Novel Therapies on the Horizon in AML

Treatment advancements for patients with acute myeloid leukemia (AML) are few and far between with marginal gains being made in the form of changes in current standard therapies or supportive care.

Roland Walter, MD, PhD

Treatment advancements for patients with acute myeloid leukemia (AML) are few and far between with marginal gains being made in the form of changes in current standard therapies or supportive care. However, several promising targeted therapies have demonstrated impressive results in early clinical trials, with the FLT3 inhibitors representing the most promising approach. Moreover, strong initial data has been generated in studies exploring immunomodulatory agents and BCL-2, IDH2, and XPO1 inhibitors, which bodes well for the continued introduction of novel AML therapeutics in the near future.

“Over the last 40 years, we have made incremental progress in the treatment of patients with AML, primarily in younger individuals,” explained AML researcher Roland Walter, MD, PhD, of the clinical research division, Fred Hutchinson Cancer Research Center, Seattle, Washington. "However, this progress is largely due to improvements in supportive care rather than the introduction of many new agents.”

FLT3 Inhibitors Generate Early Excitement

To date, FLT3 inhibitors are the furthest along the clinical pipeline of the novel treatments for AML, although none has yet received FDA approval. Activating mutations in the FLT3 gene occur in approximately 30% of patients with AML, either as internal tandem duplications (ITD) or as point mutations in the tyrosine kinase domain (TKD). FLT3/ITD is more common (~25%) and has been associated with early relapse and poorer survival. The effect of FLT3/TKD mutations on patient prognosis is less clear; however, they may represent an important mechanism of resistance to FLT3 inhibitors.1

Results of a phase II trial of the FLT3 inhibitor quizartinib were presented at the 2014 ASCO Annual Meeting.2 Trial participants, who had relapsed or had refractory FLT3/ITD-positive AML, achieved a composite complete remission (CRc) rate of 47%. The most common adverse events (AEs) reported were diarrhea (18%), febrile neutropenia (16%), and prolonged QT (15%).

Sorafenib has been found to also be a FLT3 antagonist, in addition to inhibiting VEGFR, PDGFR, and Raf. It is approved for use in hepatocellular carcinoma, renal cell carcinoma, and radioactive iodine-refractory differentiated thyroid cancer. Additionally, the treatment has shown clinical activity in a small study of 6 patients with FLT3/ITD-positive AML.3

Crenolanib, a second-generation FLT3 inhibitor now in a phase II trial (NCT01657682), has demonstrated activity against FLT3/ITD and several drug-resistant mutations,4 potentially adding to the arsenal of compounds available.

Orphan Drug Designation Given to XPO1 Inhibitor

Selinexor (KPT-330) is an inhibitor of the nuclear export protein exportin 1 (XPO1/CRM1), and has demonstrated activity against CLL cells ex vivo.5 Inhibition of nuclear export is thought to kill malignant cells by forcing the nuclear localization and activation of tumor suppressor proteins such as p53.

Selinexor is in phase I trials for several different cancer types. Results from a trial involving patients with relapsed or refractory AML were presented at the 2014 ASCO Annual Meeting. Forty-eight patients were given selinexor at 5-dose levels (16.8-55 mg/m2), and no dose-limiting toxicities were encountered. Thirty-two of the patients completed cycle 1 of the trial, and 9 of these (28%) had at least a partial response to the drug.6 The FDA has given an orphan drug designation to selinexor for the treatment of AML, potentially accelerating its path to the clinic.

Antibody-Drug Conjugates Rejuvenated

The antibody-drug conjugate (ADC) gemtuzumab ozogamicin (GO) is made up of a toxin (calicheamicin) linked to an antibody directed against the CD33 cell surface antigen. Although it was approved for use in refractory/relapsed AML, a combination of ineffectiveness in many patients plus excessive AEs resulted in its withdrawal from the market. More recent trials with different populations have again shown positive results with this drug, resulting in calls from some researchers for its reintroduction.7 Regardless of the ultimate fate of GO, it has shown the potential for therapies using antibodies targeting CD33, and a new CD33-targeting ADC, SGN-CD33A, is in a phase I clinical trial (NCT01902329).

Bispecific T-cell Engager Antibodies

Bispecific T-cell engager (BiTE) antibodies are chimeric combinations of 2 different antibodies. One of the antibodies is directed against the CD3 antigen of cytotoxic T-cells, while the second targets an antigen on the malignant cell, thereby engaging the patient’s own immune system in clearing the leukemia.

Following positive results using BiTE technology in acute lymphocytic leukemia, a BiTE antibody that targets CD33 (AMG 330) is in development for potential use in AML.8 As one of the researchers involved in the development of AMG 330, Walter, described immunomodulatory therapies as “an exciting new treatment modality” that may be effective in a large subset of patients with AML.

Early Promise for ABT-199

The BCL-2 kinase is frequently overexpressed in B-cell malignancies such as chronic lymphocytic leukemia (CLL) and follicular lymphoma. An inhibitor against BCL-2, ABT-199 (GDC-0199), has been reported to have cytotoxic effects against AML cell lines and primary patient samples with a half maximal inhibitory concentration (IC50) of approximately 10 nmol/L, a similar ex vivo sensitivity as in CLL.9 ABT-199 has proceeded to a phase II clinical trial in patients with relapsed or refractory AML (NCT01994837).

IDH2 Inhibitor Effective in Phase I Study

An early study showed promise for AG-221, a novel therapy targeted to the isocitrate dehydrogenase- 2 (IDH2)-mutant protein. In a phase I study presented at the 2014 AACR Annual Meeting, responses were observed in six of seven AML patients: three had complete hematologic responses, two had complete responses without platelet recovery, and one had a partial response.10 Three more patients are being evaluated for response to AG-221. Pharmacokinetic/pharmacodynamics data showed that the drug accumulated to high levels after multiple doses, and this was associated with greater than 90% inhibition of plasma 2-HG.


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