http://www.curetoday.com/articles/mpn-field-hitting-its-stride-but-more-work-is-needed
MPN Field 'Hitting Its Stride,' But More Work Is Needed

Brielle Urciuoli

New biomarkers are being investigated in myeloproliferative neoplasms (MPNs), pointing toward a future of advances in the field, according to David S. Snyder, M.D., associate chair and professor of the Department of Hematology and Hematopoietic Cell Transplantation at the City of Hope.

“The field of MPNs is hitting its stride with new molecular markers that are being defined,” Snyder said in an interview with OncLive, a sister publication of CURE.

Currently understood driver mutations include JAK2, CALR and NPL, but researchers are now looking at secondary mutations and their significance toward a patient’s prognosis. Snyder said that these findings will lead to targeted therapies, as they did for Jakafi (ruxolitinib), a JAK2 inhibitor that was the only FDA-approved drug that was developed for myelofibrosis.

Jakafi may also work for patients with a CALR mutation as a different mechanism, according to Snyder. He explained that there are two types of CALR mutations: type 1, which is a deletion in the protein; and type 2, which is an insertion into the protein. The CALR mutations ultimately feed through the JAK2-STAT pathway, similar to the JAK2 pathway.

“(The CALR mutation) lends itself to potentially being a target for immune reactivity because it has the unique antigen structure at the mutated site and is extracellular,” Snyder explained. “There is ongoing work looking at the immunogenicity of CALR mutations and potentially leading the way to developing a CAR-T cell strategy.”

Similar to those with a CALR mutation, patients with an MPL mutation also have responses with JAK2 pathway inhibition, and secondary mutations associated with it would be ASXL1, TET2, and IDH1/2. However, Snyder noted he is unsure how these mutations have been studied in MPNs, but are worth looking in to.

“For now, the presence of those mutations is a helpful prognostic indicator, and that’s important to give patients an idea of what to expect,” Snyder said.

Snyder said that Jakafi is “very good at what it does,” notably, shrinking spleen size in patients experiencing splenomegaly (an enlargement of the spleen), and controlling constitutional symptoms.

“It is part of the reason why patients lose weight, have decreased muscle mass, and poor performance status,” said Snyder. “If physicians can significantly reduce the spleen size and improve their patient's ability to eat, that can help performance status.”

However, while Jakafi offered a wave of hope for patients with MPNs when it was first approved, the drug is by no means a cure-all for this patient population. It does not significantly or reliably reduce molecular burden, prevent progression to acute leukemia, and can result in lower platelet counts.

“Cure is something we would all like to be able to reach for. In the meantime, there’s allogenic stem cell transplantation, which is the only curative option for myelofibrosis,” Snyder said. Still, transplants come with their own downsides, including potential morbidity and mortality. “For the right patient, it’s the only curative option,” he added.

And since MPNs are rare, Snyder emphasized that it is crucial that patients are referred to treatment centers that frequently see these types of disease, where they may have potential to participate in a clinical trial, be considered for allogeneic stem cell transplant, and where experts can go over comorbidities, risks and outcomes of the disease with patients – especially those undergoing a transplantation.

“The stakes are high because the goal of therapy is to cure the disease,” he added. “For our patients who get through it and do well, they’re hopefully restored to a full life.”
 
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