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Will newer tyrosine kinase inhibitors have an impact in AML?

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FLT3 inhibition has been a goal of acute myeloid leukemia (AML) therapy since FLT3 mutations were discovered to have a role in AML. Several FLT3 inhibitors have been developed in the last several years, beginning with less potent, less selective agents. The newer FLT3 inhibitors appear to be more potent in vivo and have shown more promise than the older agents in monotherapy trials.

Introduction

The successful development of a FLT3 inhibitor that meaningfully improves outcomes for acute myeloid leukemia (AML) patients has been a holy grail of the field for several years now. As with that mythical chalice, is the object of the current quest ever receding, or has it at last drifted almost within our reach? In fact, on reviewing the progress over the last decade, it can be argued that the development of FLT3 inhibitors has actually followed an orderly progression, and that the first important phase in development is drawing to a conclusion.

From the original discovery of the internal tandem duplication (FLT3/ITD) mutations that cause constitutive activation of the FLT3 tyrosine kinase to the subsequent large studies out of the European and US cooperative groups that confirmed their strong negative prognostic impact, the efforts to identify and characterize candidate compounds has followed a rather predictable course *[1], [2], *[3], [4], [5], [6], [7], [8]. The initial approach was to try “off-the-shelf” drugs that were already under investigation for other targets. In parallel with these efforts, pharmaceutical companies began from scratch, searching for compounds uniquely targeted to FLT3. The older drugs moved relatively rapidly into advance phase clinical trials, and while the results seemed disappointing, important information was nonetheless gleaned. The lessons learned from the earlier efforts cast a clearer light on the early results from the newer drugs, and we appear at last to be on the cusp of success. The real question here is just how much will an optimally designed FLT3 inhibitor benefit an AML patient with a FLT3 mutation. In other words, is the quest really worth the effort?

Section snippets

The FLT3 tyrosine kinase

The receptor tyrosine kinase FLT3 was first cloned from the human genome in the early 1990s.[9] Constitutive activating mutations were identified and characterized primarily in studies taking place in Japan in the late 1990s,*[1], [2], [10] and then followed a series of large studies of banked AML samples out of the European cooperative groups *[3], [5], [6]. These reports established the profoundly negative effect of FLT3/ITD mutations on patient outcomes and provided significant impetus to

Is the targeted therapy hitting the target?

As a targeted therapy such as a kinase inhibitor moves into clinical trials, it is of paramount importance to establish whether or not the target in question is actually being inhibited. That is, while preclinical studies invariably demonstrate potent inhibition of tyrosine kinase activity, with resultant cytotoxic effects, it is technically much more challenging to prove that the same degree of inhibition is achieved in vivo in sustained fashion. In this regard, the development of a surrogate

FLT3 inhibitors in clinical development

These five FLT3 inhibitors—lestaurtinib, midostaurin, sorafenib, KW-2449, and AC220 are currently being evaluated in clinical trials. The first three of these (lestaurtinib, midostaurin, and sorafenib) are older multitargeted compounds that happened to also inhibit FLT3 [19], [20, [21]. These moved relatively quickly into clinical trials *[14], *[22], *[23]. The latter two (KW-2449 and AC220) were more recently designed and more specifically developed as FLT3 inhibitors [24], *[25]. Using the

Conclusion

The perception that the clinical development of a FLT3 inhibitor is proceeding slowly is, perhaps, a reflection of the impatience of physicians treating this terrible disease. On review of the work over the past 10 years, it seems we are actually making progress. Midostaurin and lestaurtinib are broad-spectrum kinase inhibitors with some activity against FLT3. As such, results from trials of these agents should be interpreted with extreme caution. It is still important to note that a great deal

Conflict of interest statement

Mark J. Levis, MD, PhD, Consulting Fees: Ambit Biosciences Inc., Cephalon Inc.

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