Janus kinase inhibition and symptom control in myeloproliferative neoplasms

More than six years after its approval, the Janus kinase 1/2 (JAK1/2) inhibitor ruxolitinib remains the only Food and Drug Administration (FDA)-approved therapy for patients with myelofibrosis (MF). Long-term follow-up of the pivotal COMFORT trials has shown that ruxolitinib provides durable benefits to patients with intermediate-2 or high risk MF in terms of spleen shrinkage and symptomatic improvement, and extends survival in comparison to placebo or best available therapy (BAT), despite near-complete crossover^1,2. Furthermore, the drug is very well tolerated, with no new safety concerns emerging after five years of follow-up^1,2.

In the United States, ruxolitinib is approved for use in patients with intermediate-1, intermediate-2 or high risk MF, and consensus guidelines endorse its use in patients with low risk disease who have troublesome splenomegaly and/or MF-related symptoms³. In contrast, in the European Union, ruxolitinib is licensed for use in patients with MF not based on the risk of death, but rather based on the presence of splenomegaly and/or symptoms. Indeed, symptom burden can be substantial in the myeloproliferative neoplasms (MPNs) and particularly in MF^4,5, and clinical improvement (CI) in symptoms is recognized as a response criterion in MF by the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT)⁶. In general, symptoms in MF are attributed to the elevated cytokine levels characteristic of the disease that are broadly suppressed by ruxolitinib^7,8.

Oritani and colleagues⁹ reported on pooled symptom and Quality of Life (QOL) responses to ruxolitinib in 81 Japanese patients with MF collated from two studies. Thirty Japanese patients participated in A2202, a phase 2 study with eligibility criteria similar to the COMFORT trials conducted in multiple Asian countries, and 51 patients participated in AJP01, an open-label study conducted exclusively in Japan that additionally allowed patients with intermediate-1 risk disease and platelets 50–99 × 10⁹/L to be enrolled. Symptoms and patient-reported outcomes after 24 weeks of ruxolitinib were secondary endpoints of both studies, and were assessed using the MF Symptom Assessment Form (SAF) version 2.0 and the 30-item European Organization for Research and Treatment of Cancer (EORTC) QOL questionnaire (EORTC QLQ-C30). Overall, two thirds of evaluable patients (n = 65) achieved a ≥50% reduction in total symptom score (TSS) at week 24; while symptom responses were observed at all dose levels, the greatest reductions in TSS occurred at higher doses (final titrated doses of 20–25 mg twice daily). In the original phase 1/2 study of ruxolitinib in MF, doses higher than 10 mg twice daily did not lead to greater symptom benefit⁷. Improvements in EORTC QLQ-C30 scores were restricted to patients who achieved ≥50% reduction in TSS, while those who experienced <50% TSS reduction actually had worsening scores, a phenomenon not observed in COMFORT-1¹⁰. Improvements occurred in all functional scales except for cognitive functioning. Finally, symptomatic improvement (except for itching) correlated with ≥35% spleen volume reduction (SVR), as in COMFORT-1¹⁰, although patients who had lesser degrees of SVR also reported improvement in symptoms.

A number of other JAK inhibitors have been tested in patients with MF, although none has been approved to date. Momelotinib, a JAK1/2 inhibitor with the unique benefit of improving anemia, was compared head to head with ruxolitinib in JAK-inhibitor-naïve patients and was non-inferior with respect to rates of ≥35% SVR, but non-inferiority was not achieved in terms of ≥50% TSS reduction¹¹. Further development of this agent has since been discontinued. The rate of ≥50% TSS reduction up to week 24 with the JAK2-selective inhibitor pacritinib in JAK-inhibitor-naïve patients in the intention-to-treat (ITT) population of the phase 3 PERSIST-1 trial was not significantly different from that with BAT, although it was at week 48¹². While the rates of both ≥35% SVR and ≥50% TSS reduction with pacritinib in PERSIST-1 were considerably lower than those observed with ruxolitinib in the COMFORT trials, there were substantial differences between the characteristics of the patients that preclude comparisons across these trials. Another JAK2-selective inhibitor, fedratinib, produced encouraging rates of ≥35% SVR and ≥50% TSS reduction in a phase 3 placebo-controlled trial (JAKARTA-1); however, its development was halted because of suspected Wernicke’s encephalopathy in several patients¹³. Based on evidence of activity in patients previously treated with ruxolitinib, it is hoped that these agents will gain regulatory approval, perhaps in the second-line setting^14,15. Gastrointestinal adverse effects secondary to fms-like tyrosine kinase 3 (FLT3) inhibition are of concern with both pacritinib and fedratinib, and could negatively impact QOL.

Based on the premise that JAK1 inhibition may be more critical for symptomatic improvement in MF through suppression of cytokines and that JAK2 inhibition likely contributes more to myelosuppression, selective inhibitors of JAK1 such as itacitinib have been developed and tested in patients with MF. Expectedly, efficacy in terms of ≥35% SVR was modest, but symptom responses were encouraging and myelosuppression was limited¹⁶. This agent is now being tested in combination with ruxolitinib in patients in whom dose optimization of ruxolitinib, important for spleen response and thereby survival^17–19, is precluded by cytopenias, and alone in patients who lose response to ruxolitinib or have to discontinue it because of cytopenias (NCT03144687).

Drawing on its successes in MF, ruxolitinib has also been studied in patients with polycythemia vera (PV) and essential thrombocythemia (ET). In PV, ruxolitinib is currently registered for use in patients who are resistant to hydroxyurea (HU) or intolerant of it, based on the results of the RESPONSE and RESPONSE-2 trials^20,21. In the phase 3 RESPONSE trial that compared ruxolitinib to BAT in patients with HU-resistant/intolerant PV and splenomegaly, 49% of ruxolitinib-treated patients versus 5% of BAT-treated patients experienced a ≥50% reduction in TSS at week 32²⁰. However, interestingly, in the phase 3b RELIEF study that evaluated continuing HU versus switching to ruxolitinib in 110 patients with PV with controlled blood counts but persistent PV-related symptoms, the primary endpoint of a ≥50% improvement from baseline in the MPN-SAF TSS cytokine symptom cluster (TSS-C, the sum of tiredness, itching, muscle aches, night sweats and sweats while awake) at week 16 was achieved by similar proportions of patients in both groups (43.4% of ruxolitinib-treated patients and 29.6% of HU-treated patients, p = .139)²².

Symptom control in patients with ET remains a significant unmet need. Recently published results from the MPN Landmark survey show rates of fatigue of 64–71% and those of abdominal discomfort, night sweats, difficulty sleeping, depressed mood, headaches, numbness and tingling, dizziness/vertigo/lightheadedness, early satiety, bone pain, itching and concentration problems in the 20–40% range^4,5. In the US, ruxolitinib is currently being compared against anagrelide in the second-line setting after failure of HU in the pivotal RESET-272 trial (NCT03123588). The results of long-term follow-up of 39 patients with HU-resistant/intolerant ET receiving ruxolitinib in an open-label phase 2 study²³ and those of the randomized MAJIC-ET trial comparing ruxolitinib to BAT in 110 ET patients with HU-resistance or intolerance²⁴ were recently published. Although the latter study failed to show a difference between the groups in terms of rates of complete hematologic response (CHR), thrombosis, hemorrhage or transformation, in both studies ruxolitinib provided benefits in terms of disease-related symptoms^23,24.

In summary, the study by Oritani et al. provides further proof of the efficacy of ruxolitinib in improving MPN-associated symptoms and QOL in patients with MF. There remains a major unmet need for effective agents for patients with MF who discontinue ruxolitinib, most often due to disease progression²⁵. Similarly, particularly from a symptom control/QOL perspective, one hopes that ruxolitinib will become available in the near future for patients with ET.

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Declaration of funding

This work was supported in part by the MD Anderson Cancer Center support grant P30 CA016672 from the National Cancer Institute (National Institutes of Health).

Declaration of financial/other relationships

M.S. has no financial disclosures. P.B. has received research support from Incyte corporation, Celgene corporation, CTI Biopharma, Blueprint Medicines Corporation, Astellas, and Pfizer.

CMRO peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgments

None.