Four of a Kind?

Soon, there may be as many as four JAK inhibitors available for patients with myelofibrosis.

For many of his patients with myelofibrosis, ruxolitinib has been like a miracle drug, according to Stephen Oh, MD, PhD, associate professor of hematology at Washington University in St. Louis.

When it was approved in 2011, ruxolitinib – a JAK 1/2 inhibitor — was the first and only U.S. Food and Drug Administration (FDA)−approved drug for myelofibrosis.1 A second JAK inhibitor, fedratinib, was approved in 2019,2 and there are two more in phase III clinical trials (pacritinib and momelotinib).3,4

With four JAK inhibitors potentially up their sleeves, do clinicians need another option for patients with myelofibrosis? ASH Clinical News recently spoke with several experts about the status of this class of drugs, whether four JAK inhibitors is too many, and how the treatment landscape for myelofibrosis may evolve in the coming years.

Changing the Game

The introduction of ruxolitinib was a game changer for patients with myelofibrosis, Dr. Oh told ASH Clinical News.

“Ruxolitinib had a major impact in terms of providing benefit to patients with myelofibrosis, particularly as it relates to symptoms like fatigue, night sweats, weight loss, and side effects of splenomegaly,” he said.

The improvement in symptoms was significant, agreed Gaby Hobbs, MD, clinical director of the leukemia service at Massachusetts General Hospital. “This drug was so easy to take – it’s a pill – and completely changed the way patients live every day,” Dr. Hobbs said.

To appreciate why a JAK inhibitor is so important to the treatment of myelofibrosis and myeloproliferative neoplasms, one needs to understand the diseases’ underlying biology, Dr. Hobbs said. First, several groups identified the JAK2 mutation as playing a role in the disease. After that discovery, mutations in thrombopoietin receptor (TPO-R) MPL and calreticulin (CALR) were identified.

“All three mutations lead to activation of the JAK-STAT signaling pathway, a pathway through which cytokine signaling occurs,” Dr. Hobbs said. “It helped explain why patients with myelofibrosis and myeloproliferative neoplasms have high levels of circulating inflammatory cytokines that contribute to much of the symptomology. It only made sense to try to block that signaling to alleviate some of those issues.”

However, no drug is perfect, and ruxolitinib does have a few issues, she added. First, although ruxolitinib can improve symptoms and splenomegaly in many patients, it does not work in all patients. Results of the phase III, placebo-controlled COMFORT-I trial showed only about 42% of patients assigned to receive ruxolitinib experienced a reduction in spleen volume of ≥35% at 24 weeks; about 46% of patients had an improvement of ≥50% in their total symptom score.5

Second, ruxolitinib does not address the underlying biology of the disease and does not prevent disease progression, said Andrew Kuykendall, MD, assistant member in the department of malignant hematology at the Moffitt Cancer Center.

In addition, ruxolitinib is not without its side effects.

“We see an increase in nonmelanoma skin cancers and shingles reactivations and an increased risk for other infections,” Dr. Kuykendall said. “Also, ruxolitinib frequently worsens blood counts – at least in the short term.”

For example, findings from the phase III COMFORT-II trial, which evaluated ruxolitinib against best available therapy, showed that the most common hematologic adverse events associated with ruxolitinib were anemia and thrombocytopenia, but they rarely led to treatment discontinuation.6

“This is not always a problem for patients who start treatment with preserved blood counts, but the vast majority of patients have some cytopenias,” Dr. Kuykendall said.

Fedratinib, a selective, oral JAK2 inhibitor, has more in common with ruxolitinib than not, according to Dr. Oh, but it was still a welcome addition to the armamentarium.

“Its role in the management of myelofibrosis is primarily for second-line treatment of patients previously treated with ruxolitinib,” Dr. Oh said. “In that setting, we had very little to offer patients outside of clinical trials or potentially transplant.”

Results of the phase II JAKARTA-2 trial of fedratinib showed that 55% of patients with intermediate- or high-risk myelofibrosis that was resistant or intolerant to ruxolitinib achieved a 35% reduction in spleen volume.7 A reevaluation of the data with an intention-to-treat analysis and more stringent criteria for ruxolitinib failure put the spleen volume response rate closer to 30%.8

Fedratinib was temporarily put on hold in 2013 due to concerns about encephalopathy, but regulators ultimately concluded that there was no evidence that the drug directly induced encephalopathy. In addition, gastrointestinal side effects, such as nausea and upset stomach, were the most common adverse events observed with fedratinib.

“Fedratinib is approved for frontline use, but I don’t have a particular scenario where I would choose it over ruxolitinib, which has been around for almost a decade,” Dr. Oh said.

New Players at the Table

In addition to the two approved JAK inhibitors, two additional JAK inhibitors are in phase III clinical development.

“The companies developing these two drugs have been smart because they are definitely positioning them to meet some of the unmet needs left by ruxolitinib and fedratinib,” Dr. Hobbs said.

Pacritinib is a JAK2 and FLT3 inhibitor, and early data indicate that the drug might help patients with myelofibrosis who have severe thrombocytopenia.

“The niche [for pacritinib] would be the treatment of patients with platelet counts less than 50×109/L,” Dr. Hobbs said. “The approved JAK inhibitors are not approved for this type of patient and most of the clinical trials of these drugs excluded these patients.”

The PERSIST-1 trial compared pacritinib 400 mg/day with best available therapy in treatment-naïve patients with intermediate- or high-risk myelofibrosis. Pacritinib significantly improved spleen volume reduction, with a rate of spleen volume reduction of at least 35% of 19.1% for pacritinib versus 4.7% for best available therapy in the intent-to-treat population at 24 weeks, as well as symptom response rates (24.5% vs. 6.5%).9 The drug was put on clinical hold by the FDA because of concerns about intracranial hemorrhage and cardiovascular events, but longer-term follow-up mitigated these concerns and the hold was lifted in 2017.10

Results of an ongoing phase III trial in patients with severe thrombocytopenia are expected later this year.3

In contrast with the other JAK inhibitors, momelotinib, a JAK 1/2 inhibitor, has the potential to improve or at least stabilize anemia, Dr. Kuykendall said.

“Ruxolitinib and fedratinib can potentially worsen hemoglobin and other hematologic parameters,” Dr. Kuykendall explained. “That can be challenging in practice, as it may tip someone from having mild or moderate anemia into a situation where they require blood transfusions. Typically, there is a rebound in hemoglobin after four months or so, but it can be difficult to wait on that.”

To that end, he noted that, in practice, patients will often discontinue JAK inhibitors due to progressive anemia and new transfusion requirements.

Momelotinib inhibits ACVR1/ALK2 and decreases hepcidin, the key regulator of iron production. In both SIMPLIFY-1 and SIMPLIFY-2, momelotinib was associated with reduced transfusion requirements compared with best available therapy.11,12 Momelotinib is being evaluated in a registration study that is anticipated to finish enrollment by mid-2021. If successful, it would support an ensuing new drug application.13

“This would be an exciting option for patients to be able to have a JAK inhibitor that helps with symptoms and splenomegaly, and also improves anemia,” Dr. Hobbs said. “It is still too early to tell though.”

Others Following Suit

Other classes of therapies, outside of JAK inhibitors, are also in late clinical trials for myelofibrosis.

“The field is getting more complicated, but in a good way,” Dr. Oh said. “We have more than five drugs in phase III development that seem to have a good chance of ultimately getting approved.”

For example, the BET inhibitor CPI-0610, now called pelabresib, is being evaluated against ruxolitinib in the phase II MANIFEST trial of three patient groups: those resistant to, intolerant of, or ineligible for ruxolitinib (Arm 1); as an add-on therapy with ruxolitinib in patients with suboptimal response to ruxolitinib alone (Arm 2); and JAK inhibitor–naïve patients (Arm 3).

Results presented at the 2020 American Society of Hematology Annual Meeting indicated that, in Arm 1, 30% of patients who were not transfusion-dependent achieved spleen volume reduction of ≥35% at 24 weeks. In Arms 2 and 3, these rates were 29% and 67%.14

“There is a lot of excitement around CPI-0610 for a variety of reasons,” Dr. Kuykendall. “There is good preclinical rationale for the combination. It targets a different pathway than JAK inhibition, it has favorable impacts on anemia, and it seems – in combination – to achieve better spleen responses than ruxolitinib alone.”

However, he cautioned against drawing too many conclusions from the phase II data.

Other drugs under investigation in combination with ruxolitinib are navitoclax, a small molecule that targets and binds to multiple BCL2 family proteins, the PI3K inhibitor parsaclisib, the DNA methyltransferase inhibitor azacitidine, and a MDM2 inhibitor.

“We currently have 11 phase III trials actively recruiting,” Dr. Kuykendall noted.

Possibly the most exciting of these is the phase III IMpactMD trial which will test imetelstat, a telomerase inhibitor, in refractory disease. The trial will compare the drug with best available therapy in intermediate-2 or high-risk disease and has overall survival as its primary endpoint.15

What the Future Holds

As exciting as the myelofibrosis treatment landscape is right now, Dr. Hobbs encourages clinicians to keep in mind that a patient who needs a stem cell transplant will still need a stem cell transplant.

“Many times, clinicians worry about sending patients with myelofibrosis to transplant, but the thing to remember is that patients with intermediate 2 disease or greater still need to be considered for transplant,” Dr. Hobbs said. “Outcomes have improved significantly and patients are in better shape when they get to transplant, but even if a person responds to ruxolitinib, they still need to go to transplant.”

Dr. Oh agreed. “No matter how effective these treatments are, in reality, the majority of patients with myelofibrosis are not eligible for transplantation either because of age or comorbidities.”

Successful transplant is the goal when possible, and the only modality that has any likelihood of inducing complete response and eradication of underlying disease.

“From my perspective, a desirable goal is to not have to do transplant at all,” Dr. Oh said. “If we can work to get more effective therapies, transplant may not be necessary in some cases.”

Dr. Kuykendall said that some people outside of the field of myelofibrosis look at it as a chronic disease, which is why resources may be allocated to other disease types.

“If you have a patient with intermediate-2 or high-risk myelofibrosis, they have a median survival of two to five years. That prognosis is as bad, or worse, than most other malignancies out there,” Dr. Kuykendall said. “We now have a trial in myelofibrosis with an overall survival primary endpoint, which is very new for this field. It is exciting that we can begin to focus on an endpoint like that.”—By Leah Lawrence

References

  1. Incyte. FDA Approves Incyte’s Jakafi ™ (ruxolitinib) for patients with myelofibrosis. November 16, 2011. Accessed March 18, 2021. https://investor.incyte.com/press-releases/press-releases/2011/FDA-Approves-Incytes-JakafiTM-ruxolitinib-for-Patients-with-Myelofibrosis/default.aspx.
  2. U.S Food & Drug Administration. FDA approves fedratinib for myelofibrosis. August 16, 2019. Accessed March 18, 2021. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-fedratinib-myelofibrosis.
  3. CTI BioPharma. CTI BioPharma Begins Patient Enrollment in PACIFICA Pivotal Phase 3 Trial of Pacritinib in Myelofibrosis Patients with Severe Thrombocytopenia. October 1, 2019. Accessed March 18, 2021. https://www.prnewswire.com/news-releases/cti-biopharma-begins-patient-enrollment-in-pacifica-pivotal-phase-3-trial-of-pacritinib-in-myelofibrosis-patients-with-severe-thrombocytopenia-300928226.html.
  4. Sierra Oncology. Sierra Oncology Launches the MOMENTUM Phase 3 Clinical Trial for Patients with Myelofibrosis. November 20, 2019. Accessed March 18, 2021. http://investor.sierraoncology.com/2019-11-20-Sierra-Oncology-Launches-the-MOMENTUM-Phase-3-Clinical-Trial-for-Patients-with-Myelofibrosis.
  5. Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366:799-807.
  6. Harrison CN, Vannucchi AM, Kiladjian J-J, et al. long-term findings from COMFORT-II, a phase 3 study or ruxolitinib vs best available therapy for myelofibrosis. Leukemia. 2016;30:1701-1707.
  7. Harrison CN, Schaap N, Vannucchi AM, et al. Janus kinase-2 inhibitor fedratinib in patients with myelofibrosis previously treated with ruxolitnib (JAKARTA-2): a single-arm, open-label, non-randomised, phase 2, multicentre study. Lancet Haematol. 2017;4:e317-e324.
  8. Harrison CN, Schaap N, Vannucchi AM, et al. Fedratinib in patients with myelofibrosis previously treated with ruxolitinib: an updated analysis of the JAKARTA2 study using stringent criteria for ruxolitinib failure. Am J Hematol. 2020;95(6):594-603.
  9. Mesa RA, Egyed M, Szoke A, et al. Results of the PERSIST-1 phase III study of pacritinib (PAC) versus best available therapy (BAT) in primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (PPV-MF), or post-essential thrombocythemia-myelofibrosis (PET-MF). J Clin Oncol. 2015;33:LBA7006.
  10. ASH Clinical News. FDA Lifts Clinical Hold on Pacritinib for the Treamtent of Myelofibrosis. February 1, 2017. Accessed March 19, 2021. https://www.ashclinicalnews.org/news/fda-lifts-clinical-hold-pacritinib-treatment-myelofibrosis/.
  11. Mesa RA, Kiladjian JJ, Catalano JV, et al. SIMPLIFY-1: A phase III randomized trial of momelotinib versus ruxolitinib in Janus kinase-inhibitor-naïve patients with myelofibrosis. J Clin Oncol. 2017;35(34):3844-3850.
  12. Harrison CN, Vannucchi AM, Platzbecker U, et al. Momelotinib versus best available therapy in patients with myelofibrosis previously treated with ruxolitinib (SIMPLIFY 2): a randomised, open-label, phase 3 trial. Lancet Haematol. 2018;5(2):e73-e81.
  13. Sierra Oncolocy. Sierra Oncology Reports 2020 Year End Results. March 11, 2021. Accessed April 22, 2021. https://www.prnewswire.com/news-releases/sierra-oncology-reports-2020-year-end-results-301245033.html.
  14. Constellation Pharmaceuticals. Constellation Pharmaceuticals Provides Update of MANIFEST Study for CPI-0610 at ASH Meeting. December 6, 2020. Accessed March 19, 2021. https://www.globenewswire.com/news-release/2020/12/06/2140167/0/en/Constellation-Pharmaceuticals-Provides-Update-of-MANIFEST-Study-for-CPI-0610-at-ASH-Meeting.html.
  15. Geron. Geron Announces Opening of IMpactMF Phase 3 Clinical Trial in Refractory Myelofibrosis. December 11, 2020. Accessed March 19, 2021. https://www.businesswire.com/news/home/20201211005044/en/Geron-Announces-Opening-of-IMpactMF-Phase-3-Clinical-Trial-in-Refractory-Myelofibrosis.