From Interferon to TKIs in Leukemias: Moshe Talpaz, MD

At the start of his tenure at The University of Texas MD Anderson Cancer Center as a postdoctoral fellow from 1979 to 1980 followed by a stint as a clinical fellow from 1980 to 1981 at that institution, Moshe Talpaz, MD, devoted a significant amount of time to evaluating interferon-alpha (IFN-α) in the frontline treatment for chronic myeloid leukemia (CML). Though findings from early studies demonstrated long-term survival benefit, the adverse events associated with the agent proved to be detrimental.

Tyrosine kinase inhibitors (TKIs) now enjoy frontline approval, yet the role of interferon continues to be explored. As a result of ongoing research involving the agent, the FDA approved ropeginterferon alfa-2b (Besremi) in 2021 to treat adults with polycythemia vera (PV).¹

Talpaz, a professor of internal medicine at the University of Michigan Rogel Cancer Center in Ann Arbor, feels a certain level of accomplishment with the approval: “I’m very proud to see that [interferon] continues to play a role,” he said in an interview with The SOHO Daily News. Talpaz was coauthor of a phase 2 study evaluating IFN-α in patients with essential thrombocytopenia, and results suggested a potential role for the agent in larger, prospective trials.² Patients were treated with subcutaneous IFN-α at a dose of 5 × 10⁶ units/m² daily. In responding patients, the therapy lasted at least 3 years.

After a median follow-up of 174 months (14.5 years), 15 of 20 evaluable patients (75%) responded, including 14 patients who achieved a complete hematologic response (CHR; 6 of them with bone marrow remission) and 1 patient who demonstrated a partial response. The median time to response was 6 months (range, 0.5-36 months), and the median response duration was 48 months (range, 5-114 months).

What’s needed, however, is a greater understanding of how interferon generates this antitumor activity, “so we can exploit [the agent] better and generate [treatment] options that are more targeted,” Talpaz said. Despite it being a decades-old drug, interferon’s effect on mutation burden and its ability to induce durable responses continue to be explored with other therapeutic combinations.³

Imatinib

Talpaz, along with Hagop Kantarjian, MD, a colleague at MD Anderson, was also involved in the development of the TKI imatinib in CML. Investigators reported on efficacy and safety data for imatinib (then STI571), a BCR-ABL TKI, in a phase 1 dose-escalating study.⁴ The agent was administered orally to 83 patients with CML in the chronic phase in whom treatment with IFN-α had failed. Patients were assigned to 1 of 14 doses ranging from 25 to 1000 mg per day.

Investigators noted that a maximum tolerated dose of imatinib was not identified and reported a CHR in 53 of 54 patients who received 300 mg or more. Of the 54 patients treated with doses of 300 mg or more, cytogenetic responses were reported in 29, including 17 (31% of the 54 patients) with major responses. Seven of these patients had complete cytogenetic remissions.⁴

Findings from a dose-escalation study evaluating imatinib showed that the single agent was well tolerated and exhibited strong activity in leukemias characterized by the BCR-ABL fusion protein, published in The New England Journal of Medicine.⁵ The objective response rate (ORR) in the myeloid blast crisis of CML was 55%, and the rate of complete remission was 11%. Investigators reported that leukemic blasts in the marrow were reduced to 5% or less in 12 patients (32%). Data from this study also demonstrated that targeting a critical molecular abnormality was a useful strategy in patients with advanced stages of disease.⁵

Further, in that same issue of The New England Journal of Medicine, results from a phase 2 study evaluating the efficacy and safety profile of imatinib showed that the agent induced high rates of cytogenetic and hematologic responses in patients with chronic-phase CML in whom previous interferon therapy had failed.6 In the study, 532 patients were treated with 400 mg of oral imatinib daily. Patients were evaluated for cytogenetic and hematologic responses. Time to progression, survival, and toxic effects were also evaluated.

Investigators reported major cytogenetic responses in 60% of the 454 patients with confirmed chronic-phase CML, and CHRs in 95%. After a median follow-up of 18 months, CML had not progressed to the accelerated or blast phases in an estimated 89% of patients, and 95% of patients were alive.⁶

Dasatinib

Talpaz was involved in the development of other TKIs as well. The targeted therapy imatinib transformed CML into a chronic disease resulting in a shift in focus to dose optimization and second-generation TKIs. Dasatinib, a second-generation BCR-ABL inhibitor, demonstrated activity against all imatinib-resistant BCR-ABL mutations in a phase 1 trial.⁷

With a minimum follow-up of 27 months, the CHR rate was 91% (41/45). Major cytogenetic responses (MCyRs) were attained in 51% of patients (23/45), with complete CyR (CCyR) in 44% (20/45). The rates of CCyR for the 4 times and twice daily schedules were 45% (10/22) and 43% (10/23), respectively. Investigators reported that the median duration of CHR and MCyR had not been reached, with a median duration of treatment of 28 months. In a landmark analysis, the 36-month progression-free survival rate was 87% and the overall survival rate was 94% for patients who achieved an MCyR within the first year of dasatinib therapy.⁷

Looking Ahead

Talpaz has enjoyed a full career from his early days at The University of Texas MD Anderson Cancer Center to the University of Michigan Health, and has been at the forefront of the development of a number of agents in CML and other hematologic malignancies. “From the beginning, I was involved with teams of investigators, including Hagop Kantarjian, MD, whose work led to dramatic changes in the outcome of CML,” Talpaz said. His work and his fellow investigators’ work changed from researching what was once a lethal disease to a chronic disease with a near normal life expectancy.

He hopes to make a similar change in outcomes for myeloproliferative neoplasms (MPNs). “We have developed some therapies that may help patients, but we haven’t changed the trajectory and the outcome yet,” Talpaz said. But he is sure the translational and basic research that he and his colleagues have devoted to MPN will lead to future successes.

_REFERENCES

_{1. FDA approves treatment for rare blood disease. News release. FDA. November 12, 2021. Accessed August 15, 2022. https://bit.ly/35fb7AP}

_{2. Saba R, Jabbour E, Giles F, et al. Interferon alpha therapy for patients with essential thrombocythemia: final results of a phase II study initiated in 1986. Cancer. 2005;103(12):2551-2557. doi:10.1002/cncr.21086}

_{3. How J, Hobbs G. Use of interferon alfa in the treatment of myeloproliferative neoplasms: perspectives and review of the literature. Cancers (Basel). 2020;12(7):1954. doi:10.3390/cancers12071954}

_{4. Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med. 2001;344(14):1031-1037. doi:10.1056/NEJM200104053441401}

_{5. Druker BJ, Sawyers CL, Kantarjian H, et al. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med. 2001;344(14):1038-1042. doi:10.1056/NEJM200104053441402}

_{6. Kantarjian H, Sawyers C, Hochhaus A, et al; International STI571 CML Study Group. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med. 2002;346(9):645-652. doi:10.1056/NEJMoa011573}

_{7. Cortes J, Sawyers CL, Kantarjian HM, et al. Long-term efficacy of dasatinib in chronic-phase CML: results from the phase I trial (CA180002). Blood. 2007;110(11):1026. doi:10.1182/blood.V110.11.1026.1026}