved through inhibition of the target kinase, and the role of these inhibitors in AML therapy remains unclear.
  • Inhibitors of downstream signaling pathways and cell cycle mediators are undergoing clinical development, but have not yet proven broadly clinically effective and may be best utilized in selected patient populations.
  • Small molecule kinase inhibitors may prove more effective in AML when utilized in combination with other targeted agents or chemotherapy.


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