Exploring Possibilities in Disease Modification in MPNs

Treatment of myeloproliferative neoplasms (MPNs) has historically focused on delaying or avoiding transformation to acute myeloid leukemia (AML) as well as symptom relief and improving quality of life; strategies addressed thrombosis or enlarged spleen both with therapy and with nonpharmacological 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, in the way that trials do with AML and chronic myeloid leukemia (CML).

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

Now, in an essay appearing in HemaSphere, a publication of the European Hematology Association (EHA), investigator Claire N. Harrison, MD, FRCP, FRCPath, of the Department of Haematology, Guy's and St Thomas NHS Foundation Trust, asks whether the study and treatment of MPNs is ready for a new era with new end points, with data that show how survival benefits are biologically linked to changes in the spleen, reduction in fibrosis, or other responses.

The challenge, Harrison writes, is that the requirements will be different from today’s standards. “These data should hopefully influence a paradigm shift for the regulatory agencies and the field toward a focus instead of disease modification, but this will certainly require data extending 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 shift that came with arrival of Janus kinase (JAK) inhibitor–based therapy for patients with myelofibrosis (MF) who could not receive a stem cell transplant. Therapy shows the capacity to reduce spleen size and symptoms. “Both of these facets of MF do probably reflect underlying pathophysiology and, furthermore, spleen size reduction has been shown to correlate with overall survival advantage.”

More recently, momelotinib offers benefits for patients with MF and anemia. “Arguably, survival benefit reflects disease modification but here, duration of benefit for spleen and anemia are limited,” Harrison writes. “There is no robust evidence that these agents substantially modify underlying disease if this was defined as clonal response, fibrosis resolution, and so forth.”

She cited 2 phase 3 trials that did not show symptom benefit, but could still 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) might benefit from newer formulations of interferon α, which offer less toxicity. The PROUD PV trial, which studied mostly 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, hemorrhage, transformation, and death.”

Data presented this summer at 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 asks whether molecular response is a sufficient marker of disease modification, using MF as an example but exploring, again, how the history in CML is instructive. “Intriguing recent data suggest that patients with MPN may harbor driver mutations in particular JAK2V617F from an early age perhaps having the mutation for several decades,” she writes.

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

Newer Therapies

Investigations into new therapies offer new approaches in MF by taking direct aim at the underlying pathophysiology of the disease, Harrison writes; options include new mutant CALR‐directed therapies, bispecific agents, and possibly CAR T-cell therapies. Mutation-specific approaches will become more common, Harrison predicts, and the debate will rise anew over new subtype of MPNs.

“Disease modification for MPN should no longer be considered an elusive goal,” she writes. “however, 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. https://doi.org/10.1002/hem3.70003