Latest Data on JAK Inhibitors Help Optimize Treatment of Myelofibrosis

At the 14th International Congress on Myeloproliferative Neoplasms, Srdan Verstovsek, MD, PhD, reviewed the research supporting the optimal use of JAK inhibitors in patients with myelofibrosis.

JAK inhibitors have been the most effective treatment for myelofibrosis so far, and with 3 approved agents, physicians are gaining a better understanding of how to utilize JAK inhibition to treat the symptoms of the disease while pursuing overall survival (OS) benefit. At the 14th International Congress on Myeloproliferative Neoplasms, Srdan Verstovsek, MD, PhD, United Energy Resources, Inc, professor of medicine and director of the Hanns A. Pielenz Clinical Research Center for Myeloproliferative Neoplasms at The University of Texas MD Anderson Cancer Center, reviewed the research supporting the optimal use of JAK inhibitors in patients with myelofibrosis.1

JAK inhibitors play a valuable but specific role in controlling the disease, according to Verstovsek. They are not indicated directly following diagnosis or for prefibrotic primary myelofibrosis, and they do not prevent progression to acute leukemia. “It's good for quality-of-life improvements, especially in general systemic symptoms and symptomatic organomegaly; this is what these medications are for,” Verstovsek said in his presentation.

However, additional benefits are seen from the use of JAK inhibitors based on clinical trials. For example, OS benefit was observed with ruxolitinib (Jakafi) in the COMFORT-I (NCT00952289) and COMFORT-II trials (NCT00934544).2

Patients with high-risk myelofibrosis are assessed for prognostic scores based on anemia, thrombocytopenia, genetic abnormalities, and other qualities to determine patients’ eligibility for a bone marrow transplant if they have a life expectancy of less than 5 years without receiving a transplant; otherwise, they may receive JAK inhibitor therapy.

Platelet count plays a major role in determining how patients can be treated with JAK inhibitors. Ruxolitinib and fedratinib (Inrebic) are indicated for patients with a platelet count of greater than 50 x 109/L.As of February 2022, pacritinib (Vonjo) was approved as frontline therapy for patients with a platelet count of below 50 x 109/L based on the results of the PERSIST-2 trial (NCT02055781). If there is no response or a loss of response to a frontline JAK inhibitor, an alternative JAK inhibitor should be used in the second line, including pacritinib in patients with a platelet count of greater than 50 x 109/L, said Verstovsek.

With the longest follow-up, ruxolitinib has been approved since 2011 and demonstrated an OS benefit, which was supported by a retrospective study that showed a correlation between spleen reduction and OS.2,3 Real-world survival post-approval was higher in patients who were exposed to ruxolitinib.4 

However, Verstovsek said it may be a judgment call for physicians to decide when to stop or switch treatment. “When is the time to change? [Who] is the suboptimal responder? What [indicates] the loss of response? What is the optimal response?” he asked. “Of course, there is no overall accepted definition of any of these statements and so we suffer from not having any…precise measurements in place for the size of the spleen or quality of life.” Ruxolitinib failure can be due to resistance/refractoriness to the drug, drug-related toxicities, drug discontinuation, or disease progression.

In patients with anemia, an alternative dosing approach of ruxolitinib using upwards titration from a low dose was shown to be effective and reduced the need for transfusions in a phase 2 trial,5 but Verstovsek cautions that low doses of ruxolitinib are not effective in controlling spleen size in the long term and dose escalation to the maximum safe dose should be done in the first 3 to 6 months.

Another notable discovery was that effective spleen control and other beneficial outcomes were more likely if ruxolitinib was started in 12 or fewer months from diagnosis.6 “The schema of early intervention with a better dose when patients are not terribly sick may lead eventually to optimizing the care in terms of prolonging the durability of overall benefit and survival benefit in the end,” Verstovsek said.

Fedratinib, the second approved JAK inhibitor, also has been shown to improve spleen reduction and total symptom score. It was studied in phase 3 JAKARTA trial (NCT01437787) in the first line and in the phase 2 JAKARTA-2 trial (NCT01523171) in the second line following ruxolitinib. It has gastrointestinal toxicities distinct from ruxolitinib, but Verstovsek said these can be controlled and patients rarely require treatment discontinuation.

Additionally, he recommended administering thiamine for patients receiving fedratinib based on the boxed warning for encephalopathy. While no OS benefit was seen in trials due to short follow-up, he noted based on real-world data from Flatiron Health that fedratinib could have OS benefit in the second line by improving the metabolism and physical condition of patients.7

Verstovsek said it was difficult to know how to optimize use of the latest agent, pacritinib, but he advised not to reduce the dose since it is not myelosuppressive. In the PERSIST-2 trial, it was studied in patients with platelets below 100 x 109/L, but had especially notable results in those with platelets below 50 x 109/L. “Nothing compares to what you will achieve with pacritinib in this patient population: a 29.6% response rate,” he said.1 He added that toxicity can be managed with antidiarrheal medication that are prescribed with it.

Investigators explored hematologic stability in patients receiving pacritinib in the PAC203 dose-finding trial (NCT03165734) and observed stable platelet counts for most patients and a reduction in the need for blood transfusions.8 In PERSIST-2, hemoglobin levels were improved, and transfusion burden was reduced by 22% from baseline to week 24 with pacritinib twice daily versus 9% with best available therapy.9

Researchers continue to optimize treatment with JAK inhibitors to treat myelofibrosis while managing drug toxicity and the unique challenges of the disease. Many decisions are left to treating physicians, especially after failure of frontline therapy. “It is really a judgment call of a doctor to say you are not doing well enough, I'm going to do something else or I'm going to combine it with something,” said Verstovsek. “These topics here are open to debate and still I would say every practice really depends on the doctor who is prescribing the medications.”1


1. Optimizing current JAK2 inhibitors in myelofibrosis. Presented at the 14th International Congress on Myeloproliferative Neoplasms; October 27-28, 2022; New York, NY.

2. Verstovsek S, Mesa RA, Gotlib J, et al. Efficacy, safety, and survival with ruxolitinib in patients with myelofibrosis: results of a median 3-year follow-up of COMFORT-I. Haematologica. 2015;100(4):479-488. doi:10.3324/haematol.2014.115840

3. Palandri F, Palumbo GA, Bonifacio M, et al. Durability of spleen response affects the outcome of ruxolitinib-treated patients with myelofibrosis: Results from a multicentre study on 284 patients. Leuk Res. 2018;74:86-88. doi:10.1016/j.leukres.2018.10.001

4. Verstovsek S, Parasuraman S, Yu J, et al. Real-world survival of US patients with intermediate- to high-risk myelofibrosis: impact of ruxolitinib approval. Ann Hematol. 2022;101(1):131-137. doi:10.1007/s00277-021-04682-x

5. Cervantes F, Ross DM, Radinoff A, et al. Efficacy and safety of a novel dosing strategy for ruxolitinib in the treatment of patients with myelofibrosis and anemia: the REALISE phase 2 study. Leukemia. 2021;35(12):3455-3465. doi:10.1038/s41375-021-01261-x

6. Verstovsek S, Kiladijian J, Vannucchi AM, et al. Does early intervention in myelofibrosis impact outcomes? a pooled analysis of the Comfort I and II Studies. Blood. 2021;138(suppl_1):1505. doi:10.1182/blood-2021-150894

7. Passamonti F, Do Q, Lou Y, Chevli M, Abraham P. Real-world outcomes with fedratinib therapy in patients who discontinued ruxolitinib for primary myelofibrosis. Blood. 2021;138(suppl_1):3645. doi:10.1182/blood-2021-148188

8. Gerds AT, Savona MR, Scott BL, et al. Determining the recommended dose of pacritinib: results from the PAC203 dose-finding trial in advanced myelofibrosis. Blood Adv. 2020;4(22):5825-5835. doi:10.1182/bloodadvances.2020003314

9. Mascarenhas J, Hoffman R, Talpaz M, et al. Pacritinib vs best available therapy, including ruxolitinib, in patients with myelofibrosis: a randomized clinical trial. JAMA Oncol. 2018;4(5):652-659. doi:10.1001/jamaoncol.2017.5818