Evidence for Janus kinase (JAK) inhibitors for the prevention of major morbid events in patients with myeloproliferative neoplasms (MPNs)

Patients with myeloproliferative neoplasms (MPNs), a group of clonal hematologic disorders, experience a wide range of debilitating clinical symptoms.¹  Most notably, patients with myelofibrosis,²  either primary myelofibrosis (PMF) or post-polycythemia vera or post-essential thrombocytosis, can experience a particularly challenging set of MF-related morbidities. The clinical course of MPN patients (particularly MF) may include complications including thrombotic and other cardiovascular events, pulmonary hypertension, infection, hemorrhage, portal hypertension, cachexia and weight loss, anemia or other cytopenias, and potential transformation to acute myeloid leukemia.^1,3-5  In addition to complications, MPN symptom burden is a key feature of MF⁶  (with fatigue, night sweats, pruritus, abdominal symptoms, bone pain, fever, etc), even amongst those with low and intermediate-1 risk by DIPSS.³ 

The first and only approved drug for the treatment of MF thus far has been ruxolitinib, a potent JAK1 and JAK2 inhibitor.⁷  Established by 2 separate randomized phase 3 trials (COMFORT 1 and 2), patients treated with ruxolitinib (compared with control arms) not only experienced a rapid and sustained decrease in MF-related spleen size and symptom burden (weight loss, night sweats, pruritis, and fatigue),^8,9  but also improvement in terms of overall survival.^2,10  The approval for ruxolitinib for intermediate to high-risk MF patients represented the first time an oncologic drug included patient reported outcome (PRO)-related data and symptom burden data in the FDA drug-labeling, suggesting the importance of such data in the future of oncology drug development.^11,12 

In addition to ruxolitinib, there are many other JAK inhibitors in various stages of drug development.^13-15 Table 1 lists a selected group of JAK inhibitors furthest in development for treatment of MPN, with several of these drugs demonstrating symptomatic benefit and improvement in quality-of-life measures, despite differences in anti-cytokine profiles and JAK inhibition among these therapies.¹⁶  Additionally, phase 3 results have recently been reported this year at ASCO 2015 by Mesa et al¹⁷  (and subsequently updated at EHA 2015¹⁸ ), that another JAK inhibitor, pacritinib (a dual JAK2/FLT3 inhibitor) has significant activity. Specifically, pacritinib demonstrated significant splenic reduction, improvement in transfusion-dependent anemia and symptom burden benefit compared with best available therapy in the PERSIST-1 trial for patients with myelofibrosis, even in patients with significant thrombocytopenia (platelets <50 × 10⁹/L). A second clinical trial with pacritinib, PERSIST-II, is currently ongoing and will focus on enrollment of those patients with myelofibrosis with platelet count less than or equal to 100 000/μL, and will also include symptom scoring by TSS reduction as a key co-primary endpoint.

To more effectively and uniformly capture and quantitate symptom burden in MF, an MPN scoring system was initially designed in 2007 by Mesa et al,¹⁹  and then translated into a questionnaire validated for all MPN patients, called The MPN Symptom Assessment Form (MPNSAF).²⁰  Further refinement of this tool resulted in the current, widely used 10-question measurement survey, the MPN-SAF Total Symptom Score (MPN-SAF TSS)⁶  now known as “MPN 10.” Studied in 1408 patients with MPN, this shortened, concise questionnaire was derived from 2 prior validated systems. It incorporates patient-directed questions about some of the most relevant MPN symptoms: concentration, early satiety, fatigue, night sweats, pruritis, inactivity, abdominal discomfort, weight loss, fevers, and bony pains. Importantly, the results highlighted significant differences among the different MPN types (p < 0.001), with a mean patient score of 25.3 for MF, 21.8 for PV, and 18.7 for ET, demonstrating that patients with MF indeed had the highest symptom burden scores. Furthermore, the MPN 10 revealed the three symptoms with the highest intensity of scoring: fatigue (mean 4.4), problems with concentration (mean 2.5), and early satiety (mean 2.5). Finally, in terms of quality-of-life (QOL), this study showed that 42% of all patients with MF had clinically deficient QOL (defined in this study as ≥ 4 out of 10 items) which was more commonly found in patients with MF compared to patients with ET (30%) or PV (38%).⁶ 

Ruxolitinib decreases the morbidity of MF symptom burden as reported in specific analysis of PRO among patients with MF treated with ruxolitinib as part of the COMFORT-1 study.²¹  In this report, the authors demonstrated that the ruxolitinib-treated group had improved scores with regards to MF-related symptoms. Multiple recognized PRO measures were tested, including the MFSAF-TSS, the European Organisation for Research and Treatment of Cancer Quality-of-life Questionnaire-Cor 30 (EORTC QLQ-C30), Patient Reported Outcomes Measurement Information System (PROMIS) Fatigue Scale, and the Patient Global Impression of Change (PGIC). Based on these tools, it was found that 91% of patients treated with ruxolitinib that had achieved ≥50% TSS improvement also had reported that their disease had “much improved” or “very much approved” on the PGIC; these patients also had notable improvements in EORTC QLQ-C30. Ultimately, it was concluded that those patients who were treated with ruxolitinib and experienced a ≥35% decrease in splenic volume had the highest improvements in PRO measures.²¹  Further analysis of the COMFORT-1 study patients, this time focusing on the control group (placebo-treated,) by Mesa et al, demonstrated PROs worsened from baseline assessment through week 24, and that spleen volume increased in most placebo-treated patients, suggesting that the natural, untreated history of MF leads to worsened quality-of-life for patients not treated with a JAK inhibitor.²² 

Patients with other MPN subtypes (besides MF) can also exhibit debilitating symptoms. Notably, patients with polycythemia vera⁵  experience a number of acute and chronic comorbid conditions including pruritis (especially aquagenic pruritis), and signs and symptoms of hyperviscosity and cardiovascular complications secondary to hemorrhage or thrombotic events.⁵  The most devastating of these complications, cardiac death and thrombotic events, has been demonstrated to be decreased with the combination of low-dose aspirin, hydroxyurea, and therapeutic phlebotomy (with goal of keeping hematocrit ≤45%).⁵  However, there is a subset of PV patients that do not respond/or are intolerant to hydroxyurea and these patients may represent a more advanced disease stage with worse outcomes.²³  Therapy with JAK inhibitors has been hypothesized to be of benefit in these patients. Indeed, ruxolitinib was shown to be both well tolerated and have efficacy in terms of hematocrit control in patients with PV in a phase 2 trial.²⁴ 

To build on these findings, a multicenter phase 3 study (RESPONSE trial) was launched to study ruxolitinib versus best available therapy (BAT) in those patients with advanced PV found to be resistant to (or intolerant of) hydroxyurea.²⁵  In this study, the primary endpoint was measuring the percent of patients who achieved both hematocrit control and spleen response by week 32; secondary/other endpoints included symptom improvement by the MPN-SAF. Encouragingly, the RESPONSE trial for patients with PV demonstrated, in patients who received ruxolitinib compared with BAT, improved hematocrit control (without phlebotomy), reduction in spleen volume, higher rate of complete hematologic remissions, a trend toward fewer vascular events, and an improvement in symptoms. In terms of the specific breakdown for the symptom improvement, by percentage of patients with ≥50% improvement in MPN-SAF score at 32 weeks: it was greater in the ruxolitinib group in multiple categories specific to PV, including improvement in cytokine symptom clustering (fatigue, pruritis, night sweats, muscle aches, daytime sweats); hyperviscosity symptom clustering(headache, dizziness, skin erythema, visual problems, ringing in ears, concentration problems, neuropathy); and splenomegaly symptom clustering (abdominal discomfort, early satiety). Additionally, patients in the ruxolitinib-treated group had fewer thromboembolic events and the study drug was well tolerated with 85% of the patients still taking ruxolitinib at median follow-up of 81 weeks. Because the safety of the ruxolitinib therapy in this trial appears to be consistent with the ruxolitinib-treated group in the MF studies (COMFORT 1 and 2), JAK inhibitor was ultimately approved for new therapy for advanced PV patients who are resistant to or intolerant of hydroxyurea.^25,26 

The patient in our opening scenario scores 1 point each on DIPSS for: age >65, presence of constitutional symptoms, and circulating blasts ≥1%, for a total of 3 points, making him intermediate risk-2 MF; median overall survival predicted at 48 months. The patient would thus qualify for therapy with a JAK inhibitor, such as ruxolitinib, and based on published data, he would be predicted to have improvement in the morbidity of his disease including MF-related symptoms, but also improvement in overall survival. Phase 3 trials ongoing will explore whether JAK inhibition also not only decreases the morbidity of PV-related symptom burden, but also decreases vascular events and/or risk of progression.

Ruben Mesa, Mayo Clinic in Arizona, Division of Hematology & Medical Oncology, Mayo Clinic Cancer Center 13400 E. Shea Blvd, Scottsdale, AZ 85259; Phone: 480-301-8335; Fax: 480-301-4675; e-mail: Mesa.ruben@mayo.edu.