FLT3 Inhibitors in Acute Myeloid Leukemia

Khaled el-Shami; Richard M. Stone; B. Douglas Smith

Disclosures

Expert Rev Hematol. 2008;1(2):153-160. 

In This Article

FLT3 Inhibitors

Conceptually, there are several potential strategies to disrupt a signaling pathway that has been implicated in the development or maintenance of a malignant phenotype. The first focuses on neutralizing the ligands before they can associate with their cognate receptors and initiate the signaling cascade. The second approach involves the direct inhibition of the receptor(s), often through the physical blockade of the receptors with directed monoclonal antibodies or disruption of the enzymatic activity engendered by the receptor oligomerization and resultant autophosporylation by small-molecule inhibitors. The third approach relates to the inhibition of signaling of cytoplasmic second messengers, most of which are serine-threonine kinases.[50]

The initial attempt to target FLT3 utilized the phage display libraries to generate monoclonal antibodies. One such molecule was a fully human antibody that exhibited high affinity binding of FLT3, suppression of autophosphorylation and downstream signaling in a number of human leukemia cell lines, as well as prolongation of survival in mice bearing human leukemia xenografts.[51] Nonetheless, the recent development of FLT3 (and other tyrosine kinase) inhibitors has focused mainly on ATP-directed small molecules rather than monoclonal antibodies. The initial assumption that the catalytic domain among protein kinases is highly conserved (thus selectivity would be hard to achieve) has been refuted by the crystallization of protein kinases showing variability among ATP-binding domains of tyrosine kinases.[52] The design, synthesis and biological evaluation of ATP site-directed inhibitors of tyrosine kinases are beyond the scope of this article (for recent reviews, see [52]). We have chosen to focus on clinical results reported with agents currently in development ( Table 1 ).

SU5416

The SU5416 is an intravenous indolinone that targets FLT3, as well as KIT, PDGFR and VEGFR. SU5416 was tested in two separate Phase II efficacy studies in patients with AML and poor-risk MDS. The first trial enrolled 43 patients with AML who were treated with twice-weekly infusions of SU5146 administered on a 28-day cycle.[53] There was an overall partial response rate of 19% lasting for a period of 1-5 months. One patient achieved clearance of blasts in the marrow (less than 5%) but failed to meet other criteria for a complete remission, and seven patients achieved a greater than 50% reduction in marrow blasts. In this study, the status of FLT3-ITD was not ascertained, and, consequently, no biologic correlative studies to determine the impact on the phosphorylation status of the receptor were presented. A larger second trial performed simultaneously enrolled a total of 55 patients with refractory myeloproliferative disorders received SU5416 twice-weekly intravenously for a median of three 4-week cycles.[54] There was only one partial response observed at the expense of substantial toxicity. The study investigators concluded that more tolerable and active FLT3-targeted inhibitors were needed. A follow-up study of SU5416 found it capable of inhibiting FLT3 phosphorylation that lasted for only a few hours and offered biologic rationale of its lack of meaningful clinical activity.[55] It is important to note that these trials evaluated a multikinase inhibitor and as such were not restricted to patients harboring FLT3 mutations.

SU11248

SU11248 is an oral indolinone that was recently approved by the US FDA for the treatment of advanced renal cell carcinoma and gastrointestinal stromal tumors with more potency, but with similar target profiles. However, it is a more potent target inhibitor than SU5416.[56] In a Phase I study, 15 patients with refractory AML were treated with two dose levels and two schedules.[57] All patients with FLT3 mutations (n = 4) had morphologic or partial responses compared with two of ten evaluable patients with wildtype FLT3. Responses, although longer in patients with mutated FLT3, were of short duration, ranging between 4 and 16 weeks. Of note, target inhibition was achieved at the higher dose level (75 mg). Unfortunately, this higher dose was poorly tolerated. The authors concluded that the lower dose (50 mg) might be suitable for combination regimens with cytotoxic chemotherapy. Indeed, it appears that SU11248 has an additive-to-synergistic inhibitory effect on FLT3-dependent leukemic cell proliferation when combined with cytarabine or daunorubicin in vitro, presumably through enhanced induction of apoptosis.[58] Corresponding with the notion that AML cells with a FLT3 mutation are dependent upon it, SU11248 inhibited the proliferation of primary AML myeloblasts expressing mutant FLT3 ITD but not leukemias with wildtype FLT3 protein.[58]

PKC412

PKC412 is an oral indolocarbazole derivative with potent FLT3 inhibitory activity.[55] In a Phase II efficacy study, 20 patients, each with mutant FLT3 relapsed/refractory AML or high-grade MDS, were treated with a fixed dose of PKC412. The major toxicity was fatal pulmonary events of unclear etiology in two patients. PKC412 had significant biological activity, indicated by a decrease of the peripheral blast count by 50% in 14 patients (70%). A larger than 2-log reduction in peripheral blast count lasting over 2 weeks in seven patients (35%) was observed. Additionally, PKC412 reduced bone marrow blast counts by 50% in six patients.[59] Importantly, there was correlation between inhibition of FLT3 autophosphorylation and the observed clinical responses. Recently, the results of a small Phase Ib trial combining PKC412, both concurrently and sequentially, with daunorubicin and cytarabine in both induction and consolidation phases in a cohort of FLT3+ AML patients under the age of 61 years have provided background to conduct a multinational Phase III trial of PKC412 in combination with chemotherapy.[60]

CEP-701

CEP-701 is another oral indolocarbazole derivative considered to be a very potent inhibitor of FLT3.[61] A Phase I/II trial to determine the in vivo hematologic effects of single-agent CEP-701 as salvage treatment enrolled 14 patients with refractory, relapsed or poor-risk AML expressing FLT3-activating mutations.[62] The patients were treated with CEP-701 at an initial dose of 60 mg orally twice daily. CEP-701 was generally well tolerated, with most drug-related toxicities being gastrointestinally-related. Five patients had clinical evidence of biologic activity and measurable clinical response, including significant reductions in bone marrow and peripheral blood blasts. Laboratory data confirmed that clinical responses correlated with sustained in vivo FLT3 inhibition to CEP-701 as well as apoptosis of patients' leukemic blasts upon in vitro exposure to CEP-701. Further work found that CEP-701 had in vitro synergy with standard AML chemotherapeutic agents, specifically when adminstered simultaneously with or immediately following chemotherapy.[63,64] A Phase III trial of mitoxantrone/etoposide/cytarabine with or without subsequent use of CEP-701 in patients with relapsed FLT3-ITD+ AML is currently underway.

MLN518

This oral quinazoline is another compound with a range of target selectivity similar to that of the indolinones.[65,66] Following a dose escalation study in 40 patients with AML and MDS in which a decrease of bone marrow blasts from 80 to 15% in a patient with FLT3-ITD+ AML was noted,[67] a Phase II trial was recently launched. Preliminary results in 18 evaluable FLT3-ITD AML patients showed reduction in blast counts in six patients lasting 1-3 months.[68] To date, no complete or partial remissions have been reported.

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