From Mutation to Management: Risk Stratification, the Power of JAK Inhibition, and the Pharmacist’s Role

Myelofibrosis (MF) is an incurable, rare type of chronic leukemia and bone marrow disorder that affects approximately 1300 individuals in the United States. Janus kinase (JAK) inhibitors, such as ruxolitinib (Jakafi; Incyte Corp) or momelotinib (Ojjaara; GSK), are the standard of care for treatment and management of MF-related complications and have yielded significantly favorable outcomes; however, they are associated with various adverse effects (AEs). In a session at the Community Oncology Alliance 2025 Community Oncology Conference, experts discussed JAK inhibitors in MF treatment, focusing on the importance of dosage optimization, risk stratification, and transitioning between therapies to manage symptoms and improve patient outcomes.

Red blood cells | Image Credit: © Saddam - stock.adobe.com

MF is a type of myeloproliferative neoplasm characterized by the continued decreased production of red blood cells, leading to bone marrow fibrosis, extramedullary hematopoiesis, recurrent splenomegaly, and anemia. Its symptoms include fatigue, enlarged spleen, night sweats, bone pain, and weight loss. MF can occur as a primary disease (primary MF) or secondary to essential thrombocythemia (post-ET MF) and polycythemia vera (post-PV MF); in some cases, it can progress to acute myeloid leukemia.

The median survival for patients with MF is 6 to 7 years at diagnosis and is determined by various factors, including the presence of genetic mutations, being over the age of 65, the presence of anemia, leukocytosis, and symptom severity. There are multiple genetic mutations commonly seen in patients, including JAK2, CALR, MPL, and triple negative, and each has its own survival estimates:

• JAK2 mutation: About 9 years survival
• CALR mutation: About 18 years survival
• MPL mutation: About 9 years survival
• Triple Negative mutation: Shortest survival, around 3 years

The goals of MF treatment are primarily symptom management with the intent of improving quality of life. Standard-of-care treatment of patients with MF involves JAK inhibitors, which target the JAK/STAT pathway. The JAK/STAT pathway is a cellular signaling mechanism that helps cells respond to cytokines, which regulate inflammation, immunity, and other cell processes.

“The cytokines bond to bind to the cellular receptor surfaces, causing receptors to dimerize or form pairs with another cell receptor,” explained Syed Khan, PharmD, BCSCP, director of pharmacy at The START Center in San Antonio, Texas. “This brings the 2 JAKs into close proximity and allows them to phosphorylate each other and the receptor. This creates finding sites for proteins called STATS. The JAKs then phosphorylate the STATs, which later on dissociate from the receptor, and they dimerize other STATs. The STAT pairs then move into the cell nucleus, where they bind to the surface of the DNA sequences, and there they can turn on or off the expression of certain genes. This way, the cytokines can control the behavior of cells through the JAK/STAT pathway.”

In MF, the most common mutations in the JAK/STAT pathway are JAK2 mutation—the most prevalent at 60%—CALR (20% to 35%), MPL (5% to 8%), and triple negative (10%). The identification of these mutations and the integral role of the JAK/STAT pathway in MF’s underlying pathology led to the development of FDA-approved agents such as ruxolitinib, fedratinib (Inrebic; Bristol Myers Squibb), momelotinib, and pacritinib (Vonjo; CTI BioPharma), which have yielded significant clinical benefits; however, they are associated with various AEs, requiring careful risk stratification, treatment decision-making, and patient monitoring.

“I like to take into account the different receptors that the individual agents may inhibit, in addition to the unique side effect profile of each of the medications, keeping in mind, they're often fully intertwined,” said Shawn Griffin, PharmD, BCOP, health sciences assistant clinical professor in the department of clinical pharmacy practice at the University of California, Irvine School of Pharmacy & Pharmaceutical Sciences.

To categorize patients, clinicians commonly use scoring systems such as the Dynamic International Prognostic Scoring System (DIPSS), the International Prognostic Scoring System for patients under 70 (IPSS-70), and the Genetically Inspired Prognostic Scoring System (GIPSS). Based on these assessments, patients are classified into low-, intermediate-, or high-risk categories. Low-risk patients tend to be younger, have stable blood counts, fewer symptoms, and favorable genetic profiles. Intermediate-risk individuals typically show moderate to severe symptoms and laboratory abnormalities. High-risk patients often present with severe anemia, high blast counts, transfusion dependence, and high-risk genetic mutations.

Treatment decisions are primarily guided by both risk level and platelet count. For high-risk patients with platelet counts below 50,000/μL, momelotinib is the preferred category 1 therapy. If platelet counts are above 50,000/μL, fedratinib is typically initiated, followed by ruxolitinib if needed. In symptomatic patients, treatment also depends on platelet count—those with counts below 50,000/μL may receive hydroxyurea or pacritinib, while those with higher counts may be treated with ruxolitinib or hydroxyurea.

Patients who are asymptomatic and not high-risk may be managed with observation, often referred to as a "watch and wait" approach. Across all treatment pathways, the primary goals remain consistent: to reduce disease symptoms, decrease spleen size, improve overall quality of life, and minimize complications related to abnormal blood counts.

Pharmacists can play a key role in enhancing treatments and optimizing outcomes for patients due to their unique, comprehensive training in medication management, which enables them to identify potential drug interactions, manage side effects, adjust dosing, and provide patient education that supports adherence and safety.

In symptom management, pharmacists can review symptom assessment scores, address individual patient concerns, and monitor improvements in quality of life. For medication monitoring, pharmacists are trained to understand the unique side effect profiles of each JAK inhibitor, manage potential toxicities, and adjust dosing as necessary. During transitions between JAK inhibitors, pharmacists help ensure a smooth process by minimizing the risk of discontinuation syndrome and recommending appropriate tapering strategies.

“I think pharmacists, certainly oncology pharmacists, are uniquely positioned to spend the time to go through the symptom scores, to address the patient symptom by symptom, and to ensure that we're maximizing the quality of life,” said Griffin. “"But at the same time, why I would argue that pharmacists are also uniquely positioned is because all of these medications—they're not benign. They carry unique side effect profiles, and the pharmacist can play a key role in ensuring patients receive optimal therapy.”

As the treatment landscape for MF continues to evolve, pharmacists are increasingly essential members of the multidisciplinary care team. By working closely with physicians and patients, pharmacists ensure therapies are not only appropriately selected but also effectively managed throughout the treatment journey.

REFERENCES

Griffin S, Khan S. JAK(i) of all trades: Navigating myelofibrosis treatment & safety in community oncology practice. Community Oncology Alliance 2025 Community Oncology Conference. April 28, 2025 to April 30, 2025. Orlando, FL