Treatment of myeloproliferative neoplasms (MPN) has historically focused on delaying or avoiding conversion to acute myeloid leukemia (AML) as well as symptom relief and improved quality of life; strategies targeted thrombosis or enlarged spleen both with therapy and with non-pharmacological strategies such as smoking cessation or encouraging patients to lose weight.

Although these strategies were associated with improving life expectancy, they did not measure disease modification through molecular responses that signal survival benefits, as studies do with AML and chronic myeloid leukemia (CML).

Claire N. Harrison, MD, FRCP, FRCPath | Image credit: Guy’s and St Thomas

Now, in one essay appearing in HemaSpherea publication from the European Hematology Association (EHA), asks investigator Claire N. Harrison, MD, FRCP, FRCPath, at the Department of Hematology, Guy’s and St Thomas NHS Foundation Trust, whether the study and treatment of MPN is ready for a new era with new endpoints, with data showing how survival benefits are biologically linked to changes in the spleen, reduction in fibrosis or other responses.

The challenge, writes Harrison, is that the requirements will differ from today’s standards. “These data should hopefully influence a paradigm shift for regulators and the field toward a focus instead of disease modification, but this will certainly require data that extend beyond the recent standard of 24 weeks,” she writes.

In the perspective piece, “Are we ready for disease modification in myeloproliferative neoplasms?” Harrison notes that a dramatic change came with the advent of Janus kinase (JAK) inhibitor-based therapy for patients with myelofibrosis (MF) who could not receive a stem cell transplant. Therapy shows the ability to reduce spleen size and symptoms. “Both of these aspects of MF likely reflect underlying pathophysiology, and furthermore, reduction in spleen size has been shown to correlate with survival benefits.”

More recently, momelotinib offers benefits for patients with MF and anemia. “Presumably survival benefits reflect disease modification but here the duration of benefit for spleen and anemia is limited,” writes Harrison. “There is no strong evidence that these agents significantly modify the underlying disease if this were defined as clonal response, fibro resolution, and so on.”

She cited 2 phase 3 studies that did not show symptomatic benefit, but were still able to produce biological measures indicating positive responses.

Polycythemia Vera

Harrison dug into this condition as an example where even so-called “low-risk” polycythemia vera (PV) can benefit from newer formulations of interferon α, which produce less toxicity. The PROUD PV trial, which mostly studied high-risk PV, treated patients with rho-pegylated interferon α-2b and found it superior to other treatments “in producing event-free survival including thrombosis, bleeding, transformation, and death.”

Data presented this summer at the EHA Congress 2024, Harrison wrote, were linked to molecular response and showed that for PV patients the disease modification could be defined by this response (at least 50% in JAK2V617F variant allele frequent), which Harrison wrote, “is achievable with interferon α and ruxolitinib.”

Harrison questions whether molecular response is a sufficient marker for disease modification, using MF as an example but explores, again, how the history of CML is instructive. “Exciting recent data suggest that patients with MPN may have driver mutations, particularly JAK2V617F from an early age, perhaps carrying the mutation for decades,” she writes.

Could strategies such as minimal residual disease negativity some day before be explored? At present, the data are insufficient, and while there are some data in disease modification for MF and PV, there is less in essential thrombocythemia (ET).

Newer therapies

Research into new therapies offers new approaches in MF by directly targeting the underlying pathophysiology of the disease, writes Harrison; options include novel mutant CALR-targeted therapies, bispecific agents, and possibly CAR T-cell therapies. Mutation-specific approaches will become more common, Harrison predicts, and the debate will re-emerge about new subtypes of MPN.

“Disease modification for MPN should no longer be considered an elusive goal,” she writes. “But it is a complex one. Careful evidence-based current management can achieve this.”

Reference

Harrison CN. Are we ready for disease modification in myeloproliferative neoplasms? HemaSphere. Published September 15, 2024.