Akriti Jain, MD, highlights the evolving role of JAK inhibitors in managing polycythemia vera and myelofibrosis and efforts to optimize treatment sequencing.
As JAK inhibitors have continued to shape the treatment landscape of myeloproliferative neoplasms (MPNs), their expanding role in polycythemia vera and myelofibrosis has offered new therapeutic possibilities for disease management, according to Akriti Jain, MD.
“It was exciting to talk about JAK inhibitors and their use in polycythemia vera as well as myelofibrosis. It’s an exciting time in the MPN world to have tools for our patients that we did not have a few years ago,” Jain said following an OncLive® State of the Science Summit™ on hematologic malignancies.
In an interview with OncLive, Jain discussed the clinical application of JAK inhibition in polycythemia vera and myelofibrosis, as well as ongoing research efforts to optimize treatment sequencing and explore combination strategies that may further improve outcomes.
Jain is a hematologist and medical oncologist at Cleveland Clinic in Ohio.
Jain: We treat patients with polycythemia vera to decrease what we call thrombosis or thrombosis-free survival—meaning to decrease the risk of blood clots, whether [they be] heart attack, stroke, deep vein thrombosis, [or] pulmonary embolism. We have risk stratification systems that tell us which patients are at higher risk for blood clots. The 3 main factors that help us decide where our patients lie on the risk spectrum are age, JAK2 mutation status, and whether they’ve had previous blood clots. If someone is considered higher risk—meaning they are over 60 years of age and have had previous blood clots—we usually recommend cytoreductive therapy to keep their hematocrit [level] as close to, or ideally less than, 45%.
The tools in our toolbox to [accomplish this] include drugs like hydroxyurea, which has been on the market for a long time, and interferons, which have their own pros and cons. There is also a newer drug being tested—it was featured in at a plenary session [at the
Additionally, ruxolitinib [Jakafi] is an option for patients who are hydroxyurea-intolerant or -resistant. The main [criteria for defining] hydroxyurea resistance are if someone is, for example, on 2 g of hydroxyurea for at least 3 months and still requires phlebotomies, that’s when we would say they are hydroxyurea-resistant. Intolerance is usually easier to define, such as the development of mouth and leg ulcers, and the [continued need for] phlebotomies. In addition to all these cytoreductive therapies, we always have to consider phlebotomies to maintain a hematocrit [level] below 45%.
For myelofibrosis, there are 4 main JAK inhibitors approved for its treatment. The first to be approved was ruxolitinib, and it has now been on the market for over a decade. It was approved based on data from pivotal studies, [COMFORT-I, NCT00952289; COMFORT-II, NCT00934544], which showed that ruxolitinib [was highly effective] at reducing spleen size and improving symptoms associated with myelofibrosis. These end points—spleen volume reduction and symptom improvement—remain the key efficacy measures in myelofibrosis clinical trials. The one that we’ve been using—and it’s somewhat contentious—is whether that’s a good endpoint or not: a 35% reduction in spleen volume [SVR35]. About 40% to 45% of patients can achieve that on ruxolitinib.
All the subsequent JAK inhibitors have been compared with ruxolitinib and/or best available therapy. The other 3 approved agents are fedratinib [Inrebic], momelotinib [Ojjaara], and pacritinib [Vonjo].
The harder part is determining which [JAK inhibitor] to reach for first. If someone has good blood counts, meaning their hemoglobin and platelets look good, but they still need treatment for myelofibrosis—not all patients will—we decide [treatment] based on factors such as spleen enlargement or symptom burden. If treatment is needed and the counts are adequate, ruxolitinib is usually our first choice because of its [robust] responses. However, if patients have anemia or thrombocytopenia, we may need to change our approach.
For thrombocytopenia, or a platelet [count] less than 50 × 109/L, the drug that is approved is pacritinib, which can also provide anemia benefits. In addition to being a JAK2 inhibitor, it’s an ACVR1 inhibitor that helps improve anemia. For patients with good platelet [counts] but persistent anemia, momelotinib can be useful because it also inhibits ACVR1 and can confer anemia benefit. It was tested against danazol, one of our other anemia agents in myelofibrosis, in the [phase 3] MOMENTUM trial [NCT04173494] and performed significantly better in improving anemia.
[Ruxolitinib, pacritinib, and momelotinib] are the 3 main JAK inhibitors that I reach for first. Fedratinib is a great option as well, typically used in the second line because of associated [adverse] effects, including diarrhea, nausea, and vomiting. We usually check thiamine levels to ensure we supplement appropriately when using fedratinib. It remains an effective agent for spleen reduction, with response rates as high as 30% to 40%, based on the [phase 3] JAKARTA study [NCT01437787] that led to its approval.
We have many treatment options—the hard part now is determining how to sequence them. We walked through some of the current sequencing strategies, but there’s still more work to be done.
For polycythemia vera, the only JAK inhibitor that is approved right now is ruxolitinib, and it is approved for second-line therapy. Those are patients who are hydroxyurea-intolerant or -resistant. There is potential benefit with ruxolitinib; we have seen that it can potentially drive down the JAK2 allele burden, which is the amount of the JAK2 mutation [detected in the patient], and if we are driving that allele burden down, sometimes we can consider that disease-modifying. Whether that is truly disease-modifying, only time can tell, but ruxolitinib definitely has a place in polycythemia vera treatment.
For myelofibrosis, JAK inhibitors are important for symptom control and spleen volume control, but it’s hard to say if they are disease-modifying. We have not seen reversal of fibrosis as much. We are trying hard in different clinical trials, including combination studies, to see if we can improve on the work that JAK inhibitors are able to do [alone] and potentially modify disease or reverse fibrosis.
The use of JAK inhibitors in myelofibrosis is mainly for symptom control and spleen control. Ruxolitinib is the only JAK inhibitor, as far as I know for now, that has shown an [overall] survival benefit,2 so it can provide that as well. However, fibrosis benefit and true disease modification are still goals we are striving to achieve
