The Possibilities and Limitations of Ruxolitinib in the Modern MPNs Paradigm

During the 1st Annual Texas MPM Workshop, Aaron Gerds, MD, MS presented on the ruxolitinib in the present and future, as well as the possibilities for moving beyond the JAK-STAT pathway.

In myeloproliferative neoplasms (MPNs), ruxolitinib (Jakafi) has been evaluated as the experimental drug in multiple randomized clinical trials and has shown benefit, but with the emergence of novel agents, its place in the treatment landscape is undergoing further evaluation, according to a presentation during the 1st Annual Texas MPM Workshop (TMW), during which Aaron Gerds, MD, MS presented on the ruxolitinib in the present and future.

The wide use of ruxolitinib, a small-molecule inhibitor of JAK1/2, sprouted from a hypothesis in 1951 that MPNs had an undiscovered stimulus. In 2004, 4 separate groups of researchers confirmed that targeting of the JAK-STAT pathway could be the missing link for treating MPNs. It was discovered that JAK2 mutations were present in 97% of patients with polycythemia vera (PV) and 50% to 60% of patients with essential thrombocytopenia (ET) and myelofibrosis (MF). Later, research also revealed that mutations in CALR and MPL lead to JAK-STAT activation.1

Managing Disease With FDA-Approved JAK Inhibitors

Ruxolitinib is FDA approved for the treatment of both MF and PV, based on 3 clinical trials, COMFORT-1, COMFORT-2, and RESPONSE. Another JAK inhibitor, fedratinib (Inrebic) also has FDA approval for the treatment of patients with MF.

COMFORT-1 was a randomized, double-blind, placebo-controlled (NCT00952289), phase 3 study conducted in 89 centers throughout the United States, Australia, and Canada. Randomization in the study was 1:1 and patients received either ruxolitinib at a starting dose of 15 mg or matching placebo. There was a total of 155 patients in the ruxolitinib arm and 153 in the placebo arm.1,2

The design of the COMFORT-2 trial (NCT00934544) was randomized with a crossover assignment. Patients in COMFORT-2 were randomized 2:1 to receive either single-agent ruxolitinib at a 15 mg starting dose or best available therapy (BAT). The study included 217 patients in the ruxolitinib arm and 72 in the BAT arm.1,3

Both trials included patients with MF who had intermediate- to high-risk disease, and Gerd noted the spleen response in these clinical trials. In COMFORT-1, ruxolitinib led to a 41.9% spleen volume reduction compared with only 0.7% in the placebo arm at week 24 (P <.0001), and in COMFORT-2, ruxolitinib demonstrated a 28.5% spleen volume reduction versus BAT which did not induce responses in patients with MF at week 48 (P <.0001). Eliciting spleen response, Gerd explained, was just one of the positives of JAK inhibition.

“If we don’t know what JAK inhibitors can do, it is hard to know where they fail,” said Gerds during his presentation.

Ruxolitinib was also found to improve symptom burden in patients with MF in the COMFORT trials. Both trials specifically looked at abdominal discomfort, pain under left ribs, early satiety, night sweats, itching, bone and muscle pain, and inactivity. The COMFORT-1 population showed that symptoms worsened in the placebo arm and improved after treatment with ruxolitinib compared with baseline reports.1,2

A similar trend with responses from ruxolitinib was observed in patients with PV, according to the randomized, open-label, multicenter, phase 3 RESPONSE clinical trial (NCT01243944) of ruxolitinib versus BAT administered 1:1 to a pool of 222 patients. Ruxolitinib at a starting dose of 10 mg was administered to 110 patients and the remaining 112 patients received BAT.1,4

In terms of the coprimary end points of spleen volume reduction and hematocrit control, ruxolitinib was superior to standard therapy. The JAK inhibitor specifically led to a 38.2% reduction in spleen volume compared with a 0.9% reduction with standard therapy. Ruxolitinib also demonstrated 60.0% hematocrit control compared with 19.6% hematocrit control with BAT.1

“As a result [of these trials] JAK inhibitors have become a major part of our treatment algorithm. Whether it's low-risk disease, intermediate-risk disease, or high-risk disease, JAK inhibitors pop up all over the place and are the mainstay of treatment. But these drugs are not perfect by any stretch of the imagination.”

Looking back to COMFORT-1, a key secondary end point was overall survival (OS). After a median time on treatment of 3 years, ruxolitinib demonstrated a median OS of just 5.3 months (95% CI, 4.7-NE) compared with 3.8 months (95% CI, 3.2-4.6) in the placebo arm (HR, 0.70; 95% CI, 0.54-0.91; P =.0065). The survival advantage was with the ruxolitinib arm, but Gerd noted that the survival curves still go down and approach 0.

Eventually, with a significant amount of time on treatment and the possibility of disease progression and serious adverse events (AEs), ruxolitinib can become less effective in patients with MPNs.

Challenges With JAK Inhibitor Use Over Time

A true understanding of ruxolitinib challenges can be realized from ruxolitinib treatment patterns in real-world patients, Gerd stated. Such was demonstrated in a real-world analysis of patients with MF which Gerd and his colleagues presented at the 2019 American Society of Hematology Annual Meeting.1

The analysis showed significant disease burden and high drug costs in patients treated with ruxolitinib, regardless of the dosage. Gerd also considered it notable that most of the patients were also received supportive agents.1,5

A total of 495 patients were included in the analysis and stratified into cohorts of suboptimal and optimal, based on their daily ruxolitinib dosage.

The median duration of treatment was relatively short at 4.9 months in the suboptimal cohort versus 5.3 months in the optimal cohort (P =.017).

“Of the nearly 500 patients included in this analysis, the average time on ruxolitinib was only 5.2 months. It seemed that patients who were on a higher dose were on the drug longer, but clearly this duration is much shorter than what we saw in the COMFORT studies,” Gerd stated.

Notably, treatment with ruxolitinib was discontinued in 28.8% of the suboptimal cohort versus 20.4% of the optimal cohort (P =.032), which was 23.6% in the cohorts combined.

In the real-world analysis of patients with MF, reasons for treatment discontinuation included lack of response, cytopenias, and other reasons. But Gerd stressed that the key takeaway from the study was that many of the patients discontinued ruxolitinib early on. He stated that the reasons for ruxolitinib discontinuation is a key question in the overall discussion of the optimal use of the agent.

Reasons for JAK Inhibitor Discontinuation

The 3 causes of JAK inhibitor discontinuation are toxicity, lack of efficacy, and disease progression, said Gerd. The reality of this was described through another real-world analysis of 145 patients treated at the Moffit Cancer Institute and followed for 10.3 months while on ruxolitinib.1

The analysis showed that 64 patients discontinued ruxolitinib and of those, 24 were due to cytopenias, 10 due to an allogeneic hemopoietic stem cell transplant, 9 had suboptimal responses, 7 had disease progression, 8 developed acute myeloid leukemia, and 6 had a non-hematologic AE. Following discontinuation of ruxolitinib, what happened to patients was largely dependent on whether or not patients had a transplant, said Gerd. The median OS was not reached for patients who had a transplant compared with 15.0 months among those who received salvage therapy and only 4.9 months for patients who underwent observation without treatment.1,6

In conclusion, Gerd explained that JAK inhibitor failure is largely due to the development of additional mutations, chromosomal abnormalities, or activation of accessory pathways. Therefore, it is sensible to go beyond the JAK-STAT pathway.

The Future of Ruxolitinib and Other JAK Inhibitors

Before non-JAK inhibitors become more widely used in the treatment of patients who failed on a JAK inhibitor, Gerd suggested rechallenging the disease with ruxolitinib. A 2018 retrospective case series lead by Gerd showed the validity of the rechallenging strategy in a pool of 13 patients.1

It was shown that in their initial treatment with ruxolitinib, patients had a 92% reduction in spleen size and an 85% improvement in symptom burden. When re-challenged with ruxolitinib, the reduction in spleen size was 69% and the symptom burden improved by 92%. After a second drug holiday from initial treatment, 4 patients in the study were re-challenged a second time. All 4 patients had some response to ruxolitinib the third time around.1,7

Beyond ruxolitinib rechallenging, the use of other JAK inhibitors may help with survival, hematocrit control, splenic responses, and symptom burden. Gerd explained that oncologists should know that not all JAK inhibitors are created equal, as some are better at treating patients with JAK 1 mutations versus JAK 2/3 mutations.1

Across the treatment landscape for MPNs, physicians can choose from FDA approved agents like ruxolitinib and fedratinib as well as investigational drugs like pacriinib, momelotinib (formerly GS-0387), idacitinib, gandotinib, and tofatinib. The key is to know which agents are optimal for targeting cytokine production in patients with JAK1 mutations, which are best for hematopoiesis in JAK2 mutations, and which drugs address proliferation and chemotaxis in patients with JAK3 mutations.


1. Gerd A. Ruxolitinib in 2020 and beyond: The good, the suboptimal, and the failure. Presented at: Texas Virtual MPN Workshop 2020; August 27-28, 2020; Accessed August 28, 2020.

2. 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

3. 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

4. Vannucchi AM, Kiladjian JJ, Griesshammer M, et al. Ruxolitinib versus standard therapy for the treatment of polycythemia vera. N Engl J Med. 2015;372(5):426-435. doi:10.1056/NEJMoa1409002

5. Burton T, Parikh K, Patel M, et al. Real-World analysis of ruxolitinib treatment patterns and outcomes among patients with myelofibrosis. Blood. 2019;(Suppl_1): 4750. doi: 10.1182/blood-2019-124651

6. Kuykendall AT, Shah S, Talati C, et al. Between a rux and a hard place: evaluating salvage treatment and outcomes in myelofibrosis after ruxolitinib discontinuation. Ann Hematol. 2018;97(3):435-441. doi:10.1007/s00277-017-3194-4

7. Gerds A, Su D, Martynova A, et al. Ruxolitinib Rechallenge Can Improve Constitutional Symptoms and Splenomegaly in Patients With Myelofibrosis: A Case Series. Clin Lymphoma Myeloma Leuk. 2018;18(11):e463-e468. doi:10.1016/j.clml.2018.06.025