JAK Inhibition Shakes Up MPN Paradigm With 2 Potential Additions to the Armamentarium


JAK inhibitors continue to make a splash in the treatment landscape of MPNs and are be evaluated in multiple clinical trials, and the advancement of these agents should be recognized in honor of MPN Awareness Day.

John O. Mascarenhas, MD

John O. Mascarenhas, MD

Janus kinase (JAK) inhibitors have become an important therapeutic approach for treating patients with myeloproliferative neoplasms (MPNs), particularly in the treatment landscape of myelofibrosis (MF) in which 2 agents are now approved by the FDA. Ruxolitinib (Jakafi) was the first JAK inhibitor to make its debut in the treatment landscape with an FDA approval, while fedratinib (Inrebic) followed suit with a more recent approval in 2019.

The only curative approach to treating MPNs is transplantation, but not all patients are eligible, which leaves a gap in the treatment landscape for the JAK inhibitors to fulfill. Patients may not be eligible due to advanced age or comorbidities, but even those patients who are eligible will experience toxicity. The JAK inhibitors are a promising alternative treatment approach.

JAK inhibitors continue to make a splash in the treatment landscape of MPNs and are be evaluated in multiple clinical trials. The role of this therapeutic approach remains a major topic of discussion in the field, and the advancement of these agents should be recognized in honor of MPN Awareness Day, which is celebrated on September 10 annually.

“I think cure is really the lofty goal we're all interested in, so we're very excited about the idea that we could have access to many different JAK inhibitors, but we know that the JAK inhibitors themselves are not going to cure patients with this disease,” John O. Mascarenhas, MD, a clinical investigator in MPNs, associate professor of medicine at the Icahn School of Medicine, and director of the Adult Leukemia Program at Mount Sinai in New York, told Targeted Oncology in an interview.

Two JAK Inhibitors Approved by FDA Advance Field

Ruxolitinib received its approval on the basis of the COMFORT-1 (NCT00952289) and COMFORT-2 (NCT00934544) studies. In COMFORT-1, patients were randomized 1:1 to receive either ruxolitinib (n = 155) or placebo (n = 153), and in the COMFORT-2 study, patients were randomized 2:1 to receive either ruxolitinib (n = 217) or best available therapy (n = 72).1,2

COMFORT-1 demonstrated a 41.9% spleen volume reduction with ruxolitinib versus 0.7% with placebo at week 24 (P <.0001), while COMFORT-2 demonstrated a 28.5% spleen volume reduction with ruxolitinib compared with best available therapy, which induced no responses at week 48 (P <.0001). Ruxolitinib also improved symptom burden in both the studies. COMFORT-1 showed symptoms worsened in the placebo arm and improved after treatment with ruxolitinib compared with baseline.

“There has been real-world evidence that's been presented from several different countries that similarly show that efficacy and safety,” Ruben Mesa, MD, director, Mays Cancer Center at The University of Texas Health San Antonio, MD Anderson Cancer Center San Antonio, TX, said in an interview with Targeted Oncology. “Finally, there were data from the United Kingdom that had been presented not that long after the approval of ruxolitinib, where they also included intermediate-1 risk patients with MF and saw very similar safety and efficacy.”

Ruxolitinib has since been under evaluation in a variety of other settings since its approval, which have expanded into approvals for other settings, such as in the setting of the MPN polycythemia vera (PV), where the JAK inhibitor is now an approved treatment option.

According to 5-year follow-up data from the phase 3 RESPONSE study, ruxolitinib was both safe and effective as long-term treatment of patients with PV who are resistant to or intolerant of hydroxyurea (Hydrea). At 224 weeks, the duration rate of maintaining primary response was 74% (95% CI, 51%-88%), but the median duration of primary response had not yet been reached. There was a 55% duration rate of complete hematological remission at 224 weeks (95% CI, 32%-73%), and 10 of the 26 patients who had early complete hematological remission had progressed by week 256, and 24% of patients who had hematocrit control by week 32 progressed by week 256.3

The study randomized 222 patients to receive either ruxolitinib (n = 110) or the best available therapy (n = 112), and crossover was allowed from the best available therapy arm to the ruxolitinib arm. The median time to crossover was 34.7 weeks (95% CI, 33.9-35.3). Among the 79 patients who crossed over, 87% were evaluable after week 80 through week 256 and remained phlebotomy-free. Only 8% required phlebotomy.

“There is a significant role for JAK inhibitors in MPNs. Some years ago, ruxolitinib was approved as therapy for MF, and it is indicated for patients that have symptomatic splenomegaly or general systemic symptoms,” Srdan Verstovsek, MD, PhD, medical oncologist, and professor, Department of Leukemia, University of Texas MD Anderson Cancer Center, told Targeted Oncology. “In PV, the same agent, ruxolitinib, is approved as a therapy for patients that are not doing well on the hydroxyurea chemotherapy that is done in first line. The goals of therapy in PV are to control the blood cell count, symptoms, and spleen.”

The agent is also under evaluation in clinical trials as treatment of other potential patient populations, as well as in combination regimens. However, ruxolitinib is joined by the approval of fedratinib for the treatment of patients with MF.

Fedratinib received its approval from the FDA on the basis of the JAKARTA and JAKARTA-2 clinical trials. According to the findings from the JAKARTA-2 study, which were presented during the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting, there was a 35% or greater reduction in spleen volume with fedratinib. The study demonstrated a clinically meaningful reduction in both splenomegaly and symptoms. The spleen volume response rate was 30%, and the symptoms response rate was 27%. The most common adverse events of grade 3/4 included anemia and thrombocytopenia, although the FDA label includes a warning for risk of Wernicke’s encephalopathy.4

“Fedratinib is useful for the same reasons as ruxolitinib, based on the phase 3 randomized results comparing fedratinib to placebo. [In this study] it had about the same response rates on the spleen and symptom control as ruxolitinib has historically. The difference is seen a little bit in the toxicity profile,” Vertsovesek said. “The myelosuppression is about the same between ruxolitinib and fedratinib, but fedratinib has some issues with low grade GI toxicity and some distant possibility of neurological complications.”

Fedratinib is now under evaluation in the phase 3b FREEDOM study (NCT03755518) as treatment of patients who are resistant to or intolerant of ruxolitinib, which is based on a stringent definition of ruxolitinib failure. In this study, investigators will evaluate risk mitigation strategies for gastrointestinal toxicities, as well as Wernicke’s encephalopathy.

“Fedratinib, in my view, has a major role in the second-line setting after ruxolitinib,” Verstovsek explained. “Ruxolitinib has been around for a long period of time, so we know what to do and what to get out of it. I would assume any of the results are about the same in the frontline setting between the 2 agents. There is significant information of the utility of fedratinib in a second-line setting, where a recent publication showed that about 30% of the patients after ruxolitinib have a significant improvement in response by the strict definitions. I utilize that information in my own decision making in the clinic, utilizing fedratinib as my preferred choice in the second-line setting.”

More JAK Inhibitors Coming Down the Pipeline

Momelotinib may be a potential new treatment option for patients with MF. Thus far, this JAK inhibitor has demonstrated encouraging findings in multiple clinical trials. However, momelotinib may be able to fulfill a more important gap in the treatment landscape of MF.

“Momelotinib is a JAK inhibitor that that is different than others because it has other abilities to affect the biology of the patient, that is to possibly improve anemia in patients,” Verstovsek said.

Although ruxolitinib has been a promising treatment option in MF, it is often associated with problems such as anemia and transfusion dependence, which are linked with poor prognosis and survival outcomes. Momelotinib demonstrated early evidence for its ability to manage anemia in patients with MF in the phase 2 GS-US-352-1672 clinical trial, and the agent was later tested in the phase 3 SIMPLIFY-1 (NCT01969838) study, which demonstrated non-inferiority of the drug over ruxolitinib in terms of splenic response and symptomatic benefit.

In the SIMPLIFY-1 trial, momelotinib induced a statistically significant transfusion dependence rate of 66% compared with 49% in the ruxolitinib arm (P <.001). Among patients who were transfusion-dependent at baseline, the ≥12-week transfusion independence rate was 49.1% with momelotinib versus 28.8% with ruxolitinib (P =.0299).5

“Here we have a medication that can possibly improve the anemia, and it's now being tested in a phase 3 randomized blinded study in the second-line setting after ruxolitinib for improvement of anemia and symptoms,” Verstovsek said. “In fact, symptoms are first goal, and the second goal is anemia.”

The randomized, double-blind phase 3 MOMENTUM (NCT04173494) study aims to enroll 180 patients who had been previously treated with a JAK inhibitor to receive either momelotinib plus danazol (Danocrine) or danazol alone. The primary end point of the study is the total symptom score response rate at week 24, while the 2 secondary end points will explore the transfusion independence status and splenic response rate. Verstovsek serves as the chief investigator of this study.

“This is a very interesting concept of JAK inhibitor for symptoms and anemia, and if this is successful, I see a lot of patients being candidates for this therapy in the second-line setting after ruxolitinib because the main reason for failing is the anemia,” Verstovsek said.

“I think if approved, momelotinib would clearly be a consideration in transfusion-dependent MF patients, possibly in the first line because obviously we already have that SIMPLIFY-1 data that has shown it's noninferior, and most certainly in the second-line setting for people that have failed ruxolitinib and still have significant anemia,” Mesa said.

Another JAK inhibitor is currently under evaluation for the treatment of patients with MF as well and has demonstrated promise in this paradigm. Pacritinib is an oral JAK inhibitor that also offers a unique profile compared with momelotinib and the currently approved agents, ruxolitinib and fedratinib.

“What was learned early on from the clinical development of this drug is that it appears to be less myelosuppressive, which is very attractive, and through its clinical development all the way into randomized phase 3 studies called the PERSIST program, it demonstrated time and time again both efficacy and a safety profile that's reasonable in patients with low platelets, particularly less than 50,000 which is an unmet need in which we do not have approved therapies,” Mascarenhas said. “Right now, the 2 current JAK inhibitors, although very effective in treating patients and addressing spleen and symptoms, are not really adequately tested or demonstrated to have efficacy and safety in less than 50,000. Pacritinib is poised to fill this unmet niche, which is probably about 15% of patients upfront and perhaps 30% or more second-line with low platelets.”

Most of the therapies given to these patients reduces platelets, which puts patients with low platelets at greater risk of bleeding incidences. Given that pacritinib is less myelosuppressive than the other agents, this JAK inhibitor could fulfill a major unmet need in the MPN treatment landscape.

“Pacritinib has always been the JAK inhibitor that can be given to people with low blood cell count. Patients with low platelets below 50 do not receive any other drug, and it would be unusual [for these patients] to receive any of the other drugs because fedratinib or ruxolitinib could lower the platelets more,” Verstovsek said. “This agent does not do that much, and it can, in these patients with platelets below 50,000, control spleen and symptoms. That's the goal of the therapy in the PACIFICA study [NCT03165734], which is comparing pacritinib in patients that have platelets below 50,000 at the frontline and second line.”

The randomized, controlled phase 3 PACIFICA trial will compare the efficacy of pacritinib in patients with MF to the physician’s choice of treatment, which is limited to corticosteroids, hydroxyurea, danazol, or low dose ruxolitinib. The primary end point of the study is spleen volume, while secondary end points will evaluate safety, as well as symptom and survival outcomes.

“I personally am excited to see this study move forward,” Mascarenhas said. “I've been hopeful for a number of years that this drug would find its niche because I see these patients in clinic, and it's a very challenging clinical scenario.”

The PACIFICA study and the MOMENTUM study continue to enroll patients. Should these studies be positive, momelotinib and pacritinib may join ruxolitinib and fedratinib in the ranks of FDA-approved JAK inhibitors.

“Hopefully, we will have these 2 JAK inhibitors on the market in a couple of years too for the different groups of MF patients,” Verstovsek concluded.


1. Verstovsek S, Mesa R, Gotib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012(9);366:799-807. doi: 10.1056/NEJMoa1110557

2. Harrison C, Kiladjian JJ, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012;366(9):787-798. doi:10.1056/NEJMoa1110556

3. Kiladijan JJ, Zachee O, Hino M, et al. Long-term efficacy and safety of ruxolitinib versus best available therapy in polycythaemia vera (RESPONSE): 5-year follow up of a phase 3 study. Lancet Haematol. 2020; 7: e226—37. DOI: 10.1016/S2352-3026(19)30207-8

4. Harrison CN, Schaap N, Vannucchi AM, et al. Fedratinib (FEDR) in myelofibrosis (MF) patients previously treated with ruxolitinib (RUX): A reanalysis of the JAKARTA-2 study. J Clin Oncol. 2019;37(suppl; abstr 7057)

5. Mesa RA, Kiladjian JJ, Catalano JV, et al. SIMPLIFY-1: a phase III randomized trial of momelotinib versus ruxolitinib in Janus kinase inhibitor-naive patients with myelofibrosis. J Clin Oncol. 2017;35(34):3844-3850

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