Evolving Myelofibrosis Treatments Aims to Fill Unmet Needs

JAK inhibitors ease myelofibrosis symptoms but not the disease itself; newer treatments like Ojjaara aim to improve anemia and offer better quality of life.

Myelofibrosis is a Philadelphia-negative myeloproliferative neoplasms (MPN) and can occur as de novo disease. Myelofibrosis creates varying degrees of fibrosis and can cause driver mutations such as JAK2, CALR or MPL in approximately 90% of patients. These mutations cause constant activation of the JAK-STAT pathway, which can lead to uncontrolled cell growth.

Other mutations that can occur, such as ASXL1, SRSF2, EZH2, IDH1/2 and U2AF1, may also affect how the disease develops and prognosis. Moreover, common symptoms of the disease include fatigue, night sweats, fever, bone pain, cachexia, pruritus, thrombosis, and bleeding. Although disease progression is the most common reason for death and occurs in approximately 20% of patients, many patients also face serious risks from other complications. These include heart problems, infections, or bleeding due to low blood counts.

To combat the unmet needs within the myelofibrosis treatment landscape, there have been a number of studies investigating novel treatments for JAK inhibitor-ineligible or relapsed/refractory patients. To further explore these investigations, and the current and future states of the treatment landscapes, investigators broke everything down in research published in the American Journal of Hematology.

Understanding the Present Landscape and Ongoing Studies

The discovery of genetic mutations, as well as the role of the JAK-STAT pathway in the treatment of MPNs has led to the development of oral KAK inhibitors. These drugs work by blocking overactive JAK signaling involved in disease progression and symptom burden.

One such drug being used is Rituxan (ruxolitinib), which is the first ever U.S. Food and Drug Administration (FDA)-approved JAK inhibitor for myelofibrosis, approved by the regulatory agency in 2011. The agent elicits effective for symptom relief and spleen size reduction in approximately 50% of patients who are treated with it.

Common side effects of Rituxan include anemia and low platelets; other non-blood-related side effects include fatigue, diarrhea and infections. Long-term use of the agent may also increase the risk of secondary cancers (like non-melanoma skin cancer) and round 40% to 50% of individuals discontinue the drug within three years due to side effects or lack of efficacy. However, stopping Rituxan is linked to new mutations and poorer outcomes.

Another agent used in the treatment of myelofibrosis is Inrebic (fedratinib), which was approved in 2019 by the FDA for both patients with newly diagnosed disease and those who are refractory and/or intolerant to Rituxan. This agent provides similar benefits to those seen with Rituxan, including reduction of spleen size and symptoms, but with frequent gastrointestinal side effects, like nausea, diarrhea and vomiting.

Notably, Inrebic carries a black box warning for risk of Wernicke’s encephalopathy, making monitoring essential. Additionally, treatment with the agent is less effective in patients who were on high-dose Rituxan prior to switching.

Vonjo (pacritinib) is another treatment which was approved in 2022 for patients with severe low platelet counts in the myelofibrosis treatment space. Unlike Rituxan and Inrebic, it can be used in high-risk patients with more advanced disease and cytopenias. In trials such as the PERSIST-1 and PERSIST-2 studies, Vonjo showed modest spleen and symptom response but improved transfusion independence.

Vonjo is currently being tested in the PACIFICA trial for patients with platelets less than 50 × 10⁹/L.

Finally, Ojjaara (momelotinib) is also being used in the treatment space for patients with this disease and was approved by the FDA in 2023. Ojjaara targets JAK1/2 and ALK2, with a unique effect on anemia. Trials, including the SIMPLIFY-1 and SIMPLIFY-2 studies, showed similar spleen responses to Rituxan but greater improvements in anemia and transfusion independence.

The MOMENTUM study confirmed Ojjaara's improved both symptoms and anemia in symptomatic, anemic patients previously treated with a JAK inhibitor.

The Future of Treatment

“As highlighted in the current review, many new molecules have been evaluated [or are under investigation] as an initial targeted therapy or added salvage therapy in myelofibrosis, alone or in combination with other drugs, especially Rituxan,” study authors wrote in their research.

“Unfortunately, most of these clinical trials have failed, and to date, we only have the possibility of prescribing JAK inhibitors with the goal of reducing splenomegaly and alleviating symptoms,” they continued. “Among the latest approved JAK inhibitors, [Ojjaara] seems to satisfy more unmet clinical needs given its ability to also improve anemia in light of its limited myelosuppressive potential.”

With that said, the main goals of currently available therapies are to reduce splenomegaly and alleviate symptoms myelofibrosis-related symptoms, such as fatigue and discomfort; it is important to remember that even currently-approved medications do not cure the disease.

“Overall survival is likely to be the best clinical evidence of disease modification, but this impact may take many years to become apparent, creating a considerable barrier to the development of new drugs,” authors wrote.

The authors conclude their research by stating that there is a need to redefine disease modification, as well as consider long-term survival and quality of life for patients, as well as economic burdens.

For more news on cancer updates, research and education, don’t forget to subscribe to CURE®’s newsletters here.