Genetics and Genetic Testing to Inform Myelofibrosis Clinical Management

The history of primary myelofibrosis dates back to 1951 and the description of four distinct clinicopathologic entities that came to be known as myeloproliferative neoplasms (MPNs): chronic myeloid leukemia (CML), polycythemia vera, essential thrombocythemia, and myelofibrosis.

Discovery of the Philadelphia (Ph) chromosome in 1960 paved the way to identification of BCR/ABL as the principal genetic driver of CML. Another 45 years passed before the discovery of a first genetic driver of non-Ph MPNs, a mutation in the Janus kinase 2 (JAK2) gene, which occurs in 50-60% of myelofibrosis cases.

"The identification of that particular pathway was foundational, and it has changed the face of how we treat patients," said James Rossetti, DO, of the University of Pittsburgh. "The JAK2 mutation is not present in everyone with myelofibrosis, and there are other mutations as well."

A second key mutation in myelofibrosis, the myeloproliferative leukemia proto-oncogene (MPL, also known as thrombopoietin receptor), was identified in 2006. Subsequent studies have shown that the mutation occurs in 5-10% of cases.

Researchers identified a third key driver in 2013: calreticulin gene (CALR). The mutation is associated with about 25% of myelofibrosis cases.

Most studies have shown that JAK2, MPL, and CALR are mutually exclusive and do not occur together. However, a few studies have shown co-occurrence of the three key mutations. Even though JAK2, MPL, and CALR usually do not occur together, numerous other mutations have been identified in association with the three primary mutations. As many as 80% of patients with myelofibrosis have one or more other mutations.

Historically, myelofibrosis treatment was palliative in nature, aimed at relieving specific symptoms. The discovery of the JAK2 driver mutation has transformed treatment. Since 2011 four JAK2 inhibitors have received FDA approval: ruxolitinib (Jakafi), fedratinib (Inrebic), pacritinib (Vonjo), and momelotinib (Ojjaara). All four drugs demonstrated ability to reduce splenomegaly, a major clinical manifestation of myelofibrosis, as well as symptoms.

Some of the co-occurring mutations are targetable, creating interest in combination therapies that simultaneously target different signaling pathways, said Aaron Gerds, MD, of the Cleveland Clinic. One such combination was evaluated in a clinical trial that paired a JAK2 inhibitor with an IDH2 inhibitor.

"These were all patients that had very advanced disease, blast counts that were increasing and their disease was at or heading towards the point of an acute leukemia," he said. "We were able to -- with two pills, no IVs, no chemotherapy -- control the disease in these patients. A pretty remarkable event."

Such targeted combinations offer the potential to improve patients' lives, Gerds added.

Genetic testing has become standard for patients with myelofibrosis. Recognizing that mutations other than JAK2, MPL, and CALR might be present, clinicians will request a myeloid mutation panel that can identify a variety of mutations but also identify "triple negative" patients -- those who do not have JAK2, MPL, or CALR mutations. That subgroup accounts for about 10% of patients with myelofibrosis.

Triple-negative patients have a less favorable prognosis but receive the same type of clinical care as patients with mutations.

"Ruxolitinib, which is the only drug that so far has demonstrated an association with improved survival, as well as improved quality of life ... is used in all patients, regardless of the mutation underpinnings," said Gary Schiller, MD, of the University of California Los Angeles.

The four JAK2 inhibitors differ in their approach to disrupting JAK/STAT signaling. Genetic testing has yet to provide many clues to guide the selection of the different agents.

"The complicated molecular details probably don't inform us very much, except for the younger patient who's a potential recipient of allogeneic bone marrow transplant," said Schiller. "There the [genetic] mix might be important. But in terms of how you choose among the available therapies, right now, we often look at other factors, particularly the blood counts."

Mutation testing could play a role in developing new treatment strategies, particularly novel combination.

"BCL2 inhibition is one that is continuing to be explored, and PI3K inhibition is another," said Rossetti. "There are other pathways that we know are intimately linked to certain parts of the disease, and those studies are ongoing, usually with the backbone of JAK inhibition as sort of the gold standard for disease."

A number of mutations already have proven informative for prognosis. For example, SRSF2, ASXL1, and U2AF1-Q157 mutations predict shorter survival. RAS/CBL mutations predict resistance to ruxolitinib. Type 1-like CALR mutation is associated with better survival.

"We are certainly hopeful that in the future, mutations carry therapeutic information, and we've already seen a few examples of that," said Gerds. "If we see a JAK mutation, it helps us in the diagnosis, but if we see other mutations like ASXL1 or U2AF1, we know that those patients have disease that can be more aggressive over time. Thus, we're thinking more about curative therapies upfront, even allogeneic bone marrow transplant."

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