Improving symptom burden and quality of life in patients with myelofibrosis: current strategies and future directions

ABSTRACT

Introduction

Myelofibrosis (MF) is a complex and aggressive hematologic malignancy resulting from JAK/STAT-driven myeloproliferation and abnormal fibrogenesis. The clinical manifestations are heterogeneous and negatively impact quality of life and survival. JAK inhibitors improve symptoms and splenomegaly to a variable degree in a proportion of patients, but the effects for many patients are insufficient or short-lived.

Areas covered

This review examines the constellation of symptoms that befall patients with MF, describes methods to quantify and serially monitor these symptoms, and evaluates pharmacologic and non-pharmacologic interventions for disease-related symptoms. The review also includes a discussion of areas of unmet medical need, and proposes future methods for meeting this need.

Expert opinion

The treatment landscape for MF is evolving rapidly. The most effective therapies or combinations of therapies will likely simultaneously impact both the malignant hematopoietic stem cell and mechanisms of aberrant fibrogenesis that drive this disease. The goals of treatment for patients with myelofibrosis should be to improve length and quality of life. Clinical trials must be designed with these goals in mind, with endpoints focused on overall survival and symptom reduction, as opposed to surrogate endpoints such as spleen volume reduction.

KEYWORDS:

• Myelofibrosis
• myeloproliferative neoplasms
• symptoms
• quality of life
• JAK inhibitor

1. Introduction

Myelofibrosis (MF) is a complex myeloproliferative neoplasm (MPN) that profoundly impacts the lives of patients. Hallmark features of MF include a significant burden of constitutional and psychosocial symptoms, massive splenomegaly, bone marrow failure, and risk of transformation to acute leukemia (See Figure 1). Unfortunately, many patients with myelofibrosis will experience considerable declines in quality of life (QOL) and length of a life as a result.

Figure 1. A pictorial summary of the hallmark symptoms experienced by patients with myelofibrosis

The pathophysiology underlying these clinical features is multifactorial and incompletely understood. All of the classical BCR/ABL-negative MPNs – MF, polycythemia vera (PV), and essential thrombocytosis (ET) – are driven by constitutive activation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway, most commonly caused by mutations in JAK2, CALR, or MPL [1]. Additional clonal mutations can modulate disease phenotype and some, including those involving SRSF2, IDH 1/2, ASXL1, EZH2, confer additional risk [2,3]. Epigenetic dysregulation in MPNs is also common and contributes to MPN development and progression [4]. The downstream effects include proliferation of myeloid cells, mobilization of hematopoietic cells to extramedullary sites, aberrant production of reticulin and collagen fibrosis, and excess secretion of pro-inflammatory cytokines [5].

The development of JAK inhibitors has revolutionized the treatment of patients with MF. Two JAK inhibitors are approved in the United States for use in myelofibrosis – ruxolitinib and fedratinib. Both have the potential to improve patients’ symptoms and QOL, however major areas of unmet need remain. Responses to JAK inhibitors are often sub-optimal or short-lived. Also, cytopenias commonly limit the dose of JAK inhibitors that can be safely delivered, or may preclude their use entirely. However, recent discoveries unraveling MF pathophysiology have illuminated many potential new targets for therapy. An explosion of clinical trials has ensued, and the prospect of more effective treatments for the disease and its symptoms has ignited significant optimism in the field.

This review will describe the symptom burden and impact on quality of life for patients with MF, discuss methods to quantify and serially monitor disease-related symptoms, and detail pharmacologic and non-pharmacologic interventions that may address these symptoms. A comprehensive review of all published literature was performed using the PubMed database, and key data are presented and discussed here.

2. Symptom burden and impact on quality of life

MPNs are notorious for inflicting bothersome symptoms and impairing quality of life. However, the constellation of symptoms that patients experience varies widely between MPN subtypes and between individual patients. Even among those with MF, approximately 25% are asymptomatic at the time of diagnosis [6]. Later in the disease course, patients experience constitutional symptoms including fevers, chills, night sweats, weight loss, and arthralgias [6]. Table 1 summarizes the frequency and severity of the symptoms that afflict patients with MF based on a survey of 96 patients [7].

Table 1. Frequency and severity of symptoms in patients with MF [7]. Frequency and severity of symptoms in patients with MF. Frequency is reported as percentage of patients experiencing the listed symptom. Mean severity of symptom is reported on the scale of 0 to 10. Republished with permission of American Society of Hematology, from ‘The Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF): international validation and reliability trial in 402 patients’ by Scherber R, Dueck AC, Johansson P et al, originally published in volume 118, 2011 of Blood; permission conveyed through Elsevier Copyright Clearance Center, Inc

Symptom	Frequency (%)	Severity (mean score out of 10)
Fatigue	98.9	3.7
Early satiety	75.5	2.7
Abdominal pain	63.0	2.4
Abdominal discomfort	71.7	3.0
Inactivity	76.5	3.0
Headache	44.6	1.5
Concentration problem	72.5	3.0
Dizziness	58.1	2.0
Numbness	58.1	2.4
Insomnia	73.9	3.1
Sad mood	68.5	2.3
Sexuality problems	71.0	4.0
Cough	55.4	1.7
Night sweats	63.4	2.4
Itching	53.8	1.9
Bone pain	55.3	2.2
Fever	29.0	0.6
Weight loss	48.9	1.9

The clinical sequelae of MPNs are driven by multiple pathologic processes. Constitutive activation of the JAK-STAT pathway yields increased production of pro-inflammatory cytokines including IL-1, IL-6, IL-8, and TNF-α [8]. This chronic inflammatory state likely contributes to the heterogeneous, nonspecific symptoms that MF patients experience, such as fevers, chills, and night sweats. Inflammatory cytokines, in combination with cellular stasis and microthrombosis, explain the peculiar microvascular symptoms seen in MF such as dizziness, vertigo, numbness, tingling, and sexual dysfunction [8]. Dysregulated trafficking of hematopoietic cells to organs outside of the bone marrow and subsequent proliferation in those environments, known as extramedullary hematopoiesis (EMH), contributes to many MF-associated symptoms. The combination of EMH and local deposition of reticulin and collagen fibrosis in areas of EMH can result in massive splenomegaly and hepatomegaly [9]. Subsequently, patients can experience any combination of abdominal distension, discomfort, early satiety, or weight loss [10]. Approximately 67% of patients have hepatomegaly, and virtually all patients have splenomegaly at time of diagnosis. Severe left upper quadrant pain and left shoulder pain can result from splenic infarction or perisplenitis [6].

Of all MF-associated symptoms, fatigue is the most frequent and the most burdensome. In a 2007 survey of 456 patients with MF, 84% of patients reported significant fatigue. This symptom was reported at a much higher frequency than other symptoms including pruritus (50%), night sweats (56%), arthralgias (47%), and unintended weight loss (18%). When the burden of fatigue was quantified using the Brief Fatigue Inventory (BFI), a questionnaire validated to measure fatigue levels in patients with cancer, patients with myelofibrosis had a mean BFI score of 5.2, compared to 2.2 in the general population (p < 0.0001) [11].

Psychological symptoms of MPNs have been increasingly recognized in recent years. In one cohort of patients with MPNs, self-reported distress, anxiety, and depression were prevalent with frequencies of 40%, 31%, and 12.5%, respectively [12]. In another large survey of over 1300 patients with MPNs, 23% were found to have significant reported depressive symptoms [13]. Notably, both of these studies found that the burden of psychological symptoms correlated with the presence of other MPN-associated symptoms. Sexual dysfunction, defined as problems related to sexual desire or function, is common among those with MPNs, and likely has both physical and psychological underpinnings. One study reported sexual dysfunction in 64% of patients with MPNs to some degree [14]. Symptoms were more severe in patients over age 65, or those requiring transfusions, immunomodulators, or steroids. Sexual symptoms are easily overlooked in the clinical setting but should be specifically queried and managed, as they are associated with a reduced quality of life among patients with MPNs [14].

Several groups of patients may have differential susceptibility to developing severe MPN-associated symptoms. Women with MPNs tend to experience a higher total symptom burden than men [15]. Specifically, women report more abdominal symptoms and more microvascular symptoms such as headache, fatigue, and dizziness. Despite reporting more frequent and severe symptoms, women had equivalent quality of life to men in a survey of 2006 patients with MPNs [15]. Body mass index (BMI) has also been shown to correlate with symptom burden in the setting of MPNs. Obesity is known to incite a chronic inflammatory state with increased circulating cytokines [16]. A combined analysis of two large survey studies demonstrated that obesity among patients with MPNs correlated with increased overall symptom burden as well as an increased level of nearly all individual symptoms assessed [17]. Notably, being underweight was also associated with an increased symptom burden compared to those with normal BMI.

MPN-associated symptoms can profoundly impact the ability of patients to function, both from a physical and a psychosocial standpoint, as impair self-reported QOL. In one study of 592 patients with MPNs who were working at the time of their diagnosis, 25% reported taking at least one medical disability leave as a result of their MPN [18]. In another study of 1179 patients with MPNs, 11.2% reported being medically disabled as a result of their disease [11]. Productivity at work is commonly impacted as well, as 41% of patients with MF have reported some degree of work impairment [19]. Even activities of daily living are commonly impacted by MPNs; about one-third of patients reported an inability to independently perform some activities of daily living due to their MPN symptoms [11]. In an international study of 699 patients with MPNs, 26% reported that their disease frequently caused emotional hardship [19]. Furthermore, 27% reported that their condition had a high impact on their relationship with their caregiver, and 26% reported a high impact on their family or social life. Chronic symptoms and resulting functional disturbances lead the vast majority of patients with MPNs to report feelings of impaired quality of life due to their disease. In the aforementioned surveys, 83% to 94.7% of patients with MF reported a reduced QOL due to MPN symptoms [7,19].

The presence of constitutional symptoms provides important, independent prognostic information. In an early prognostic tool developed for MF, the Dynamic International Prognostic Scoring System (DIPSS), five clinical features were identified that correlated with overall survival (OS): age older than 65 years, hemoglobin lower than 10 g/dL, white blood cell count greater than 25 x 10⁹/L, peripheral blasts ≥1%, and the presence of constitutional symptoms (defined as weight loss >10% of baseline in the preceding year and/or unexplained fever or excessive sweats persisting for more than 1 month) [20,21]. Constitutional symptoms were significantly associated with shorter survival, with a hazard radio of 1.97 (95% CI 1.62–2.40) [20]. The presence of constitutional symptoms has maintained its prognostic importance even in newer models that include sophisticated cytogenetic and molecular information, namely the DIPSS+, Myelofibrosis Secondary to PV and ET-Prognostic Model (MYSEC-PM), Mutation and Karyotype-Enhanced IPSS (MIPSS70), and MIPSS70+ version 2.0 [21–23]. The finding of constitutional symptoms strongly correlates with the presence of cytopenias, another independently adverse prognostic factor, as well as the presence of splenomegaly [11]. Interestingly, symptom improvements resulting from MF treatment do not necessarily correlate with spleen improvements, highlighting the heterogeneous factors driving MPN disease features [24].

3. Quantification of symptom burden in MF

Scales to assess and serially monitor symptom burden have become crucial tools in MF management. Mesa et al previously conducted a study of 1179 patients with MPNs in order to identify and describe the key symptoms afflicting patients with these disorders, and demonstrating their impact on function and quality of life [11]. From this, an international collaboration of MPN investigators developed and validated the first MPN-specific patient reported outcomes tool, known as the Myelofibrosis Symptom Assessment Form (MF-SAF) [25]. The MF-SAF was later modified to incorporate more vasomotor symptoms such as headache, difficulty concentrating, light headedness, and changes in mood in order to expand its applicability to ET and PV as part of the 17-item Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) [7]. The MPN-SAF is widely accepted internationally as a standard measure by which to assess MPN response, and has been validated in multiple languages including Italian, Swedish, German, French, Spanish, and Dutch [7]. The 17-question MPN-SAF was later abbreviated into the 10-question MPN Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) for ease of administration, which assesses the most symptoms deemed to be the most clinically important: fatigue, early satiety, abdominal discomfort, inactivity, concentration problems, night sweats, itching, bone pain, fever and weight loss (see Table 2) [26]. Serial monitoring of symptom burden using these tools has become an important standard of care in patients with MPNs in order to quantitatively assess response to treatment as well as monitor for signs of disease progression [27]. A ≥ 50% reduction in MPN-SAF TSS has been deemed the cutoff to define symptom response somewhat arbitrarily, though improvements that fall short of this threshold may still provide meaningful benefit to patients.

Table 2. JAK inhibitors and symptom reduction in myelofibrosis. Summary of JAK inhibitors and their effect on symptom reduction and other endpoints in myelofibrosis. EORTC QLQ-C30 = European Organization for Research and Treatment of Cancer quality of life questionnaire. BAT = best available therapy. TSS ≥ 50 = reduction in total symptom score by at least 50%. SVR≥35% = spleen volume reduction by at least 35%

Clinical Trial	Intervention	Patient Population	Results of Note	Reference
COMFORT-I	Ruxolitinib (dose based on platelet count) versus placebo	Patients with intermediate-2 or high risk MF	Reduction in total symptom score (TSS) by ≥50% at 24 weeks in 45.9% with ruxolitinib and 5.3% with placebo (p < 0.001)	[28]
COMFORT-II	Ruxolitinib (dose based on platelet count) versus best available therapy (BAT)	Patients with intermediate-2 or high risk MF	Improvement in EORTC QLQ-C30 global health status and quality of life score from baseline at 48 weeks, mean change +9.1 points with ruxolitinib versus +3.4 with BAT Improvement in EORTC QLQ-C30 role functioning score from baseline at 48 weeks, mean change +9.9 points with ruxolitinib versus −5.4 points with BAT	[29]
JAKARTA	Fedratinib 400 mg daily, versus 500 mg daily, versus placebo	Patients with higher-risk MF, regardless of prior JAK inhibitor exposure	Reduction in TSS by ≥50% at 24 weeks in 34% with fedratinib 500 mg daily dose, 36% with fedratinib 400 mg daily dose, and 7% with placebo	[33]
JAKARTA2	Fedratinib 400 mg daily	Patients with higher-risk MF with prior JAK inhibitor treatment	Reduction in TSS by ≥50% at 24 weeks in 26%	[34]
PERSIST-1	Pacritinib 200 mg twice daily versus BAT (excluding JAK inhibitors)	Patients with higher-risk MF, regardless of cytopenias	Reduction in TSS by ≥50% at 24 weeks in 25% in pacritinib arm versus 7% in BAT arm per protocol (p < 0.0001) Reduction in TSS by ≥50% at 24 weeks in 19% in pacritinib arm versus 10% in BAT arm per intention to treat protocol (p = 0.24). Reduction in TSS by ≥50% at 48 weeks in 15% in pacritinib arm versus 0% in BAT arm per intention to treat protocol (p = 0.0027).	[35]
PERSIST-2	Pacritinib 200 mg twice daily versus pacritinib 400 mg once daily versus BAT (BAT was ruxolitinib in 45%)	Patients with intermediate-1, intermediate-2, or high risk MF with platelet count ≤100,000/µL. Approximately half of patients had prior JAK inhibitor treatment in each cohort	Reduction in TSS by ≥50% at 24 weeks seen in 25% of patients treated with pacritinib (both dosing arms combined) versus 14% with BAT (p = 0.08)	[37]
SIMPLIFY-1 [38]	Momelotinib 200 mg daily versus ruxolitinib 20 mg twice daily	JAK inhibitor naïve patients with intermediate-1 (with symptoms), intermediate-2, or high risk MF	Reduction in TSS by ≥50% at 24 weeks seen in 28.4% of momelotinib group, versus 42.2% in ruxolitinib group (p = 0.98) Transfusion rate and transfusion independent rate improved with momelotinib	[37]
SIMPLIFY-2	Momelotinib 200 mg daily versus BAT (BAT was ruxolitinib in 89%)	Patients with MF with prior JAK inhibitor treatment complicated by red cell transfusion requirements or requiring ruxolitinib dose reduction due to anemia, thrombocytopenia, or bleeding	SVR ≥35% at 24 weeks reported in 7% with momelotinib versus 6% with BAT (p = 0.90) Reduction in total symptom score by ≥50% in 26% with momelotinib versus 5% with BAT (unable to test for statistical significance as no statistical significance seen in primary outcome, SVR≥35%)	[39]

4. Pharmacologic interventions and symptom reduction

Management of MF must be individualized for the specific patient, taking into account the disease risk, clinical features, and symptom burden. Allogeneic hematopoietic stem cell transplant (AlloHSCT) represents the only potentially curative treatment modality. However, the intensity of alloHSCT limits its use to quite fit, healthy patients who harbor a high enough disease risk disease to justify taking on transplant-associated risks [27]. Short of transplant, therapy for MF is largely aimed at improving symptom burden and quality of life.

4.1. JAK inhibitors

JAK inhibitors are the cornerstone of pharmacologic therapy for most patients with symptomatic MF. The main benefits of JAK inhibitors lie in their ability to decrease splenomegaly and improve constitutional symptoms. More modest benefits are seen in survival, marrow fibrosis, and mutation allele frequency, and there is likely no benefit in preventing leukemic transformation. Table 2 summarizes the symptom effects reported thus far with the approved JAK inhibitors and several JAK inhibitors still in clinical trials.

Ruxolitinib, a selective inhibitor of JAK1/2, was approved in 2011 based on two phase 3 trials known as COMFORT-I and COMFORT-II. COMFORT-I was a randomized controlled trial conducted at multiple sites across the U.S. in which 309 patients with intermediate-2 or high risk myelofibrosis were enrolled and randomized in a 1:1 fashion to ruxolitinib or placebo [28]. The primary endpoint of spleen volume reduction (SVR) of ≥35% at 24 weeks was achieved by 41.9% of patients treated with ruxolitinib, versus 0.7% with placebo. A secondary endpoint was ≥50% reduction in total symptom score measured by the MF-SAF; 45.9% of patients treated with ruxolitinib achieved this response, compared to 5.3% with placebo. With regards to specific symptoms that improved with ruxolitinib compared to placebo, notable differences were noted in scores relating to pain under left ribs (mean change from baseline −46.9% versus +62.8% in the ruxolitinib group and placebo group, respectively), early satiety (−43% versus +70.3%), night sweats (−42.1% versus +51%), itching (−42% versus +112%), bone or muscle pain (−21.2% versus +37.7%), and inactivity (−32.1% versus +60%). COMFORT-II enrolled patients across European centers, and randomized patients with intermediate-2 or high-risk MF in a 2:1 fashion to ruxolitinib or best available therapy (BAT) [29]. SVR ≥35% was again the primary endpoint, which was achieved in 28% of patients in the ruxolitinib group versus 0% in the control group. Significant improvements were noted in QOL measures, physical function, and specific symptom scores in those treated with ruxolitinib compared to BAT. Interestingly, changes in spleen size did not necessarily correlate with improvements in symptom burden. A post hoc analysis of COMFORT-I data revealed that similar degrees of symptom improvements were reported by patients with worsening spleen length and those with only mild reduction in spleen length, as compared to those with significant reductions in spleen length [24]. Long-term follow up data show that spleen responses are relatively durable but not indefinite, as median duration of SVR was 3.2 years in both COMFORT-I and COMFORT-II. Ruxolitinib did appear to have an impact on overall survival with long-term follow up [30,31]. In a pooled analysis of five-year follow up data from COMFORT-I and – II, the risk of death in those initially randomized to ruxolitinib was reduced by 30% compared to those in the control arm (median OS 5.3 years versus 3.8 years, respectively) [32]. This advantage was even more pronounced after correcting for the extensive cross-over that occurred in these trials. While ruxolitinib is generally quite well tolerated, the dosage is commonly limited by cytopenias, in particular thrombocytopenia (Grade 3–4 in 8–13%) and anemia (Grade 3–4 in 42–45%) [28,29].

Fedratinib, a multi-kinase inhibitor with selectivity for JAK2 over other JAK family kinases, was approved in the U.S. in 2019 for patients with intermediate-2 or high-risk MF, both for treatment-naïve and previously treated populations. The JAKARTA trial enrolled patients with higher-risk MF who did not have prior JAK inhibitor exposure, and randomized them to 2 doses of fedratinib (500 mg daily or 400 mg daily) versus placebo [33]. Treatment with fedratinib was associated with SVR responses in 36% of patients and 40% of patients receiving 500 mg and 400 mg doses, respectively, as compared to only 1% of patients in the placebo group. Symptom responses were reported in similar proportions – 34% and 36% of those receiving fedratinib 500 mg and 400 mg, respectively, compared to 7% of those receiving placebo. JAKARTA2 was a single-arm study of fedratinib 400 mg daily in patients with higher-risk MF who had been previously treated with ruxolitinib. Even in this second-line setting, fedratinib was associated with SVR response in 55% of patients, and a symptom response in 26% [34]. JAKARTA-2 data was re-analyzed using intention-to-treat (ITT) protocol and more stringent criteria for ruxolitinib failure. In this re-analysis, SVR was seen in 31% in the ITT population, and 30% in the stringent criteria population [35].

Several other JAK inhibitors are in development for niche populations. Pacritinib, a dual JAK2/FLT3 inhibitor, may meet a specific need for patients with thrombocytopenia. In the PERSIST-1 and −2 studies, pacritinib demonstrated superiority over BAT (which included ruxolitinib in PERSIST-2) in terms of spleen and symptom responses. However, concerns over cardiovascular toxicity and bleeding events led to a clinical hold on development of pacritinib, which has since been lifted [36,37]. Momelotinib, a JAK1/2 inhibitor, was compared to ruxolitinib in the frontline setting in the SIMPLIFY-1 trial, and compared to BAT (which was primarily ruxolitinib continuation) in the second line or later setting in SIMPLIFY-2. As frontline treatment, there were no significant differences between momelotinib and ruxolitinib in terms of symptom or spleen responses, though anemia parameters were improved with momelotinib [38]. Similarly in those previously treated with ruxolitinib, momelotinib provided no significant benefit compared to BAT in terms of SVR, although there was a suggestion of symptom benefit seen [39]. Peripheral neuropathy may be a limiting toxicity with momelotinib, and was reported in 8.4%-11% of patients treated on the SIMPLIFY-1 and −2 protocols, respectively. While most cases were low-grade and did not require treatment discontinuation, there has been 1 case of grade 3 neuropathy reported [38] Additional phase 3 studies of both pacritinib and momelotinib are underway in more selective patient populations: pacritinib versus physician’s choice is being studied for those who are JAK inhibitor naïve with platelet counts <50,000/µL (NCT03165734); and momelotinib versus danazol is being studied for those with prior JAK inhibitor exposure who are symptomatic and anemic (NCT04173494).

In practice, several considerations should be taken into account with regards to JAK inhibitor therapy. Ruxolitinib and fedratinib are both approved for MF in patients with higher-risk prognostic scores, however clinical guidelines support their use in patients with significant disease-related symptoms regardless of disease risk [27]. The choice of which JAK inhibitor to deploy in the frontline setting has become more complex in the current era of rapid drug development for MF, given the availability of newer agents with potentially less myelosuppression and newer combinations with the hope of synergy. Clinical trial participation should be strongly considered for all patients with MF when available, including in the frontline setting. Outside of a research setting, there is little data to guide the decision between ruxolitinib and fedratinib, and a future head-to-head trial is unlikely. Practical considerations include insurance reimbursement, compliance considerations (once daily versus twice daily dosing), and the potential for toxicities in the individual patient. In the COMFORT and JAKARTA studies, a similar proportion of patients discontinued treatment for toxicities (8% to 11% with ruxolitinib, and 14% to 19% with fedratinib), but specific issues differ between the two agents [28,29,33,34]. In particular, for those starting fedratinib, consideration should be given to early gastrointestinal side effects as these can be significant. Uncontrolled gastrointestinal toxicity from fedratinib has the potential to cause thiamine malabsorption and subsequent Wernicke encephalopathy in rare cases, so these complaints should be approached aggressively and thiamine levels monitored periodically [40].

4.2. Non-JAK inhibitor therapies

A better understanding of MF pathophysiology has spurred the study of many therapeutic targets outside of the JAK/STAT signaling pathway, and an explosion of clinical trials has followed. Clinicians are optimistic that some of these novel agents, or more likely combinations of these agents, will have a significant impact on outcomes including symptoms and quality of life. While a comprehensive review of novel therapies in development for MF exceeds the scope of this review, we would be remiss in not highlighting several emerging themes.

Numerous epigenetic therapies have demonstrated clinical activity in patients with MF, both as single agents and in combination with JAK inhibitors. CPI-0610 is an oral bromodomain and extraterminal motif protein (BET) inhibitor, which displaces BET proteins from chromatin resulting in repressed transcription of target genes involved in inflammatory response, namely NF-κB [41]. An ongoing phase 2 study of CPI-0610 with or without ruxolitinib has reported improvements in symptoms, spleen size, and anemia [42]. A phase 3 randomized controlled trial of ruxolitinib monotherapy versus ruxolitinib plus CPI-0610 in the upfront setting (MANIFEST-2) is beginning (NCT04603495). The histone demethylase enzyme lysine specific demethylase 1a (LSD1) represents another potential epigenetic target for MPN therapy. In an ongoing phase 2 trial in refractory MF, LSD1 inhibitor IMG-7289 improved symptoms in the majority (86%) of patients, improved spleen volume in a subset, and decreased variant allele frequencies in 33% [43]. IMG-7289 is also being studied in the settings of ET and PV (NCT04262141, NCT04081220), and a study combining this agent with ruxolitinib in patients with MF is forthcoming. DNA hypomethylating agents azacitidine and decitabine have been used in MPNs with varying results, and doses are often limited by cytopenias in this population [44,45].

Another promising strategy involves targeting other intracellular signaling pathways that are up-regulated in parallel to the JAK/STAT pathway that may concurrently drive cytokine production and constitutional symptoms. Activation of the PI3K/AKT/mTOR pathway has been shown to contribute to chemotaxis and cytokine production in MPNs. Several clinical trials investigating combinations of PI3K inhibitors and ruxolitinib are underway (NCT02718300, NCT02493530) [46]. Similarly, activation of the RAS/RAF/MEK pathway has been implicated in JAK inhibitor resistance, and RAS pathway mutations confer a negative prognostic impact in MF in terms of survival and risk of leukemic transformation [47,48]. A clinical trial of a MEK inhibitor in patients with MPNs is ongoing (NCT03326310), and another combining a MEK inhibitor and JAK inhibitor is planned. Other signal transduction inhibitors including PIM kinase inhibitors and HSP90 inhibitors are also in clinical development (NCT04176198, NCT02587598, NCT03935555).

A miscellany of agents in other therapeutic classes are also under investigation in MF. Harnessing aberrant apoptotic pathways has demonstrated clinical benefit, both alone and in combination with JAK inhibition. Interim reports from ongoing studies of BCL2/BCL-xL inhibitor Navitoclax and MDM2 inhibitor KRT-232 both demonstrated spleen and symptom improvements in the difficult-to-treat second-line setting [49,50]. Manipulating the marrow microenvironment is also a major area of study. Luspatercept, a TGFβ family ligand trap, promotes late-stage erythroid differentiation and improves anemia in a proportion of patients with MF [51]. Similarly, TGFβ inhibitor AVID200 is being studied in patients with MF for its potential to improve anemia, reduce fibrosis, and lessen symptom burden (NCT03895112). Telomerase inhibitor imetelstat has demonstrated clinical benefit in the second-line setting, with 32% of patients reporting at least a 50% reduction in total symptom score in the phase 2 study [52]. Notably, the phase 3 study of this agent will be the first in the MF field to use OS as primary endpoint, with symptom improvement and spleen volume reduction as secondary endpoints (NCT04576156).

5. Non-pharmacologic methods of MF symptom management

There has been increasing interest in studying the role of non-pharmacologic interventions in alleviating MF-related symptoms. Lifestyle modifications including physical activity, yoga, mindfulness activities, and nutrition may help maximize physical function and control certain symptoms for some patients. Patients with MF may need to adjust to certain lifestyle modifications: attention to discomfort with bending at the waist due to splenomegaly; caution with environmental exposure to infections when neutropenic; and avoiding trauma or inverted positions in setting of thrombocytopenia.

5.1. Exercise

Many studies have demonstrated the utility of various aerobic exercise programs in improving fatigue, QOL, and physical function among patients with cancer [53]. In patients with MPNs, a survey study demonstrated a positive association between physical activity and higher QOL, independent of the degree of fatigue reported [54]. In a prospective study, the Danish Knowledge Center for Rehabilitation and Palliative Care conducted an exercise intervention for 48 patients with MPNs [55]. The intervention consisted of a 5-day exercise-based rehabilitation program, followed by 12 weeks of independent exercising. From baseline to end of the study, there were no significant differences in participants’ levels of fatigue or QOL scores, however there was an improvement in their aerobic capacity from 27.2 to 33.6 mL O₂/kg/minute. Larger prospective studies would be helpful to elucidate the impact of exercise for patients with MF.

5.2. Yoga

Physical and mental health benefits of yoga programs have been reported by patients with MPNs. A qualitative study of 39 patients with MPNs explored the perceptions of patients who participated in an online yoga program [56]. Patients were asked to complete 60 minutes of an online yoga program every week for 12 weeks. Upon completion, 69.2% reported improvement in their activity level, 51.3% reported improvement in fatigue, and 35.8% reported improvement in stress reduction or achieving calm. A follow up study investigated the impact of the online yoga intervention on symptoms and serum inflammatory markers by comparing MPN patients who participated in the yoga program (n = 27) to those who did not (n = 21) [57]. Compared to the control group, the intervention group reported small improvements in sleep, pain, anxiety, and depression. A decrease in inflammatory markers TNF-alpha and IL-6 was seen among yoga participants, though conclusions were limited by the small number of patients and lack of cytokine assessments in the control group.

5.3. Nutrition

An online survey of 1329 MPN patients (24% of whom who had MF) asked respondents about their nutritional habits, supplement use, and symptom burden [58]. Patients were overwhelmingly interested in the impact of nutrition on their disease, as 96% of respondents reported willingness to modify their diet if it would help with their symptom or disease and 72% of respondents reported using nutritional supplements. Intake of alcohol, baked foods, dairy, and pasta were associated with lower total symptom burden, while intake of fast food, pre-made snacks, soda, and refined sugar were associated with higher symptom score. Symptom burden was also significantly lower in patients using amino acid supplements (2.8 vs. 3.4, p = 0.02) and N-acetylcysteine (2.4 vs. 3.4, p = 0.02). The NUTRIENT trial was subsequently started, which is a feasibility study randomizing patients with MPNs to a Mediterranean diet versus a USDA diet, and measuring dietary adherence, symptom and QOL measures, and inflammatory cytokine levels (NCT03907436). Participation in this trial is ongoing with final results pending.

5.4. Integrative oncology

Given the positive associations between non-pharmacologic interventions and clinical outcomes, there is growing interest in the role of integrative medicine to manage symptoms. Integrative oncology is a field of cancer medicine that uses evidence-based practices involving meditation, exercise, nutrition and other lifestyle modifications to complement traditional interventions [59]. The Survey of Integrative Medicine in Myeloproliferative Neoplasms (SIMM) study was conducted to assess the use of integrative medicine by MPN patients and its association with symptom burden, quality of life, depression, and fatigue [60]. A total of 858 participants were included in the analysis, which showed that decreased symptom burden was associated with aerobic activity and strength training, while increased symptom burden was associated with massage and use of support groups. Higher quality of life was reported in patients using massage and support groups, while lower quality of life was reported in patients using aerobic activity and strength training. Increase in fatigue was associated with massage therapy and breathing techniques. The authors attributed the paradoxical association of some of these integrative medicine interventions with worse outcomes to the assumption that more symptomatic patients may be more willing to seek out these services.

6. Approach to specific challenging symptoms

6.1. Fatigue

Fatigue is the most common and most severe symptom reported by patients with MPNs, and largely drives the decline in quality of life that can ensue [11]. The causes of fatigue in patients with MF are multifactorial, with contributions from aberrant cytokine production, anemia, malnutrition/cachexia, deconditioning, medications, and psychologic factors such as depression or anxiety. As a result of its complex origins, fatigue poses a major therapeutic challenge in patients with MF.

Lifestyle modifications including good sleep hygiene, exercise, nutrition, and mindfulness may help mitigate chronic fatigue symptoms for some patients. More research is needed regarding the impact of such interventions, and some relevant ongoing studies are described in the previous section.

Pharmacotherapy options to combat MF-associated fatigue are largely aimed at treating the underlying disease. JAK inhibition can help with fatigue by suppressing myeloproliferation and cytokine secretion. In the COMFORT-II study, ruxolitinib treatment resulted in a mean of −12.8% reduction in fatigue score as compared to essentially no change with best available therapy [29]. Interestingly, an exploratory analysis from the COMFORT-I study demonstrated similar improvements in fatigue scores even in those with worsening of spleen volume or minimal improvements in spleen volume, underscoring the limitations of SVR as a primary endpoint for research [24].

MF-associated anemia is a significant contributor to fatigue. As the anemia is often multifactorial in this disease, it is important to rule out any reversible causes such as iron deficiency, vitamin B12 or folate deficiencies, or hemolysis (due to a paroxysmal nocturnal hemoglobinuria clone, for example). In those with inappropriately low endogenous erythropoietin levels (i.e. <500 mU/mL), an erythropoiesis stimulating agent (ESA) may help [27]. Other adjunctive agents for anemia include danazol, or predisone plus either thalidomide or lenalidomide [27]. Luspatercept, a TGFβ superfamily ligand trap described above, has not received FDA approval for MF-associated anemia to date, but may be available for off-label use in select patients. Participation in clinical trials testing novel anemia-directed agents in patients with MF is highly encouraged.

Outside of JAK inhibition and anemia management, medication options for fatigue are limited. Attention to management of concurrent psychiatric manifestations of the disease is key, and may help improve fatigue in some as reviewed below. Stimulant medications such as methylphenidate and modafinil have been studied in patients with severe cancer-associated fatigue, with mixed results [61]. These agents have not been studied specifically in the setting of MPNs to date, and require consideration of patient comorbidities and dependency issues. Little evidence exists to support the use of vitamin or herbal supplements in treating MF-associated fatigue, and close attention should be paid to potential interactions with the patient’s prescribed therapies.

6.2. Psychiatric symptoms

Psychotherapy in general, and cognitive behavioral therapy specifically, can be helpful in managing symptoms related to cancer [62]. In terms of antidepressant or anxiolytic medications, we recommend less sedating selective serotonin receptor antagonists (SSRIs) such as citalopram, escitalopram, or fluoxetine, which may have additional benefits of increasing appetite and decreasing pruritus. For patients who struggle with insomnia, nortriptyline, amitriptyline, or mirtazapine may be good options. None of the aforementioned antidepressants interact directly with ruxolitinib or fedratinib, but potential overlapping GI toxicities should be considered for patients taking fedratinib.

6.3. Refractory splenomegaly

Extramedullary hematopoiesis resulting in splenomegaly is a hallmark feature of MF. In addition to discomfort or overt pain, severe splenomegaly can result in early satiety, weight loss, nausea, gastroesophageal reflux, dyspnea, and in extreme cases portal hypertension with resulting sequelae. JAK inhibitors are the mainstay of therapy for patients with MF and symptomatic splenomegaly, however their use is often limited by insufficient response, loss of response, or resulting cytopenias, and less often limited by medication intolerance. Management of JAK inhibitor-refractory splenomegaly is challenging. Novel agents under investigation as described above should be considered in these situations. Options outside of a clinical trial setting include hydroxyurea, interferon formulations, or JAK inhibitor re-challenge after drug holiday [63]. Surgical splenectomy or splenic irradiation may be beneficial for palliation in specific circumstances [64]. In a series of 223 patients with MF who underwent palliative splenectomy at the Mayo Clinic, relief of mechanical symptoms was reported in all patients with symptomatic splenomegaly (n = 87), and transient improvements in constitutional symptoms, portal hypertension symptoms, and red cell transfusion dependence were described in some patients [65,66]. However, these temporary benefits are hampered by significant peri-operative morbidity and mortality rates of 31% and 9%, respectively, with adverse effects driven by thrombosis, bleeding, infection, and accelerated hepatomegaly. Low-dose splenic irradiation may also provide transient benefit in spleen size and associated symptoms, but effects are short-lived (median 6 months in one series) and toxicities such as cytopenias and nausea are frequent [67,68]. Another important consideration is the impact of spleen-directed therapy on clinical trial participation, as many studies will exclude patients after splenectomy and/or splenic irradiation. Given all of these considerations, spleen-directed surgical or radiation options should only be deployed if no other appropriate medical options exist, and only after careful discussion with the patient.

6.4. Pruritus

Pruritus, particularly after exposure to warm water (aquagenic pruritus), is one of the most common symptoms reported by patients with PV [11,69]. Pruritus is relatively common in those with MF as well, with series reporting anywhere from 16% to 50% incidence in this setting [26,70]. Aquagenic pruritus is described by patients as an intense itching, tingling, stinging, or burning sensation triggered by contact with water, especially warm water, without visible skin lesions [69]. Aquagenic pruritus can be debilitating from both a physical and a psychosocial perspective; 15% of patients with PV rate it as ‘unbearable,’ and in extreme cases can prohibit bathing entirely [69].

The cause of pruritus in patients with MPNs is not entirely clear, and is likely multifactorial. Contributors may include release of histamine, fibrinolytic factors, and prostaglandins from mast cells, release of certain growth factors or pro-inflammatory cytokines from activated granulocytes, and release of adenosine diphosphate and prostaglandins from erythrocytes [70–73]. Improvements in pruritus noted with aspirin use suggests that prostaglandins are at least one key driver of this symptom [71]. Review of a series of consecutive patients with MF treated at the Mayo Clinic discovered that those with pruritus were more likely to have leukocytosis or a JAK2 V617F mutation [70]. Homozygosity for JAK2 V617F has been associated with pruritus compared to the heterozygous state [74,75]. The presence of pruritus was not associated with prognostic risk category or leukemic transformation [70]. Interestingly, plasma levels of 20 cytokines commonly increased in patients with MPNs were measured and not found to correlate with a history of pruritus [70]. It is important to consider the presence of a concurrent mast cell disorder in those with pruritus, as MPN is one of the most frequent associated hematologic neoplasms accompanying systemic mastocytosis (SM) [76,77]. SM should be considered particularly when a skin rash is present or flares in response to non-aquagenic triggers are noted.

The bulk of the literature regarding management of aquagenic pruritus comes from the PV setting, but can be extrapolated to those with other MPNs. Lifestyle modifications like bathing with cool water, patting dry, and frequent skin moisturizing can help to some extent. JAK inhibitors are quite effective treatments for MPN-associated pruritus. JAK inhibition likely helps both by inhibiting cytokine release and preventing mast cell degranulation [78]. In the COMFORT-I trial of ruxolitinib versus placebo in patients with MF, those treated with ruxolitinib experienced a reduction of their itching by a mean of −43%, while those treated with placebo had an increase in their itching by a mean of +111% [28]. Other cytoreductive agents such as interferon formulations and hydroxyurea may be helpful as well in some cases. Low-dose aspirin, with its inhibition of prostaglandin synthesis, improves pruritus for many [71]. If symptoms persist, twice daily low-dose aspirin dosing may provide further relief. In the MF setting, however, thrombocytopenia and bleeding tendency may limit the ability to use aspirin, particularly at higher doses. Antihistamines such as H1 and H2 receptor antagonists are commonly prescribed, but results vary widely with some reports describing no improvement and others reporting symptom control in up to 47% of patients [79–81]. Selective serotonin reuptake inhibitors (SSRIs) have also been used with some success. In one series, 10 MPN patients with intractable pruritus were given paroxetine 20 mg/day (n = 9) or fluoxetine 10 mg/day (n = 1) [82]. Eight of those patients (80%) had significant improvement or resolution of their pruritus within 48 hours. Phototherapy – both narrow band ultraviolet B (UVB) phototherapy and oral psoralen photochemotherapy (PUVA) – may help with refractory pruritus. In one series of 10 patients with refractory pruritus associated with PV, 8/10 experienced complete resolution of their itching with UVB phototherapy [83].

7. Conclusion

Patients with MF suffer from a unique constellation of symptoms that impair physical and psychosocial function and significantly impact quality of life. Managing these symptoms presents a considerable clinical challenge. JAK inhibitor therapy can improve MF-associated symptoms for some, however the effects are insufficient or short-lived for many and therefore significant areas of unmet medical needs remain. A deeper understanding of the disease pathophysiology has ignited the development of many promising new agents; participation in clinical trials of these novel agents or combinations should be considered for symptomatic patients whenever possible.

8. Expert opinion

Myelofibrosis is a complex hematologic malignancy that necessitates a multi-pronged and individualized approach to therapy. Optimal management should be fourfold: (1) treat the underlying disease (i.e. JAK inhibitor and/or investigational therapies), (2) consider lifestyle interventions (i.e. exercise, nutrition), (3) focus attention on the psychologic and social manifestations of the disease, and (4) deploy adjunct treatments to address specific, bothersome symptomatology that persists despite all of the above measures. The best outcomes for patients will occur when all four of these areas are addressed simultaneously. Ideally, this complex management would occur within a multidisciplinary team, which might involve any combination of hematologists, oncologists, palliative care specialists, psychologists, psychiatrists, physical and occupational therapists, and social workers.

Research describing the pathology driving MF continues to plow forward, and more effective therapies are following quickly in the wake. A second JAK inhibitor, fedratinib, was approved in 2019, offering a much-needed additional therapeutic option for patients. Many other agents in development hold the potential to fill important unmet needs that still exist for this disease. JAK inhibitors pacritinib and momelotinib may help treat patients with thrombocytopenia and anemia, respectively. Novel therapeutic classes such as BET inhibitors, anti-apoptotic protein inhibitors, MDM2 inhibitors, epigenetic agents (i.e. LSD1 inhibitors), and many others in development may be effective against JAK inhibitor-refractory disease, and may help deepen responses in combination with JAK inhibitors. Novel combinations that simultaneously target both the malignant hematopoietic stem cell and the drivers of aberrant fibrogenesis will likely provide the greatest impact on this disease. There is significant, warranted optimism in the field that many of these newer agents currently under investigation will transform the lives of patients with MF, but there is still a long way to go. In light of the preponderance of promising agents in development at the moment, it is in the best interest of most patients to consider clinical trial participation whenever possible. This includes the front-line setting, where there are now several ongoing randomized controlled trials available for patients with higher-risk MF.

As the field moves toward combination therapies, the tolerability of these combinations should be scrutinized carefully. Certain toxicities (i.e. thrombocytopenia) may be additive with some combinations, and may limit the safety or tolerability of some strategies. As any MF-directed therapy may optimistically be used for a period of years, even low-grade toxicities may adversely affect quality of life. As such, attention must be paid to even grade 1 and 2 toxicities that are sometimes minimized by clinicians but may be very important to many patients.

Importantly, the definition of ‘treatment success’ for patients with MF deserves further discussion. The primary endpoint in most MF interventional studies to date is spleen volume reduction of ≥35% from baseline. This surrogate endpoint is largely arbitrary, and fails to adequately capture the outcomes that matter most in this disease: quality of life and length of life. For patients treated with JAK inhibitors, the lack of association between spleen length reduction and symptom improvement suggests that responses can come in different ‘flavors’ for different patients, a recognition with implications for both clinical practice and drug development. Fortunately, validated tools now exist to quantify and serially monitor changes in symptoms and QOL in patients with MF. These assessment tools, in addition to overall survival, are increasingly recognized as key endpoints in clinical study design. Despite the challenges that continue to face the field, the pace of research surrounding MF treatment offers considerable cause for optimism.

Article highlights

• Myeloproliferative neoplasms are pathologically complex disorders associated with including systemic inflammation, extramedullary hematopoiesis, and eventual bone marrow failure. The associated symptomatology is often devastating for patients, who may experience profound fatigue, disability, and impaired quality of life.

• Symptoms should be quantified serially by a well-validated tool such as the MPN-SAF TSS (MPN-10) to monitor for progression and assess response to therapy.

• JAK inhibitors have revolutionized symptom management for patients with MF. However, the effects of JAK inhibitor therapy may be insufficient or short-lived for many. In addition, JAK inhibitor use may be limited by toxicities, most commonly cytopenias.

• Going forward, the most effective therapies to manage MF symptoms will likely address the two major underlying mechanisms of disease—the malignant hematopoietic stem cell and aberrant fibrogenesis.

• Traditionally, the primary endpoint for clinical trials in MF has been spleen volume reduction, a surrogate endpoint that does not necessarily predict for the most important outcomes—length of life and quality of life. We propose that future MF trials focus on improving overall survival, symptom scores, and quality of life.

Declaration of interest

K Pettit received payment from advisory board participation for CT Biopharma and PharmaEssentia. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

A reviewer on this manuscript has disclosed honoraria from Incyte, Celgene (now BMS), CTI Biopharma, Sierra Oncology and Kartos; and research support from Incyte, Celgene (now BMS), Constellation, Kartos and CTI Biopharma. All other peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.