Interferon Alfa Combination Therapy for the Treatment of Myeloproliferative Neoplasms

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Though IFN alfa-2 has been shown to be effective in treating MPNs, it is not the therapy of choice outside of Europe.
Though IFN alfa-2 has been shown to be effective in treating MPNs, it is not the therapy of choice outside of Europe.

Interferon (IFN) alfa-2 has an established history of effectiveness in treating myeloproliferative neoplasms (MPNs) in Denmark and across Europe. Despite this, it is not the therapy of choice for MPNs elsewhere, including in the United States.

In a recent review article in Seminars in Immunopathology, Hans Carl Hasselbalch, MD, PhD, of the department of hematology at the Zealand University Hospital in Denmark, and Morten Orebo Holmström, MD, PhD, at the Center for Cancer Immune Therapy at Herlev Hospital in Denmark, revisited the history and clinical use of IFN alfa-2, described its mechanism of action and current combination therapies, and addressed key questions about MPNs and treatment options.

“I introduced IFN 20 years ago in Denmark,” Dr Hasselbalch told Hematology Advisor. “We have a lot of experience with IFN in patients [with MPNs]. We have shown for the first time that when you treat patients with MPNs at the early cancer stage, you are able to induce minimal residual disease with normal bone marrow after 5 years.”

Over 30 Years of Clinical History

Production and purification of IFN alfa-2 took place in the late 1970s, opening the door for the first clinical trials studying its efficacy and safety in treating various MPNs — Philadelphia-negative chronic MPN, essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis — as well as multiple myeloma, hairy cell leukemia, chronic myelogenous leukemia, hypereosinophilic syndromes, and systemic mastocytosis. In patients with hairy cell leukemia and chronic myelogenous leukemia, IFN alfa-2 was able to achieve complete remission.1,2

In the 1980s, Linkesch and colleagues demonstrated that IFN alfa-2 was effective for the treatment of myeloproliferative diseases with severe thrombocytosis.3,4 In the past decade, certain genetic variants have been associated with MPNs and, in numerous studies, IFN alfa-2 has been shown to induce not only molecular remission in patients with JAK2 V617F-associated MPNs but also reduced mutational loads in patients with CALR-associated MPNs. Furthermore, recent studies have confirmed that long-term treatment with IFN alfa-2 can lead to molecular remission in large proportions of patients with MPNs.

IFN Alfa-2 Restores Immune System Functioning

Early studies demonstrated that IFN alfa-2 functions through the Janus-activated kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathway, which leads to changes in gene expression. In patients with MPNs, IFN alfa-2 treatment increased natural killer (NK) cell levels and upregulated human leukocyte antigen (HLA) genes.5,6

“By using IFN long term, we restore and repair the defective tumor immune system that we believe these patients have,” said Dr Hasselbalch, “We believe this because they have a 40% increased risk of second cancers.”

Dr Hasselbalch emphasized that patients with MPNs have an increased risk of second cancer 5 to 10 years prior to diagnosis of MPN, which fuels motivation for early treatment strategies.

“We have to change our clinical approach to these patients worldwide,” stated Dr Hasselbalch. “[In the United States, clinicians] follow the watch-and-wait strategy and stratify their patients according to low risk and high risk, and patients are diagnosed too late, when they are hit by the complications from the diseases. You have to attack the cancer from a very early stage. Then the chance of survival of the patient is the best.”

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