Addressing Symptom Burden in Myeloproliferative Neoplasms

Best Practice & Research Clinical Haematology xxx (xxxx) xxx
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Best Practice & Research Clinical Haematology

journal homepage: www.elsevier.com/locate/issn/15216926
Addressing symptom burden in myeloproliferative neoplasms

Douglas Tremblay a, Ruben Mesa b, *
a
Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
b
Mays Cancer Center at UT Health San Antonio Cancer Center, San Antonio, TX, USA
A R T I C L E I N F O A B S T R A C T
Keywords: Patients with myeloproliferative neoplasms (MPNs) suffer from often debilitating constitutional
Myelofibrosis symptoms that negatively impact quality of life to a degree similar to patients with metastatic
JAK inhibitor solid tumors. Despite heterogeneity in the breadth and severity of symptoms in MPNs, research
Systemic symptoms
into symptom assessment has led to the creation of well validated patient reported outcome tools,
Quality of life
including the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score.
Currently available pharmacologic therapies, particularly JAK inhibitors, result in substantial
reduction in symptom burden for patients with myelofibrosis, as well as select patient with
polycythemia vera and essential thrombocythemia. Non-pharmacologic therapies including yoga
and meditation have also been investigated. In this review, we focus on the pathogenesis and
assessment of constitutional symptoms in MPNs. We detail currently available therapies to
address symptom burden and highlight several novel agents in development. We end by dis
cussing unmet needs and exploring the future of symptom assessment and treatment in MPNs.
1. Introduction
The Philadelphia chromosome negative myeloproliferative neoplasms (MPNs) are chronic hematologic malignancies that are
clinically interconnected and share biologic features including overactivation of the JAK-STAT pathway [1]. The three most common
MPNs are essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF). MPNs share phenotypic fea
tures including panmyelosis, extramedullary hematopoiesis leading to splenomegaly, an increased risk of leukemic progression, and
debilitating constitutional symptoms [2]. MPN-related symptoms include fevers, night sweats, fatigue, weight loss, as well as vascular
symptoms (headaches, difficulty concentrating), and consequences of splenomegaly (abdominal pain/fullness, early satiety) [3]. These
symptoms significantly and negatively impact quality of life among MPN patients and interfere with activities of daily living and work
productivity [4].
The biological underpinnings are poorly understood but are largely a consequence of the MPN pro-inflammatory state, charac
terized by the elaboration of multiple cytokines [5]. Accurate assessment of these complex and heterogenous symptoms has evolved
over the years and now includes validated MPN Patient Reported Outcome (PRO) tools that are integrated into clinical practice as well
as clinical trial endpoints for novel therapeutic efficacy assessment. Currently available treatments for MPN are aimed at ameliorating
symptom burden and improving quality of life, among other goals.
In this review, we focus on symptom burden in MPNs by first describing our current pathobiologic understanding of contributing
* Corresponding author. FACP Executive Director Mays Cancer Center at UT Health San Antonio MD Anderson Mays Family Foundation
Distinguished University Presidential Chair Professor of Medicine Office, USA.
E-mail address: mesar@uthscsa.edu (R. Mesa).
https://doi.org/10.1016/j.beha.2022.101372
Received 25 July 2022; Received in revised form 6 August 2022; Accepted 8 August 2022
Available online 12 August 2022
1521-6926/© 2022 Elsevier Ltd. All rights reserved.
Please cite this article as: Douglas Tremblay, Ruben Mesa, Best Practice & Research Clinical Haematology,
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D. Tremblay and R. Mesa Best Practice & Research Clinical Haematology xxx (xxxx) xxx
factors to systemic symptoms in MPNs. We then move to detail modern symptom assessment using validate PROs and then explore
interventions, both pharmacologic and non-pharmacologic, that are aimed at improving symptoms in MPNs. Throughout, we will
judge therapeutic intervention on their ability to reduce symptom burden; other efficacy measures such as spleen volume reduction
and survival are outside the scope of this review. We end by surveying the future directions in MPN symptom assessment and
treatment.
2. Symptom burden in MPNs
There is substantial heterogeneity in both the severity and types of symptoms MPN patient endure, making quantification chal
lenging. The first attempt at quantifying the MPN symptom profile was an international internet-based survey of 1179 MPN patients.
This study revealed a heavy burden of disease, with fatigue reported in 81%, pruritis in 52%, night sweats in 49%, bone pain in 44%,
fevers in 14%, and unintended weight loss in 13%. Symptom burden was highest in MF patients, but was still considerable in the PV
and ET patients surveyed. This study, performed in the era before JAK inhibition, was also notable in that 35% of patients required
assistance with activities of daily living and 11% reported medical disability because of their MPN [3]. In fact, the burden of symptoms
has been shown to be similar to patients with advanced solid malignancies. A study utilizing the European Organisation for Research
and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) PRO found similar limitations in physical functioning,
quality of life, fatigue, and financial toxicity in MPN patients as those with metastatic cancer [6]. In addition to heterogeneity in the
types and severity of symptoms, the kinetics of symptom burden is also not consistent between patients. In a cohort study of 1443 MPN
patients, some symptoms (concentration, insomnia, night sweats, overall quality of life) worsened over time while other symptoms
were not impacted by disease duration [7]. These present substantial challenges for the accurate measurement of symptoms in MPN
patients.
3. Developing the MF-SAF and MPN-SAF
The first MPN-specific PRO was published in 2009 and utilized data from the previously described internet-based survey of over
Fig. 1. Timeline and individual components of MPN symptom assessment forms. There has been substantial evolution of these PROs over time,
although many core symptoms are measured in all or nearly all iterations.
D. Tremblay and R. Mesa
Table 1
Summary of symptom efficacy with approved agents in MPNs.
Agent Mechanism of action MPN Trial Setting PRO TSS50% Other symptom-related efficacy measures
Ruxolitinib JAK1/2 inhibitor MF COMFORT-I JAKi naïve MF-SAF 46% Mean improvement in the TSS from baseline to week 24 was
[28] − 46%
COMFORT-II JAKi naive EORTC- QLQ-C30 – Changes in specific symptom scores at week 48: Fatigue − 12.8, Pain − 1.9,
[30] Dyspnea − 6.3, Insomnia − 12.3, and appetite loss − 8.2
PV RESPONSE R/R to MPN-SAF 49% Itching and night sweats were most improved symptoms,
[13] − 94.9% and − 99.5% from baseline, respectively
RESPONSE-2 R/R to MPN-SAF 45% Mean improvement in TSS from baseline to week 28 was − 45%
[45]
RELIEF [46] with persistent MPN-SAF cytokine 43% PGIC “very much improved” or “much improved” in 48%
symptoms symptom cluster
ET MAJIC-ET [47] R/R to MPN-SAF 29%
Fedratinib JAK2/FLT3 inhibitor MF JAKARTA [12] JAKi naïve MF-SAF 36%
MF JAKARTA-2 Previous MF-SAF 27% Baseline platelet count did not impact symptom reductions
3
[32] ruxolitinib
Pacritinib JAK2/IRAK1 MF PERSIST-1 JAKi naïve MPN-SAF 19% Evaluable patient TSS50% was 36%
inhibitor [56]
MF PERSIST-2 Prior JAKi allowed MPN-SAF 32% Means TSS change at week 24 was − 41%
[34] Platelet <100x109/ PGIC “very much improved” or “much improved” in 57%
L
Pegylated Immunomodulation PV/ MPN-RC 111 R/R MPN-SAF – Mean TSS change − 3.6 from baseline to 3–12 months
interferon ET [49]
Best Practice & Research Clinical Haematology xxx (xxxx) xxx

MPN-RC 112 Newly diagnosed MPN-SAF – Mean TSS change 0.6 from baseline to 3–12 months
[49]
HU Antimetabolite PV/ MPN-RC 112 Newly diagnosed MPN-SAF – Mean TSS change 0.7 from baseline to 3–12 months
ET [49]
EORTC-QLQ-C30; European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30; ET = essential thrombocythemia; HU = hydroxyurea; JAKi = JAK
inhibitor; MF = myelofibrosis; MF-SAF = myelofibrosis symptom assessment form; MPN-RC = Myeloproliferative Neoplasm Research Consortium; MPN-SAF = myeloproliferative neoplasm symptom
assessment form; PGIC = patient global impression of change; PV = polycythemia vera; R/R = relapsed/refractory; TSS = total symptom score; TSS50% = TSS reduction of at least 50%.
MPN patients, including 458 patients with MF. The MF Symptom Assessment Form (MF-SAF) includes 20-items that were reported in
>10% of MF patients, grading on a 0–10 scale. The MF-SAF responses were shown to highly correlated with the Memorial Symptom
Assessment Scale and the Brief Pain Inventory and was validated against a prospective trial of MF patients [8]. To expand the MF-SAF
to other MPNs including ET and PV, the MPN-SAF was developed. This 27-item assessment tool was validated in an international study
of 402 MPN patients, including 161 with ET, 145 with PV, and 96 with MF. There was strong correlation between individual items on
the MPN-SAF and on the EORTC QLQ-C30. In addition, there was high correlation between patient responses and enrolling physician
blinded opinion of symptoms [6]. An updated version of the MPN-SAF reduced the number of questions from 27 to 10 which assess
concentration, early satiety, inactivity, night sweats, pruritis, bone pain, abdominal discomfort, weight loss, and fevers. The MPN-SAF
Total Symptom Score (TSS), which is calculated as the total score from these questions rated from 0 to 10, has demonstrated strong
correlation with overall quality of life and has excellent internal consistency [9]. Additional iterations of the MPN-SAF TSS have been
made to include a fatigue item [10,11], modified to include only six elements [12], and clustered into splenomegaly, hypervelocity,
and cytokine-related symptoms [13]. The evolution of MPN-specific PROs is shown in Fig. 1.
The MPN-SAF TSS has been widely adopted in clinical trial response criteria, where a decrease of 50% or more (TSS50%) is
considered a symptom response by International Working Group- Myeloproliferative Neoplasms Research and Treatment (IWG-MRT)
and European LeukemiaNet (ELN) consensus criteria [14]. In addition, the most recent National Comprehensive Cancer Network
(NCCN) guidelines recommend MPN-SAF TSS assessment for MF patients at baseline and during the treatment course in order to
quantify symptomatic response to treatment [15].
4. Pathobiology of systemic symptoms in myeloproliferative neoplasms
Inflammatory cytokines are elevated in patients with MPNs, at least in part a consequence of dysregulating JAK-STAT signaling
[16]. There are also additional cellular pathways including NF-κB that are responsible for maintaining cytokine overproduction in MF
[17]. Multiple lines of evidence link cytokine elevations to constitutional symptoms in MPNs. Numerous inflammatory cytokines are
elevated compared in PMF patients compared with normal, including IL-1β, IL-6, IL-8, and IL-10. In a study of 127 PMF patients,
elevations in IL-8 were independently correlated with constitutional symptoms [18]. Interestingly, in solid cancer patients, elevations
in IL-6 are associated with fatigue and depression [19,20]. In PV patients, cytokines are also nearly universally elevated, with IL-4
elevations being correlated with microvascular symptoms [21]. Further evidence of the link between inflammatory cytokines and
MPN symptoms is provided by a post-hoc analysis of the phase 3 COMFORT-I study. When controlled for multiple factors including
age, sex, and body mass index (BMI), 5 cytokines were significantly associated with changes in MPN-SAF TSS: VCAM1, LEPTIN,
TNFRII, TIMP1, and B2MICG [22]. In a separate analysis of the COMFORT-II study, lower ferritin levels were associated with itching
and night sweats, higher IL1RA were associated with loss of appetite and higher CD40L, Pal1, and RANTES levels were associated with
insomnia [23]. Despite these correlations, cytokine analysis is not currently incorporating into the routine symptom management of
MPN patients.
Spleen related complaints, such as early satiety and left upper quadrant fullness, are a direct result of splenomegaly, which itself is
caused by multiple factors including extramedullary hematopoiesis due to abnormal trafficking of hematopoietic stem cells (HSCs)
from a dysregulated bone marrow microenvironment [24]. C-X-C motif chemokine ligand 12 (CXCL12), normally responsible for
maintenance of HSCs in the bone marrow, is truncated in patients with MPNs, leading to mobilization of HSCs and migration to the
spleen [25]. Several inflammatory markers are also associated with splenomegaly in MPN patients [18], although the mechanistic link
between inflammation and splenomegaly remains to be fully elucidated.
5. Pharmacologic interventions
JAK inhibitors are the primary pharmacologic tool to improve symptoms in MPN patients. Although currently available JAK in
hibitors have limited ability to prevent progression, they have undoubtedly improved the quality and likely quantity of life for patients
with MPNs, in particular MF [26]. Other pharmacologic interventions have been evaluated from a symptom perspective in PV and ET,
namely cytoreductive therapy. Table 1 describes symptom outcomes of approved MPN pharmacologic therapies, which are detailed
below.
5.1. Ruxolitinib in MF
Ruxolitinib is a JAK1/JAK2 inhibitor that was approved for the treatment of intermediate or high-risk MF patients based on the
combined results of the COMFORT I and –II studies [27]/The COMFORT I study was a phase 3, randomized, double-blind placebo
controlled study of ruxolitinib in 309 intermediate-2 or high risk MF patients. The trial met its primary endpoint of spleen volume
response reduction of greater than 35% (SVR35%), which occurred in 41.9% of ruxolitinib treated patients versus 0.7% in the placebo
arm. The proportion of patients who achieved TSS50% was 45.9% in the ruxolitinib versus 5.3% in the placebo group. The mean
improvement in the TSS from baseline to week 24 was 46.1%, while patients in the placebo group had a mean worsening of 41.8%.
Breaking this down further, ruxolitinib-treated patients had improvement in individual symptoms, including abdominal discomfort,
pain under left ribs, early satiety, night sweats, itching, bone or muscle pain and inactivity [28]. In an exploratory analysis, the degree
of spleen volume reduction with ruxolitinib correlated with improvement in TSS, EORTC Global Health Status, and Patient Global
Impression of Change (PGIC). Specifically, patients in the ruxolitinib arm who achieved a SVR35% experienced the greatest
improvement in these symptomatic assessments. Importantly, patients who experienced grade 3/4 anemia had similar TSS
improvements as those who did not experienced anemia [29]. This suggests that symptomatic benefits, including in fatigue, may be
achieved despite worsening anemia with ruxolitinib.
The COMFORT II study, which randomized patients to either ruxolitinib or best available therapy (BAT), enrolled 219
intermediate-2 or higher MF patients. There was a significant improvement in quality of life and role functioning, as measured using
the EORTC QLQ-C30, in the ruxolitinib group versus BAT. At week 48, there was also significant reduction in MF specific symptoms
including appetite loss, dyspnea, fatigue, insomnia, and pain with ruxolitinib while patients in the BAR group had worsening of most of
these symptoms. Similarly, Functional Assessment of Cancer Therapy–Lymphoma (FACT-Lym) and FACT trial outcome index (FACT-
LOI) improved and stabilized in the ruxolitinib arm while they worsened in the BAT arm [30].
5.2. Fedratinib
Fedratinib is a JAK2/FLT3 inhibitor that was FDA approved for the treatment of MF in August 2019 based on the JAKARTA study,
in JAK inhibitor naïve patients, as well as the JAKARTA-2 study in patients previously treated with ruxolitinib [12,31]. In the
JAKARTA study, 289 patients were randomized to 400 mg or 500 mg of fedratinib or placebo. Using the modified MF-SAF TSS, 36% of
patients in the 400 mg group, 34% in the 500 mg and 7% of patients in the placebo group achieved TSS50%. Changes in TSS overtime
showed a steady decline in percent change starting at 4 weeks and continuing to 24 weeks in the fedratinib arms [12]. In the
JAKARTA-2 study, 97 patients previously treated with ruxolitinib and either resistant or intolerant after at least 14 days of treatment.
In the 90 patients evaluable for symptom response, 26% achieved a TSS50% after 6 cycles [31]. In an updated analysis of JAKARTA-2
using more stringent definition of relapsed/refractory/intolerant to ruxolitinib, 27% of patients had a TSS50%. Of note, these relapsed
and refractory definitions relied entirely on spleen metrics and not on lost or lack of symptom response [32]. It is important to evaluate
thiamine levels as fedratinib has previously been associated with Wernicke’s encephalopathy [33]. Although occasionally used in the
front line setting, fedratinib is more commonly utilized as a second line therapy. However, for patients who do not have a symptom
response with ruxolitinib, there is insufficient data to quantify the symptom-specific efficacy of fedratinib.
5.3. Pacritinib
Pacritinib is a JAK2/IRAK1 inhibitor and is the most recently approved agent for the treatment of MF. Unlike ruxolitinib and
fedratinib, pacritinib is approved for patients with severe thrombocytopenia, defined as a platelet count less than 50 x 109/L. Approval
was primarily based on the PERSIST-2 study, which included 311 patients with MF and a platelet count of less than 100 x 109/L,
including patients who were previously treated with ruxolitinib, and randomized them to pacritinib 400 mg daily, 200 mg twice daily
or best available therapy which could have included ruxolitinib. Focusing on symptom improvements, TSS50% (measured by MPN-
SAF TSS v2.0) was obtained in 32% of pacritinib 200 mg twice daily treated patients and only 14% of patients in the BAT arm. Of
note, of BAT treated patients who received ruxolitinib, only 19% had achieved a TSS50%. Pacritinib twice daily also resulted in “much-
improved” or “very much-improved” PGIC in 57% of patients compared with 28% of BAT treated patients [34]. In a subset analysis
including only patients with a platelet count of less than 50 x 109/L from PERSIST-2 and PERSIST-1, which evaluated pacritinib in the
JAK inhibitor naïve setting, similarly showed superior TSS50% rates for pacritinib compared to BAT, 25% versus 8.1%, respectively
[35]. Pacritinib represents a welcomed addition to the MF symptom targeting therapeutic armamentarium since it can be safely
administered in patients with a platelet count less than 50 x 109/L, a group of patients that are ineligible for ruxolitinib or fedratinib.
5.4. Future therapies in MF
There are several pharmacologic agents in development for MF that may significantly improve the symptoms of patients with MF.
Momelotinib is a JAK2 inhibitor that also has a unique mechanism of action by additionally antagonizing activin A receptor type I
(ACVR1), leading to decreased hepcidin expression and increased iron availability to participate in erythropoiesis [36]. Momelotinib
has been evaluated in multiple clinical trials both in the JAK inhibitor naïve and ruxolitinib refractory setting. In the SIMPLIFY-1 study,
JAK inhibitor naïve patients were randomized to either ruxolitinib or momelotinib. Although the study met criteria for non-inferiority
for the primary endpoint of spleen volume reduction, the key secondary endpoint of TSS50% occurred significantly less in the
momelotinib group compared with ruxolitinib (28% vs 42%, p = 0.98 for non-inferiority) [37]. However, in SIMPLIFY-2, where
patients who had previously been treated with ruxolitinib were randomized to momelotinib or BAT which could have included
ruxolitinib, the TSS50% rate was significantly higher in the momelotinib arm compared to BAT (26% vs 6%, p = 0.0006) [38]. Of note,
in both of these trials, momelotinib led to increased rates of red blood cell (RBC) transfusion independence compared with the control
arm. Recently, the results of the MOMENTUM were reported. This study randomized anemic MF patients previously treated with
ruxolitinib to either momelotinib or danazol. The primary endpoint of this study was TSS50% and occurred in 24.6% of momelotinib
treated patients and 9.2% of danazol treated patients (p = 0.0095 for superiority). The median decrease in TSS from baseline was 9.36
in the momentum arm compared with 3.13 in the danazol arm [39]. Momelotinib may therefore be an effective symptom reducing
therapy in patients with MF who have anemia.
In addition to JAK inhibitor, combination strategies are being evaluated which may increase the number of patients who have a
symptom response in MF. For instance, pelabresib is a BET inhibitor which dampens inflammatory cytokine production when com
bined with ruxolitinib in preclinical models [40]. In the phase 2 MANIFEST study, the combination of pelabresib and ruxolitinib in JAK
inhibitor naïve patient led to a TSS50% of 57% [41]. In addition, the BCL-2/BCL-xL inhibitor navitoclax has been evaluated in patients
who have had a suboptimal response to ruxolitinib and demonstrated a TSS50% of 30% [42]. In patients who no longer benefit from
ruxolitinib, additional agents are being explored outside the JAK-STAT pathway. For instance, the telomerase inhibitor imetelstat at a
dose of 9.4 mg/kg produced a TSS50% response rate of 32%, in addition to being associated with a prolonged overall survival [43].
Finally, bomedemstat, an LSD1 inhibitor, has been explored in the JAK inhibitor relapsed/refractory setting and shown that 30% of
patients had a TSS50% [44]. Many of these agents, including other drugs targeting PI3k, MDM2, nuclear export, and CD123 may be
part of the future therapeutic arsenal to address symptoms complaints. With the availability of novel therapies outside of JAK inhi
bition, it will be important to understand not only the impact on TSS50%, but also the duration of response. There may also be dif
ferential response based on specific symptoms, allowing clinicians to design a treatment regimen to address spleen related symptoms,
for example, versus a different treatment which may be more geared towards fatigue.
5.5. Ruxolitinib in PV and ET
As demonstrated above, ruxolitinib can significantly improve symptoms in patients with MF and has also been explored in other
MPNs. The phase 3 RESPONSE trial randomized PV patients with splenomegaly who had an inadequate response or were intolerant to
hydroxyurea (HU) to either ruxolitinib or standard therapy, which was largely HU. The primary endpoint of hematocrit control and
SVR35% was met in 21% of patients in the ruxolitinib group and only 1% of those in the standard therapy arm. Importantly, 49% of
patients in the ruxolitinib group had a TSS50%, compared to 5% of patients treated with standard therapy. Among MPN symptoms,
itching and night sweats were the most dramatically improved (− 94.9% and − 99.5% from baseline, respective) [13]. The
RESPONSE-2 trial was a separate open-label phase 3b study that included PV patients without splenomegaly. Similar to RESPONSE,
this study showed that the median percentage decrease in TSS was 45.3%. There were similar improvements in other symptom scoring
metrics such as the Pruritus Symptom Impact Scale, PGIC, EuroQol-5D-5L, and the Work Productivity and Activity Impairment [45].
Given that RESPONSE and RESPONSE-2 were open-label studies, the RELIEF trial was created. This double-blind, double-dummy
phase 3b study enrolled PV patients on a stable dose of HU but had persistent PV-related symptoms and randomized 1:1 to ruxolitinib
or HU. The primary endpoint of 50% reduction in TSS-C at week 16 was achieved in 43.4% of ruxolitinib patients and 29.6% of patients
treated with HU, a difference that trended towards statistical significance (p = 0.139). However, itching was significantly improved in
patients treated with ruxolitinib versus HU. The fact that nearly one-third of patients who were maintained on HU achieved a symptom
response was unanticipated, which may have been secondary to a placebo effect or an overreporting bias of symptoms during
screening. To evaluate the later possibility, the authors performed an analysis of patients who had a stable TSS-C between screening
and baseline visit and found that these patients were more likely to achieve a 50% reduction in TSS-C [46]. This study suggests that
there may be benefit to ruxolitinib for specific symptom control, particularly pruritis, in PV patients who are being treated with HU.
Finally, ruxolitinib has been explored in ET in the MAJIC-ET trial where 110 patients resistant or intolerant to HU were randomized
to ruxolitinib versus BAT. While there was no difference in the rates of complete response between the arms, the maximum percentage
TSS reduction at any point during the first 12 months was significantly higher in the ruxolitinib group. However, the overall TSS50%
rate did not different between the two arms. Similar to the PV experience, pruritis was significantly improved with ruxolitinib
compared with BAT [47].
5.6. Other cytoreductive therapy in PV and ET
HU and pegylated interferon alfa-2a (peg-IFN) after two cytoreductive agents used in the first and second line for patients with PV
and ET in order to reduce thrombotic burden [48]. The highest quality evidence on the symptomatic impact on these two agents comes
from a post-hoc analysis of the MPN Research Consortium (MPN-RC) 111 and 112 trials, which evaluated HU versus peg-IFN in early
disease and peg-IFN in HU resistant/intolerant patients, respectively. In these studies, patients completed the MPN-SAF and EORTC
QLQ-C30 through 12 months after initiation of treatment. At 12 months, TSS50% was achieved in 32% of peg-IFN complete responders
and 20% of partial responders in the MPN-RC 111 trial and 19% and 18% of complete and partial responders in the MPN-RC 112 trial,
respectively. In terms of HU, 27% and 22% of complete and partial responders, respectively, achieved a TSS50%. More complete and
partial responders had TSS50% as compared with non-responders, however most responders did not have clinically significant im
provements in symptoms burden. As expected, patients with a high symptom burden (defined as a TSS ≥20) experienced a greater
likelihood of symptom reduction than less symptomatic patients. In fact, symptom burden worsened between 3 and 12 months in
patients with low baseline symptom burden in both HU and peg-IFN treated patients, which may be a consequence of treatment related
toxicities being worse than their baseline symptoms [49].
This study highlights the limitations of HU and peg-IFN on significantly impacting symptoms. In particular, patients with low
symptom burden may have worsening of their symptoms as a result of cytoreductive therapy and this should be highlighted when
counseling patients on the expected benefit of treatment.
5.7. Future therapies in PV and ET
Several novel therapies are being explored in PV which may improve symptoms of patients with PV and ET. The LSD1 inhibitor
bomedemstat is also being tested in patients with ET, in addition to those with MF. In the ET study, 44 patients who are resistant or
intolerant to at least one standard therapy were treated with bomedemstat to target a platelet count of 200–400 x 109/L. For patients
treated for at least 12 weeks, 91% were able to obtain a platelet count of less than 400 x 109/L. In the 23 patients who had a baseline
TSS of ≥10, 69% showed reductions and 38% had reductions of greater than 10 points. Fatigue in particularly showed reductions with
bomemdemstat treatment over time, from a median of 5 at baseline to 3 at week 24 and 1 at week 48 [44]. A phase 3 study in ET is
being planned.
In PV, among the most exciting therapeutic developments have been hepcidin modulating agents. Fatigue in PV patients may
because, in part, by iron deficiency which is a consequence of increased iron utilization and exacerbated by frequent phlebotomies. In
addition, therapeutic phlebotomies themselves can have a negative impact on quality of life in some PV patients. Rusfertide is a
hepcidin mimetic that functions to close ferroportin, depriving the bone marrow of iron while trapping it in macrophages allowing for
non-cytoreductive hematocrit control [50]. In PV, rusfertide has been explored in two phase 2 studies where it essentially eliminates
the need for therapeutic phlebotomy. In one study that enrolled PV patients with both low and high-risk disease and who required
frequent phlebotomy (≥3 phlebotomies in 6 months prior to enrollment), rusfertide was found to induce a steady decline in TSS scores
overtime from a mean of 15.2 at baseline to 11.4 at week 28. In particular, problems with concentration, which may be a symptom of
iron deficiency, was decreased from a mean of 1.9 to 0.9 at week 28. Fatigue and pruritus scores also improved during the study from
3.2 to 2.3 to 2.7 and 1.6, respectively [51]. Rusfertide is now being explored in a registrational phase 3 study (NCT05210790).
6. Non-pharmacologic interventions
Therapeutic interventions that are non-pharmacologic (meditation, yoga, dietary interventions, among others) have been inves
tigated in non-hematologic malignancies, specifically breast cancer, although their role in patients with hematologic malignancy has
traditionally been poorly explored. However, among MPNs, several non-pharmacologic interventions have been studied (Table 2). The
first such study investigated the feasibility of home-based online yoga among MPN patients. A total of 55 patients were recruited and
participated in a 12-week home-based yoga intervention. Thirty-eight patients (69%) completed the intervention and were analyzed.
Three-fourths of patients reported that yoga was helpful for their MPN-related symptoms. There were significant improvements in
depressive symptoms, sleep disturbances, and fatigue at 12-weeks. Only 1 adverse event (irritated enlarged spleen) was reported [52].
This was followed by another pilot study that enrolled 48 MPN patients and randomized them to 60 min of yoga per week for 12 weeks
as well as pre-post study blood draws, or a control group, who were asked to maintain their normal of level of activity. There were no
differences in MPN-SAF fatigue and MPN-SAF QoL scores between the two groups, but there was a significant decrease in the NIH
PROMIS QoL score in the yoga group compared to the control group. Interestingly, TNF-α levels significantly decreased after 12 weeks
of treatment [53]. A qualitative study that interviewed patients from both of these yoga studies demonstrated that patients experienced
self-reported improvements in sleep, fatigue, stress and increased overall activity levels [54].
Another non-pharmacologic intervention that has been explored in MPNs is meditation. In a 4-group randomized controlled trial
with a cross-over design, 128 MPN patients were randomized to 4-week increments of the 10% Happier or Calm app followed by the
other app (group 1 and 2), or to educational control followed by one of the meditation apps (group 3 and 4). At total of 73.4%
completed the intervention. Participants in the 10% Happier app saw improvements in anxiety, depression, sleep disturbances, fatigue
and physical healthy, while participants in the Calm app saw effects on anxiety, depression, sleep disturbances, physical healthy, and
fatigue. Importantly, the educational control participants did not have effects on patient-reported outcomes except for a moderate
improvement in physical health [55].
The efficacy of other non-pharmacologic interventions to reduce symptom burden has not been significantly explored, including
diet modification and other forms of exercise/medication. However, these studies demonstrate that it is possible to objectively
evaluate non-pharmacologic studies in patients with MPNs.
7. Summary
As described in this review, MPNs are a prime example of how advances in symptom assessment can lead to approved therapies that
improve the quality of patient’s lives. Despite significant advancements in the quantification of patient reported outcomes and in
terventions that can measurably improve symptoms, there remain several unmet needs. For one the pathophysiologic mechanisms that
explain the heterogeneity in symptom burden have been only minimally explored. The exact relationship between specific cytokines,
for instance, and specific symptoms remains only preliminary investigated [23]. With more translational understanding of the
mechanistic underpinnings of symptom burden in MPNS, it may be possible in the future to construct a therapeutic regimen targeted to
Table 2
Summary of non-pharmacologic studies in MPNs.
Intervention Study design Intervention Findings
Yoga Feasibility study [52] 12-week online yoga Improvements in: total symptom burden, anxiety, depression, sleep
disturbances and fatigue
Randomized pilot study 12-week online yoga versus normal No difference MPN-SAF fatigue or QoL. NIH PROMIS QoL significantly
[53] activity better in Yoga group
Meditation Randomized feasibility 8-week of 10% Happier app, Calm app 10% Happier app: improvements in anxiety, depression, sleep disturbance,
study [55] or educational control total symptom burden, fatigue and physical health
Calm app: improvement in anxiety, depression, sleep disturbances, physical
health, total symptom burden and fatigue
Educational control: improvements in physical health
MPN-SAF = myeloproliferative neoplasm symptom assessment form; NIH PROMIS = National Institute of Health Patient-Reported Outcomes
Measurement Information System; QoL = quality of life.
a patient’s specific symptoms.

The endpoint of TSS50% is widely propagated as a standard measure of the success of symptom-targeting agents in MPNs.
However, it is important to note that patients who do not hit this metric still derive symptomatic benefit. In one post-hoc analysis of
ruxolitinib-treated patients in the COMFORT-I study found that among patients with a decrease of MPN-SAF TSS of less than 50%, 46%
reported their condition as “much improved” or “very much improved” and had significant improvements in over placebo for all
subscales of the EORTC QLQ-C30 except Emotional Functioning and Cognitive Functioning [29]. Therefore, the commonly reported
symptom endpoint (i.e. TSS50%) may underestimate the symptomatic benefit of MPN therapies. Novel endpoints may be needed to
understand the granularity of symptom improvement in MPN patients both in the clinical trial arena but also in routine practice.
With the advent of novel pharmacologic therapies, particularly those outside the JAK-STAT pathway, and the further exploration of
non-pharmacologic interventions, we are hopeful that the debilitating burden of systemic symptoms that has been a hallmark of this
hematologic malignancy will continue to decline and lead to longer and more fulfilling lives for MPN patients.
Practice points
- MPN patients suffer from debilitating symptoms that are heterogeneous in nature and negatively impact on quality of life.
- Symptom assessment tools, particularly the MF-SAF and MPN-SAF, are valuable both in clinical practice and as clinical trial
endpoints.
- JAK inhibitors effectively reduce symptom burden in MF patients and PV patients who are refractory to HU or have poorly
controlled symptoms.
- Non-pharmacologic therapies, including yoga and meditation, may also improve quality of life.
Research agenda
- All new drugs in development for the treatment of MPNs should be judged on their ability to reduce symptom burden, in addition to
other endpoints such as survival and spleen volume reduction.
- Novel symptom burden endpoints beyond TSS50% are needed understand the granularity of quality of life improvement with the
next generation of MPN therapeutics.
- Efforts should be focused on delineating the pathobiology of symptom burden, including the impact of specific cytokines, which is
only minimally understood.
- Additional rigorous clinical evaluations of non-pharmacologic modalities are warranted as an adjunct to pharmacologic therapies.
Declaration of competing interest
Douglas Tremblay receives contracted research funding paid to his institution from Astellas Pharma and consulting fees from
AbbVie. Ruben Mesa receives contracted research funding paid to his institution from Celgene, Incyte, AbbVie, Samus, Genotech,
Promedior, CTI Biopharma, Constellation and the Mays Cancer Center P30 Cancer Center Support Grant from the National Cancer
Institute (CA054174). He receives consulting fees from Novartis, Sierra Oncology, LaJolla Pharmaceutical, and Constellation.
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Contents lists available at ScienceDirect

Best Practice & Research Clinical Haematology

Addressing symptom burden in myeloproliferative neoplasms

2. Symptom burden in MPNs

3. Developing the MF-SAF and MPN-SAF

Best Practice & Research Clinical Haematology xxx (xxxx) xxx

4. Pathobiology of systemic symptoms in myeloproliferative neoplasms

5.4. Future therapies in MF

5.5. Ruxolitinib in PV and ET

5.6. Other cytoreductive therapy in PV and ET

5.7. Future therapies in PV and ET

a patient’s specific symptoms.

Declaration of competing interest

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