In the Pipeline: Potential New Treatments for AML

Kinase Inhibitors

In the spring of 2014, a search of the clinicaltrials.gov web site with the key wordsacute myeloid leukemiaandphase II,IIIreturned a list of just over 340 open studies. Most of those trials involving novel agents can be grouped into 1 of 2 general categories: immunomodulators or kinase inhibitors.FLT3

To date, inhibitors of FMS-like tyrosine kinase 3 (FLT3) are the furthest along the clinical pipeline of the novel treatments for acute myeloid leukemia (AML), although none has yet received US Food and Drug Administration (FDA) approval. Activating mutations in theFLT3gene 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

Timothy S. Pardee, MD, on Outcomes Among Intensively Treated AML Patients

Pardee is a professor at Wake Forest University Baptist Medical Center

Results of a phase II trial of the FLT3 inhibitor quizartinib were presented at the 2014 ASCO Annual Meeting (NCT01565668).²Trial participants, who had relapsed or had refractory FLT3/ITD+ 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, another FLT3 antagonist that is approved for use in hepatocellular carcinoma and renal cell carcinoma, has shown clinical activity in a small panel of 6 patients with FLT3/ITD+ AML.³

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

BCL-2

Immunomodulators

A second class of kinase inhibitors being investigated in connection with AML target the B-cell CLL/lymphoma 2 (BCL-2) kinase. As implied by its name, this antiapoptotic kinase is frequently overexpressed in B-cell malignancies such as chronic lymphocytic leukemia 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 an half maximal inhibitory concentration (IC₅₀) of approximately 10 nmol/L, a similar ex vivo sensitivity as CLL.⁵ABT-199 has proceeded to a phase II clinical trial in patients with relapsed or refractory AML (NCT01994837).Antibody-Drug Conjugates

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.⁶Regardless 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).

Clinical Pearls

Most trials involving novel agents for AML involve immunomodulators or kinase inhibitors.

FLT3 inhibitors are the furthest along in studies, but have not yet received FDA approval.

A BCL-2 inhibitor, ABT-199 (GDC-0199), has been reported 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 CLL. ABT-199 has proceeded to a phase II clinical trial in patients with relapsed or refractory AML.

A BiTE antibody that targets CD33 (AMG 330) is in development for potential use in AML.

Strong initial data generated by immunomodulatory agents as well as BCL-2 and XPO1 inhibitors may mean introduction of novel AML therapeutics in the near future.

Bispecific T-cell Engager Antibodies

Selinexor

Another strategy similar to ADCs uses bispecific T-cell engager (BiTE) antibodies. These agents 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.⁷One of the researchers involved in the development of AMG 330, Roland Walter, MD, PhD, of the clinical research division, Fred Hutchinson Cancer Research Center, Seattle, Washington, described immunomodulatory therapies as “an exciting new treatment modality” that may be effective in a large subset of patients with AML.Selinexor (KPT-330) is an inhibitor of the nuclear export protein exportin 1 (XPO1/CRM1), and has demonstrated activity against CLL cells ex vivo.⁸Inhibition of nuclear export is thought to kill malignant cells by forcing the nuclear localization and activation of tumor suppressor proteins such as p53.

Conclusion

Selinexor is in phase I trials for several different cancer types. The results of a trial involving patients with relapsed or refractory AML (NCT01607892) 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.⁹The FDA has given an orphan drug designation to selinexor for the treatment of AML, potentially accelerating its path to the clinic.“Over the last 40 years,” Walter explained, "we have made incremental progress in the treatment of patients with AML, primarily in younger individuals; however, this progress is largely due to improvements in supportive care rather than the introduction of many new agents.”

References

Of the 3 classes of new therapeutics covered here, the FLT3 kinase inhibitors are more advanced in the developmental pipeline. However, the strong initial data being generated by the immunomodulatory agents as well as the BCL-2 and XPO1 inhibitors bodes well for the continued introduction of novel AML therapeutics in the near future.

1. Levis M. FLT3 mutations in acute myeloid leukemia: what is the best approach in 2013?Hematology Am Soc Hematol Educ Program. 2013;2013:220-226.
2. Schiller GJ, Tallman MS, Goldberg SL, et al. Final results of a randomized phase 2 study showing the clinical benefit of quizartinib (AC220) in patients with FLT3-ITD positive relapsed or refractory acute myeloid leukemia.J Clin Oncol. 2014;32:5s(suppl): Abstract 7100.
3. 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(26):6567-6571.
4. Galanis A, Ma H, Rajkhowa T, et al. Crenolanib is a potent inhibitor of FLT3 with activity against resistance-conferring point mutants.Blood. 2014;123(1):94-100.
5. Pan R, Hogdal LJ, Benito JM, et al. Selective BCL-2 inhibition by ABT-199 causes on-target cell death in acute myeloid leukemia.Cancer Discov. 2014;4(3):362-375.
6. Estey EH. Acute myeloid leukemia: 2013 update on risk-stratification and management.Am J Hematol. 2013;88(4):318-327.
7. Laszlo GS, Gudgeon CJ, Harrington KH, et al. Cellular determinants for preclinical activity of a novel CD33/CD3 bispecific T-cell engager (BiTE) antibody, AMG 330, against human AML.Blood. 2014;123(4):554-561.
8. Zhong Y, El-Gamal D, Dubovsky JA, et al. Selinexor suppresses downstream effectors of B-cell activation, proliferation and migration in chronic lymphocytic leukemia cells.Leukemia. 2014;28(5):1158-1163.
9. Yee KWL, Savona M, Sorensen M, et al. A phase 1 dose-escalation study of the oral selective inhibitor of nuclear export (SINE) KPT-330 (selinexor) in patients (pts) with relapsed/refractory acute myeloid leukemia (AML).J Clin Oncol2014; 32:5s(suppl): Abstract 7032.

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