Myeloproliferative Neoplasm Symptom Assessment Form Research Articles

Translation, Cultural Adaptation, and Validation into Romanian of the Myeloproliferative Neoplasm Symptom Assessment Form-Total Symptom Score (MPN-SAF TSS or MPN-10) Questionnaire.

Background: Patients with myeloproliferative neoplasms (MPNs) experience a high disease-related symptom burden. A specific instrument to evaluate quality of life (QoL), i.e., the MPN Symptom Assessment Form Total Symptom Score (MPN-SAF TSS; MPN-10), was developed. We conducted the translation, cultural adaptation, and validation into Romanian of the MPN-10. Methods: We translated the MPN-10 and tested its psychometric properties. Results: We recruited 180 MPN patients: 66 polycythemia vera (36.67%), 61 essential thrombocythemia (33.89%), 51 primary and secondary myelofibrosis (SMF) (28.33%), and 2 MPN-unclassifiable (1.11%). The mean TSS was 19.51 ± 16.51 points. Fatigue, inactivity, and concentration problems were the most cumbersome symptoms. We detected scoring differences between MPN subtypes regarding weight loss (p < 0.001), fatigue (p = 0.006), early satiety (p = 0.007), night sweats (p = 0.047), pruritus (p = 0.05), and TSS (p = 0.021). There were strong positive associations between TSS and inactivity, fatigue, and concentration problems, and moderate negative correlations between QoL scores and all MPN-10 items. Cronbach's α internal consistency coefficient was 0.855. The Kaiser-Meyer-Olkin construct validity test result was 0.870 and the Bartlett Sphericity Test was significant (p < 0.001). Symptom scores were loaded into one single factor according to the exploratory factor analysis. Conclusions: The Romanian MPN-10 version displayed excellent psychometric properties and is a reliable instrument for assessing symptom burden and QoL in Romanian MPN patients.

Patient reported outcomes among U.S. Veterans living with myeloproliferative neoplasms.

e18528 Background: Myeloproliferative Neoplasms (MPNs) profoundly affect patients' well-being, necessitating effective symptom relief. Patient-reported outcomes are pivotal for care improvement, aligning with Centers for Medicare and Medicaid Services priorities. This study aims to assess MPN symptom burden among U.S. Veterans, examining risk levels, thrombo-hemorrhagic complications, medication use, information access, care, and service-connected benefits. Methods: Conducted as a cross-sectional survey from December 1, 2023, - January 22, 2024, all Veterans in the MPN Advocacy Education &amp; International database were recruited. Symptom burden was assessed using the validated MPN Symptom Assessment Form Total Symptom Score (MPN SAF TSS), with descriptive statistics and T-tests employed for analysis. Results: Of 61 respondents, 88% were male, 92% Caucasian, 88% served during the Vietnam war. The mean age was 73±7, with MPN diagnosis at 64±9 and a mean duration of 44±10 years from service-connected exposure. Key findings included 56% Polycythemia Vera, 26% Essential Thrombocythemia, 16% Primary Myelofibrosis, 70% JAK2, 10% CALR, 3% MPL, 14% unaware of their mutation status, and 34% unaware of MPN risk status. Seventeen (28%) underwent phlebotomy, 64% used Hydroxyurea, 29% Ruxolitinib, and 3% Interferon. Fatigue and itching were the predominant and severe symptoms (Table), with 43% reporting no symptom improvement. Mean MPN SAF TSS of all respondents was higher than prior study by Emanuel et.al. which adjusted for MPN subtype (36.4 vs. 21.6, p&lt;0.0001). Twelve (20%) reported bleeding and 10% reported venous thrombosis after MPN diagnosis, while 13% reported arterial thrombosis before MPN diagnosis. Twenty-two (36%) are not seeing an MPN specialist and 61% are not seeing a hematologist at their local Veterans Affairs Medical Centers. Twenty-three (38%) did not seek a second opinion while 43% do not have a caregiver. Respondents turn to MPN organizations (75%), physician offices (74%), Google Search (49%), Webinars (41%), and Facebook (23%) for information. Five (8%) received service-connected disability benefits. Conclusions: Veterans with MPNs endure a substantial symptom burden, surpassing previous studies, signifying suboptimal management. Limited access to care persists, necessitating enhanced support. However, self-reporting bias and potential limitations in activity assessment must be acknowledged. Efforts to enhance MPN awareness, specialized care, and support mechanisms are imperative for comprehensive management. [Table: see text]

Rusfertide, a Hepcidin Mimetic, for Control of Erythrocytosis in Polycythemia Vera

BackgroundPolycythemia vera is a chronic myeloproliferative neoplasm characterized by erythrocytosis. Rusfertide, an injectable peptide mimetic of the master iron regulatory hormone hepcidin, restricts the availability of iron for erythropoiesis. The safety and efficacy of rusfertide in patients with phlebotomy-dependent polycythemia vera are unknown.MethodsIn part 1 of the international, phase 2 REVIVE trial, we enrolled patients in a 28-week dose-finding assessment of rusfertide. Part 2 was a double-blind, randomized withdrawal period in which we assigned patients, in a 1:1 ratio, to receive rusfertide or placebo for 12 weeks. The primary efficacy end point was a response, defined by hematocrit control, absence of phlebotomy, and completion of the trial regimen during part 2. Patient-reported outcomes were assessed by means of the modified Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) patient diary (scores range from 0 to 10, with higher scores indicating greater severity of symptoms).ResultsSeventy patients were enrolled in part 1 of the trial, and 59 were assigned to receive rusfertide (30 patients) or placebo (29 patients) in part 2. The estimated mean (±SD) number of phlebotomies per year was 8.7±2.9 during the 28 weeks before the first dose of rusfertide and 0.6±1.0 during part 1 (estimated difference, 8.1 phlebotomies per year). The mean maximum hematocrit was 44.5±2.2% during part 1 as compared with 50.0±5.8% during the 28 weeks before the first dose of rusfertide. During part 2, a response was observed in 60% of the patients who received rusfertide as compared with 17% of those who received placebo (P=0.002). Between baseline and the end of part 1, rusfertide treatment was associated with a decrease in individual symptom scores on the MPN-SAF in patients with moderate or severe symptoms at baseline. During parts 1 and 2, grade 3 adverse events occurred in 13% of the patients, and none of the patients had a grade 4 or 5 event. Injection-site reactions of grade 1 or 2 in severity were common.ConclusionsIn patients with polycythemia vera, rusfertide treatment was associated with a mean hematocrit of less than 45% during the 28-week dose-finding period, and the percentage of patients with a response during the 12-week randomized withdrawal period was greater with rusfertide than with placebo. (Funded by Protagonist Therapeutics; REVIVE ClinicalTrials.gov number, NCT04057040.)

Physical exercise recommendations for patients with chronic myeloid leukemia based on individual preferences identified in a large international patient survey study of the East German Study Group for Hematology and Oncology (OSHO #97).

Tyrosine kinase inhibitors (TKIs) have significantly lowered mortality of chronic myeloid leukemia (CML) patients adjusting life expectancy to that of the standard population. However, CML and its treatment with TKIs causes a high disease burden. Physical exercise (PE) could be a non-pharmacological approach to reducing these and improving quality of life. The aim of this study was to determine the individual disease burden as well as PE preferences of CML patients and to deduce thereof specific PE recommendations. This multicenter survey was conducted in cooperation with the LeukaNET/Leukemia-patient network including CML patients aged ≥18 years (German Registry of Clinical Trials, DRKS00023698). The severity of selected symptoms was assessed using the adapted Myeloproliferative Neoplasms Symptom Assessment Form: 0 (absent), 1-30 (mild), 31-70 (moderate), or 71-100 (severe). Information about patients' PE needs and preferences depending on their motivation was recorded. A total of 212 questionnaires were analyzed (52% female, median age 54 years). The prevalence of moderate-to-severe symptoms was 49% for fatigue, 40% for musculoskeletal pain, and 37% for concentration problems. Other commonly reported symptoms included skin reactions (42%) and weight gain (24%). The proportion of overweight/obese patients was 52%. Half of all respondents requested more information regarding PE. Patients with CML preferred individual training (82%), located outdoors (71%), at home (47%), or in an indoor swimming pool (31%). Regarding the training frequency, sports-inactive patients preferred a frequency of 1-2 training sessions per week, whereas sports-active patients preferred 3-4 sessions per week (p <0.001). Sports-inactive patients preferred a training time of 15-45 minutes, while sports-active patients preferred 30-60 minutes (p = 0.002). Subsequently, PE recommendations were developed for patients with CML. Combined resistance and endurance training (moderate intensity twice per week for 30 minutes) was recommended for beginners. Obese patients should prioritize joint-relieving sports. To reduce the risk of skin reactions, direct sunlight and possibly water sports should be avoided, and UV protection should be used. Counseling and motivation of CML patients to be physically active should be part of the standard of care as well as support for implementation.

Phase 2 study of add-on parsaclisib for patients with myelofibrosis and suboptimal response to ruxolitinib: final results

AbstractRuxolitinib reduces spleen volume, improves symptoms, and increases survival in patients with intermediate- or high-risk myelofibrosis. However, suboptimal response may occur, potentially because of signaling via the phosphoinositide 3-kinase (PI3K)/protein kinase B pathway. This phase 2 study evaluated dosing, efficacy, and safety of add-on PI3Kδ inhibitor parsaclisib for patients with primary or secondary myelofibrosis with suboptimal response to ruxolitinib. Eligible patients remained on a stable ruxolitinib dose and received add-on parsaclisib 10 or 20 mg, once daily for 8 weeks, and once weekly thereafter (daily-to-weekly dosing; n = 32); or parsaclisib 5 or 20 mg, once daily for 8 weeks, then 5 mg once daily thereafter (all-daily dosing; n = 42). Proportion of patients achieving a ≥10% decrease in spleen volume at 12 weeks was 28% for daily-to-weekly dosing and 59.5% for all-daily dosing. Proportions of patients achieving ≥50% decrease at week 12 in Myelofibrosis Symptom Assessment Form and Myeloproliferative Neoplasms Symptom Assessment Form symptom scores were 14% and 18% for daily-to-weekly dosing, and 28% and 32% for all-daily dosing, respectively. Most common nonhematologic treatment-emergent adverse events were nausea (23%), diarrhea (22%), abdominal pain and fatigue (each 19%), and cough and dyspnea (each 18%). New-onset grade 3 and 4 thrombocytopenia were observed in 19% of patients, each dosed daily-to-weekly, and in 26% and 7% of patients dosed all-daily, respectively, managed with dose interruptions. Hemoglobin levels remained steady. The addition of parsaclisib to stable-dose ruxolitinib can reduce splenomegaly and improve symptoms, with manageable toxicity in patients with myelofibrosis with suboptimal response to ruxolitinib. This trial was registered at www.clinicaltrials.gov as #NCT02718300.

Ruxolitinib Versus Best Available Therapy for Polycythemia Vera: A Systematic Review and Meta-Analysis

Background: Polycythemia vera (PV) is characterized by dysregulated Janus kinase (JAK) activation, leading to excessive production of blood cells, increased risk of thrombotic and hemorrhagic events, and an impairment on the quality of life of patients. Ruxolitinib, a JAK1/JAK2 inhibitor, has shown promising results in recent trials, but its comparative efficacy to best available therapy (BAT) remains unclear. We aimed to perform a systematic review and meta-analysis comparing the efficacy and safety of Ruxolitinib versus BAT for patients with PV. Methods: We systematically searched PubMed, Embase, and Cochrane Central for clinical studies published up to July 1st comparing Ruxolitinib to BAT. BAT was defined as hydroxyurea, interferon or pegylated interferon, pipobroman and anagrelide. Efficacy outcomes assessed were complete response to therapy and reduction in the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) score; safety outcomes were thromboembolism, anemia, and herpes. We pooled outcomes as risk ratios (RR) with 95% confidence intervals (CI). Statistical analysis was performed with Review Manager version 5.4.1. Heterogeneity was assessed with I² statistics. The protocol was registered in PROSPERO (ID: CRD42023427977). Results: A total of five studies met our inclusion criteria, of which four were randomized trials. Our analysis encompassed a population of 684 patients, including 336(49%) allocated to the Ruxolitinib group, and 348(51%) allocated to the BAT group. Ruxolitinib had a significantly greater response to treatment compared to BAT (RR 1.97; 95% CI 1.03 -3.77; p=0.04; I²=60%; Fig 1A) and significantly reduced MPN-SAF score by at least 50% (RR 2.50; 95% CI 1.29-4.86; p=0.007; I²=76%; Fig 1B). Additionally, use of Ruxolitinib showed a significantly higher incidence of herpes infection (RR 3.57; 95% CI 1.27 -10.04; p=0.02; I²=0%; Fig 1C) and anemia (RR 1.97; 95% CI 1.15-3.37; p=0.01; I²=50%; Fig 1D). There were no significant differences between the two treatment groups regarding thromboembolic events (p=0.07; Fig 1E). Conclusion: Our meta-analysis reveals that Ruxolitinib exhibits superior efficacy in achieving a complete response for PV patients compared to BAT and in reducing MPN-SAF score by ≥50%. While no significant difference was observed in thromboembolic events, Ruxolitinib demonstrated significant risk of anemia and herpes infection.

Ruxolitinib Treatment in Polycythemia Vera Results in Reduction in JAK2 Allele Burden in Addition to Improvement in Hematocrit Control and Symptom Burden

Introduction:In the pivotal RESPONSE and RESPONSE 2 trials, the Janus kinase (JAK)1/JAK2 inhibitor ruxolitinib was superior to best available therapy (BAT) at providing hematocrit control and complete hematologic response, as well as in improving disease-related symptoms, in patients with polycythemia vera (PV). Here we report the results of a post hoc pooled efficacy analysis using data from the RESPONSE studies. Methods:RESPONSE and RESPONSE 2 were randomized, open-label, multicenter phase 3 trials that assessed efficacy and safety of ruxolitinib in adults with PV who had resistance or intolerance to hydroxyurea. Splenomegaly was required for enrollment into RESPONSE but not for RESPONSE 2; patients in both studies were randomized 1:1 to ruxolitinib (starting dose, 10 mg twice daily) or BAT (most commonly hydroxyurea [59%, 49%] or interferon formulations [12%, 13%] in RESPONSE and RESPONSE 2, respectively). Patients in either trial who were randomized to BAT could cross over to ruxolitinib at the time of primary analysis (Week 32 in RESPONSE; Week 28 in RESPONSE 2) or later for efficacy or safety reasons. In this pooled analysis, hematocrit control was assessed in the pooled population at Weeks 28 and 80 and was defined as hematocrit &amp;lt;45% that was maintained since Week 16 with ≤1 phlebotomy occurring postrandomization and before Week 4. Symptom control (using the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score [MPN-SAF TSS]) and changes over time in JAK2V617F allele burden were also assessed. Response rate 95% CIs were calculated using the Clopper-Pearson exact method, and the odds ratio (OR) and 95% CI for comparisons of the proportion of patients achieving ≥50% reduction from baseline in MPN-SAF TSS were calculated by the Mantel-Haenszel method. Results:Overall, 371 patients were randomized in RESPONSE and RESPONSE 2 (ruxolitinib, n=184; BAT, n=187). Patient baseline characteristics were similar across trials and treatment groups and have been previously published. Mean (SD) age in the overall pooled analysis population was 61.8 (11.0) years; most patients were male (62.5%) and White (88.1%). At Week 28, 62.0% (95% CI, 54.5%-69.0%) of ruxolitinib patients achieved hematocrit control compared with 18.2% (12.9%-24.5%) of BAT patients (Figure 1). Durable hematocrit control was maintained to Week 80 by 47.3% (95% CI, 39.9%-54.8%) of patients randomized to ruxolitinib (nearly all patients in the BAT arm crossed over to ruxolitinib). The percentage of patients achieving ≥50% reduction from baseline in MPN-SAF TSS at Week 16 (the only common timepoint in both studies) was higher for ruxolitinib vs BAT (48.7% [95% CI, 40.7%-56.8%] vs 18.0% [95% CI, 12.5%-24.6%]; OR, 4.3 [95% CI, 2.6-7.2]). Mean (SD) change from baseline to Week 16 in MPN-SAF TSS was −4.4 (10.0) for ruxolitinib patients and 0.6 (6.9) for BAT patients. JAK2V617F allele burden decreased consistently from baseline to Week 208 in patients randomized to ruxolitinib. Mean JAK2V617F allele burden decreased from 66.1% to 41.4% at 4 years. Best change from baseline in JAK2V617F allele burden is shown in Figure 2, with a decrease of ≥25% in 57.1% of patients randomized to ruxolitinib and ≥50% decrease in 38.9%. Similar reductions in JAK2V617F allele burden were observed following crossover from BAT to ruxolitinib (Figure 2), with a best decrease of ≥25% and ≥50% in 48.7% and 35.3% of patients, respectively. Analysis of the BAT group is limited by small patient numbers after Week 32, as most patients crossed over to ruxolitinib, with a best decrease of ≥25% and ≥50% in 7.2% and 2.6% of patients respectively. Conclusions:In this pooled analysis of RESPONSE and RESPONSE 2, patients with PV treated with ruxolitinib achieved durable hematocrit control through Week 80 and had better symptom control at Week 16 than those who received BAT. Reductions in JAK2V617F allele burden were consistently observed through Week 208 in patients treated with ruxolitinib, including those who crossed over from BAT. Taken together, these results provide further evidence of the patient benefit of ruxolitinib in patients with PV with or without splenomegaly.

Bromodomain and Extra-Terminal Inhibitor INCB057643 (LIMBER-103) in Patients with Relapsed or Refractory Myelofibrosis and Other Advanced Myeloid Neoplasms: A Phase 1 Study

Introduction: Bromodomain and extra-terminal (BET) proteins are epigenetic readers that regulate expression of critical oncoproteins involved in the pathophysiology of myelofibrosis (MF) and other hematologic malignancies including B-lymphoma-2, nuclear factor kappa, and c-Myc. In a previous phase 1/2 clinical trial, the small-molecule oral BET inhibitor INCB057643, evaluated as monotherapy and in combination with ruxolitinib, was associated with favorable tolerability and encouraging clinical activity in patients with advanced malignancies. Methods: This ongoing phase 1, 3+3 dose-escalation/expansion study (NCT04279847) is evaluating the safety and tolerability of INCB057643 (4 mg once daily [qd] with escalation up to 12 mg qd) in patients aged ≥18 years as (1) monotherapy (part 1) in relapsed or refractory (R/R) MF, myelodysplastic syndromes (MDS), or MDS/myeloproliferative neoplasm (MPN) overlap syndromes (MDS/MPN) or (2) added to ruxolitinib (part 2) in patients with MF and suboptimal response to ruxolitinib. The primary endpoints are safety and tolerability, including identification of dose-limiting toxicities (DLTs). Secondary endpoints in patients with MF include spleen volume response (≥35% reduction from baseline at Week 24 per magnetic resonance imaging/computed tomography scan) and symptom response (≥50% reduction from baseline at Week 24 in MPN-Symptom Assessment Form Total Symptom Score [MPN-SAF TSS]). Results: As of data cutoff on June 1, 2023, 14 patients were treated in part 1 (4 mg, n=6; 8 mg, n=4; 10 mg, n=2; 12 mg, n=2), and 6 were treated in part 2 (4 mg, n=3, 6 mg, n=3). In part 1, patients had a median (range) age of 69.5 (50.0-79.0) years and a median (range) study treatment duration of 177 (9-375) days; 8 were men. In part 2, patients had a median (range) age of 71 (64-76) years; median (range) study treatment duration of 92.5 (46-274) days; 3 were men. 16 patients had MF; 4 had MDS/MPN, including 1 with chronic myelomonocytic leukemia. A total of 10 patients discontinued treatment, 4 for lack of efficacy or disease progression and 4 due to adverse events (AEs; 3 in the monotherapy group, 1 in the combination group). Thrombocytopenia (n=3) and anemia/thrombocytopenia (n=1) were the only treatment-emergent AEs (TEAEs) leading to discontinuation, and thrombocytopenia was the most common TEAE (n=11). Grade ≥3 TEAEs occurring in ≥1 patient were thrombocytopenia (n=5), anemia (n=4), and hypokalemia (n=2). 12 serious AEs occurred across 5 patients (only COVID-19 occurred in &amp;gt;1 patient [n=2]); all but one serious AE (pneumonia) was considered unrelated to study treatment. There were 2 DLTs: thrombocytopenia in 1 patient with MDS/MPN in the 12 mg cohort and hyperbilirubinemia in 1 patient with MF in the 12 mg cohort. 2 deaths occurred on study, both in the 4 mg monotherapy cohort due to disease progression (MF, n=1; MDS/MPN, n=1). Overall, 5 patients on monotherapy and 2 on combination therapy demonstrated a reduction in spleen volume at Week 12 (≥35% reduction in 2 patients and 1 patient, respectively); at Week 24, 3 patients on monotherapy and 2 on combination therapy had a reduction in spleen volume (≥35%: 1 patient and 1 patient, respectively; Figure 1). Percentage change from baseline in MPN-SAF TSS in individual patients is reported in Figure 2; at Week 12, ≥50% improvement from baseline occurred in 3 patients on monotherapy and 1 on combination therapy (≥50% improvement at Week 24: 2 patients and 1 patient). Conclusions: INCB057643 monotherapy (4 and 8 mg qd) and combined (4 and 6 mg qd) with ruxolitinib was generally well tolerated, whereas the 12 mg qd monotherapy dose caused 2 DLTs. There were no treatment-related fatal events. Improvements in spleen size and symptom burden were observed in patients receiving ≥8 mg in the monotherapy group and 4 mg in the combination therapy group. Dose finding (part 1) is ongoing with 10 mg qd, after which the recommended dose(s) for expansion will be declared. Dose escalation is also ongoing in the combination therapy group.

Prospective Symptom Burden Analysis in 784 Patients with Myeloproliferative Neoplasms: High Burden Correlates with Inflammatory/Genetic Biomarkers and Reduced Survival

Background: Myeloproliferative neoplasms (MPN) are associated with significant symptom burden, influencing patient quality of life and management. Thorough assessment of this burden is crucial; however, data from large populational registries are limited. Our objective was to characterize symptom burden in a large MPN cohort, determining: i) age-associated differences; ii) treatment effect; iii) biologic correlatives, and iv) impact on overall survival (OS) in a large, real-world population based setting. Methods: This is a multicenter prospective study analyzing patient-reported outcomes per MPN-Symptom Assessment Form Total Symptom Score (MPN-SAF TSS), a validated questionnaire grading (0-10) ten MPN symptoms ( JCO, 2012). Recruitment: Quebec CML-MPN Research Group registry (&amp;gt;20 community/academic centers). Eligibility: i) diagnosis of polycythemia vera (PV), essential thrombocytosis (ET), or myelofibrosis (MF) per WHO criteria; ii) completion of 1+ MPN-SAF TSS between 2013-2022. Conventional statistics were used (JMP® Pro 14.1.0 software; SAS Institute, NC, USA). Results: 4105 MPN-SAF TSS were completed by 784 patients (n= 285 PV, n=422 ET, n=77 MF). Median age at diagnosis was 63 years (range 19-96); female preponderance (56%). A median of 5 questionnaires were completed/patient (range 1-16). Mean symptom score was 16.7 (+/-12.3). A clinically significant total score, defined as &amp;gt;20, was reported by 33% of patients (n=261); most frequently women (p&amp;lt;0.0001) and MF cases (p=0.03). Symptom burden in the young: N=74 (9%) were age &amp;lt;40 years at diagnosis. At recruitment, mean aggregate and maximum MPN-SAF TSS scores were comparable across younger and older subsets (p=0.3-0.9) (Table 1), despite lower risk scores in the former (p&amp;lt;0.05). When scores were deconstructed, younger patients - vs older, had significantly higher levels of fatigue (p=0.03) and abdominal pain (0.007). Impact of therapy: Of those with high MPN-SAF scores, a considerable proportion were not treated (n=69/179, 39%). Higher mean scores were also reported in those having initiated therapy &amp;gt;36 months from diagnosis (p=0.0009). Of those with available MPN-SAF pre/post treatment, 37% showed deteriorating scores following cytoreduction, regardless of agent (p=0.4). Notably, those not on antiplatelet therapy had significantly higher mean (p=0.0006) and sub-item scores (excluding fever/night sweats). Over time, all interventions confounded, n=338 (43%) experienced worsening of MPN-SAF scores. Clinical biomarkers: Patients with anemia (hemoglobin &amp;lt;100 g/L) had significantly higher mean MPN-SAF scores and worse fatigue, inactivity, concentration, bone pain, and weight loss (all p&amp;lt;0.05). Increased C reactive protein (CRP) associated significantly with higher MPN-SAF scores (p=0.03), as well as fatigue, inactivity, early satiety, and bone pain (all p&amp;lt;0.05). Notably, patients with JAK2V617F variant allele frequency &amp;gt;50% (VAF) had higher average (p=0.03) and maximum (p=0.001) MPN-SAF, higher inactivity scores (p=0.02), and more frequent worsening scores over time (p=0.05). Survival impact: Higher mean MPN-SAF score had a significantly detrimental impact on OS (p=0.05) (Figure 1). Multivariate analysis revealed absence of antiplatelet therapy, age at diagnosis &amp;gt;65 years, male sex, and high-level inactivity to be independent predictors of inferior OS (HR 29, 6, 3 and 3 respectively). Conclusions: This is a large-scale study comprehensively appraising symptom burden in MPN patients, disclosing several novel findings. First, it unexpectedly exposes disproportionately severe symptoms (fatigue/abdominal pain) in younger patients. Second, it reveals deterioration of symptoms in the face of therapy in a significant number of patients, underscoring inadequacy of current therapies in symptom control. Third, it discloses anemia, elevated CRP, and JAK2 VAF&amp;gt;50% as putative biomarkers of symptom burden; potential adjuncts in identifying highly symptomatic subsets, particularly in situations where symptom assessment is challenging. Finally, it confirms negative survival impact of high symptom burden in a real-world setting. Overall this data exposes a critical unmet need for new therapeutic avenues aimed at alleviating symptom burden in patients with MPN. Further delineation of the inflammation-symptom relationship and future studies using novel prevention strategies are warranted.

Exploratory Study on Impact of Comorbid Sleep Apnea Treatment in Patients with Polycythemia Vera and Essential Thrombocythemia

Background: Systemic inflammation has been implicated in the progression of myeloproliferative neoplasms (MPNs), polycythemia vera (PV) and essential thrombocythemia (ET). Obstructive sleep apnea (OSA) is a highly prevalent disorder that can lead to TNF-driven systemic inflammation. OSA leads to oxidative stress and NF-kB driven inflammatory gene expression through the mechanistic pathways of intermittent hypoxia and autonomic activation. We therefore sought to understand the prevalence of OSA in patients with MPNs and the feasibility of understanding the impact of treating comorbid sleep apnea in patients with PV and ET. Methods: Patients with PV and ET diagnosed using the 2008 or 2016 WHO criteria underwent STOP-BANG questionnaires to evaluate for the likelihood of OSA. Based on the finding of 3 or more positive responses on STOP-BANG questionnaire (PLoS One 2015;10:e0143697), patients underwent further evaluation with polysomnography or home sleep apnea test to diagnose OSA at an American Academy of Sleep Medicine-certified sleep laboratory (Figure 1). Patients with apnea-hypopnea index (AHI) of 5 or more events per hour and Eastern Cooperative Oncology Group scale score of 0-2 underwent continuous positive airway pressure therapy (CPAP). Effects of CPAP therapy on MPN-symptom assessment form total symptom scores (MPN-SAF TSS), JAK2V617F, MPL and CALR allelic burden, and exploratory endpoints of changes in inflammatory and thrombotic markers were ascertained (Figure 1). Comparisons with observational cohorts were planned to ascertain changes in the above endpoints at 0-, 3- and 6-months intervals (Figure 1). Based on a 40% reduction in allele burden (SD of 25%) and correlation of 0.5 between paired measurements, it was estimated that using a paired t-test with 27 evaluable patients will provide a 95% power to detect a 20% change in JAK2V617F burden from 40% to 20%. Similarly, assuming a 50% correlation (SD of 16) between pre- and post-therapy MPN-SAF TSS scores, 27 evaluable patients will provide a 80% power to detect a change of 10 at the two-sided 0.025 significance level. Results: Screening for OSA in patients with ET and PV revealed a high prevalence of OSA risk based on STOP-BANG scores. 26/29 males (mean age 63.6±11.8 years; BMI 29±3.3) and 16/26 females (mean age 61.5±12.8 years; BMI 28.2±6.5) had STOP-BANG scores of 3 or more. 8 patients with PV and ET have so far been enrolled into this study. 6/8 patients (age ranges from 41-74 years; 4 females and 2 males) with OSA (AHI 5-56 events/hr; 4% oxygen desaturation index 4.7-30/hr) underwent CPAP therapy. 1/6 patients in the CPAP arm did not tolerate CPAP and was excluded. 5/6 patients completed study procedures as did 2 additional patients without OSA in the observational study arm. Of 5/6 patients undertaking CPAP, 3/5 had the JAK2V617F mutations whereas 2/5 had the CALR mutation. JAK2V617F allele burdens at baseline in 2/5 patients were 80.7% and 4% at baseline and reduced to 73% and 1% at 6 months respectively whereas the third patient had undetectable JAK2V617F burdens throughout the study. All except one patient experienced improvement in MPN-SAF TSS scores after 6 months of CPAP therapy. While all 5 patients treated with CPAP showed improvements in C-reactive protein levels, analysis of NFkB1, TNF and IL-6 transcript levels showed mixed results. Similar mixed results were found with hypoxia-inducible factor (HIF) target gene expression ( SLC2A1, VEGF-A, EDN1) and markers of iron turnover (% transferrin saturation, transferrin, iron and ferritin levels) despite reduction in erythropoietin values in 4/5 patients with CPAP therapy at 6 months. Conclusions: Given the significant likelihood of OSA in patients with PV and ET (as based on STOP-BANG scores of 3 or more), there is need to evaluate and treat for OSA. Preliminary results show abnormalities in inflammatory markers with reductions in C-reactive protein and erythropoietin levels following CPAP therapy even though mixed results were noted in inflammatory and HIF-target gene transcripts, and markers of iron turnover. Larger studies and longer follow-up are required to understand the impact of OSA on not only the thrombotic and inflammatory milieu in patients with MPNs, but also the benefit of treating on prevention of disease progression and thrombotic manifestations common in MPNs. Funding: Huntsman Interventional Trial Grant CTO #HCI-17-HEM 28.

The JAK2V617F mutation and the role of therapeutic agents in alleviating myeloproliferative neoplasm symptom burden.

Alleviating symptom burden in patients with myeloproliferative neoplasms (MPNs) is imperative to achieving optimal management. Research remains to elucidate the relationship between the JAK2V617F (Janus kinase 2) mutation present in many MPN patients, and the symptomatology they experience. This retrospective study analysed data collected from MPN patients included in the Myeloproliferative Neoplasms: An In-depth Case-Control (MOSAICC) pilot study. The MPN Symptom Assessment Form was administered, and median symptom scores were compared between JAK2V617F-positive and JAK2V617F-negative groups. Multivariate logistic regression analysis adjusted for confounding variables. Overall, 106 MPN patients participated: 65.1% were JAK2V617F positive, 30.2% were JAK2V617F negative and 4.7% had an unknown status. Multivariate analysis revealed a low symptom burden for early satiety (p<0.01), dizziness (p<0.05), cough (p<0.05) and bone pain (p<0.01) in those receiving venesection alone. Interferon alpha was significantly associated (p<0.05) with severe burden for 16 of the 27 symptoms. JAK2V617F-positive females experienced a greater symptom burden than JAK2V617F-positive males. There was no discernible relationship between the JAK2V617F mutation and symptom burden in MPN patients, unlike the therapeutic agents investigated. Larger studies are required to validate these results and identify mechanisms of symptom development and control in MPN patients.

BCR::ABL1 negative myeloproliferative neoplasms: A review focused on essential thrombocythemia and polycythemia vera.

The classical myeloproliferative neoplasms are divided into chronic myeloid leukemia, and the Philadelphia negative polycythemia vera, essential thrombocythemia and primary myelofibrosis. These are heterogenous diseases, originating from the clonal proliferation of myeloid stem cells, resulting in increased mature cell numbers in one or more myeloid lineages. The most commonly seen mutations in the Philadelphia negative myeloproliferative neoplasms include those in Janus kinase, myeloproliferative leukemia protein and the calreticulin genes. Philadelphia negative myeloproliferative neoplasms occur infrequently, with a combined annual incidence of 2.58 per 100,000. There are many overlapping symptoms of Philadelphia negative MPNs, such as fatigue, night sweats, hepatosplenomegaly and circulatory symptoms due to increased cell numbers. Total Symptom Score of the MPN Symptom Assessment Form is used to assess symptom burden on patients. The most worrisome complications are thrombo-hemorrhagic events, and risk stratification is especially important as treatment of disease is based on their category. Phlebotomy and aspirin are the mainstay of treatment in low-risk polycythemia vera and essential thrombocythemia patients, whereas high-risk disease calls for additional cytoreduction, usually with hydroxyurea.

Physical exercise recommendations for patients with polycythemia vera based on preferences identified in a large international patient survey study of the East German Study Group for Hematology and Oncology (OSHO #97).

Exercise therapy during cancer treatment reduces symptom burden and improves quality of life (QoL). Polycythemia vera (PV) is a myeloproliferative neoplasia associated with good overall survival (up to decades) but a significant symptom burden, including thromboembolic events and dysesthesias. There are no specific exercise recommendations for patients with PV. Thus, we aimed to determine the exercise preferences of patients with PV and to derive specific recommendations based on the most commonly reported symptoms. This multicenter survey included patients with PV ≥18 years old. Demographic, clinical, and disease burden data were collected. The severity of selected symptoms was assessed using the adapted Myeloproliferative Neoplasms Symptom Assessment Form: 0 (absent), 1-30 (mild), 31-70 (moderate), or 71-100 (severe). The patients' information needs about physical activity (PA) and exercise preferences were recorded depending on their motivation and analyzed with regard to demographic aspects. The sample comprised 182 patients (68% female, 61 ± 12 years). The prevalence of moderate-to-severe symptoms was 60% for fatigue, 44% for concentration problems, and 35% for bone/muscle pain. Other commonly reported symptoms included skin reactions (49%), splenomegaly (35%), and increased bleeding tendency (28%). Overall, 67% of respondents requested more information regarding PA. Patients with PV preferred individual training (79%) located outdoors (79%) or at home (56%). Regarding the amount of training, sports-inactive patients preferred a frequency of 1-2 times/week and session durations of 15-45 min, whereas sports-active patients preferred 3-4 times/week and 30-60 min (p < 0.001). Higher sport-inactiveness was observed in patients with lower educational level compared to patients with higher educational level (69% vs. 50%, p = 0.021). For beginners, combined resistance-endurance (circuit) training two times/week, which can be performed outdoors or at home, should be recommended. In the case of splenomegaly or bleeding symptoms, exercises with a low injury risk should be chosen. PA is important for patients with PV; therefore, counseling should be integrated into the treatment plan. Specifically, patients with low educational level should be addressed. Prospective studies are warranted to evaluate the effects of the novel exercise recommendations.

Phase Ib, open-label study of add on therapy with CK0804 in participants with myelofibrosis, with suboptimal response to ruxolitinib.

TPS7087 Background: Drugs targeting JAK2 inhibition including ruxolitinib have led to significant improvement in quality of life and survival of myelofibrosis (MF) patients, however almost 30% have suboptimal response and disease remains incurable. Novel therapies are urgently needed. In addition to mutation-driven stem cell-derived clonal myeloproliferation, recent data support role of reactive cytokine- and chemokine-driven inflammatory fibrosis that contribute to MF pathogenesis, specifically, abnormal CXCR4/CXCL12 axis can drive disease progression and extramedullary hematopoeisis. Targeting bone marrow inflammation is emerging as potential therapeutic strategy for MF. Adoptive therapy with allogeneic, cord blood (CB) derived Regulatory T cells (Tregs) have shown to be safe in bone marrow failure patients. CXCR4 enriched CB Tregs (CK0804) show faster egress across transwell membrane in response to SDF1α and preferential homing to bone marrow, in vivo. We hypothesize that multiple infusions of CK0804 may decrease inflammation and improve clinical outcomes in MF. Methods: Single arm study consisting of safety run-in of 9 participants followed by expansion cohort of additional 15 participants using 3+3+3 study design. MF patients receiving ruxolitinib therapy &gt; 3 months prior to enrollment with stable dose for at least 8 weeks prior to Day 1, unlikely to benefit from further ruxolitinib monotherapy in opinion of investigator would be eligible. Each participant will receive single infusion of CK0804 at fixed dose of 100 million Treg cells administered every 28 days. Participants will continue their ruxolitinib therapy. Participants with no treatment limiting toxicity (TLT) after 28 days or those with toxicity with clear alternative explanation (e.g. disease progression) or transient (≤72 hrs) abnormal laboratory values without associated clinically significant signs or symptoms based on investigator determination will receive up to six 28-day treatment cycles AND 6 months of follow up after last infusion of CK0804. Primary Objective: Determine safety and tolerability of CK0804 as add-on therapy in MF, with suboptimal response to ruxolitinib. Primary endpoint: Safety, tolerability and TLTs of CK0804 as assessed by incidence and severity of AE and SAEs determined by NCI CTCAE Version 5.0. Secondary Objective: Determine efficacy of CK0804 as add-on therapy in MF, with suboptimal response to ruxolitinib. Secondary endpoint: Assessment of overall response rate and its duration, using modified International Working Group Myeloproliferative Neoplasm Research and Treatment and European Leukemia Net consensus report; Rate of anemia response and Rate of spleen response by imaging at and after 24 weeks; Symptom burden assessed using Myeloproliferative Neoplasms Symptom Assessment Form Total Symptom Score scale. Safety data from cohort 1 will be presented. Clinical trial information: NCT05423691 .

EXCEED-ET: A single-arm multicenter study to assess the efficacy, safety, and tolerability of ropeginterferon alfa-2b-njft (P1101) in North American adults with essential thrombocythemia.

TPS7088 Background: Essential thrombocythemia (ET) is a myeloproliferative neoplasm (MPN) characterized by a high platelet count due to an overacting JAK-STAT pathway as a result of the most common mutations in JAK2, CALR and MPL genes. There is a high, unmet clinical need for safe and effective treatment options for patients with ET who require cytoreduction, both naïve and previously exposed to hydroxyurea (HU) or anagrelide (ANA). In addition to blood count control and thrombohemorrhagic risk reduction, treatment for ET should also halt/prevent disease progression to post-ET myelofibrosis. Reduction in variant allele frequency and changes in marrow morphology may lead to the elimination of the malignant clone, and treatment with an interferon may achieve this outcome. Interferons have been used in the treatment of MPNs for over 30 years with well-established improvements in hematological and molecular rates, but interferons are not approved by a regulatory agency for the treatment of ET. The objective of this study is to assess the efficacy of ropeginterferon alfa-2b-njft, a new generation interferon alfa, in adults with ET who live in the US or Canada. Methods: This single-arm, open-label study includes a 28-day screening period, a 12-month treatment phase, and a 28-day follow-up period, for a total trial duration of 14 months. An extension phase will supply ropeginterferon alfa-2b-njft to patients deriving benefit for a total of 3 years of treatment. Adults diagnosed with ET according to the WHO 2016 criteria with a platelet count at screening &gt; 450 x 109/L, cytoreductive treatment naïve, or with prior use or currently on HU and/or ANA may participate. Prior treatment with an interferon is an exclusion factor. Patients with a history or presence of clinically relevant depression, risk of suicide, or autoimmune disease may not participate. Ropeginterferon alfa-2b-njft will be administered subcutaneously every 2 weeks at the starting dose of 250 mcg (Week 0), 350 mcg (Week 2), and target dose of 500 mcg (Week 4) and remain fixed for the 12-month treatment period. Subjects currently on HU or ANA will follow a pre-specified dose-tapering schedule. All subjects will receive low-dose aspirin unless contraindicated. The primary endpoint is a durable response defined as the proportion of subjects who achieve simultaneous peripheral blood count remission (platelets ≤400 x109/L and WBC &lt; 10 x 109/L) for at least 80% of bi-weekly measurements consecutively between weeks 32-52, a durable resolution of disease-related symptoms according to the MPN Symptom Assessment Form Total Symptom Score (MPN-SAF TSS), and absence of bleeding or thrombotic events. This study is being sponsored by PharmaEssentia USA. Clinical trial information: NCT05482971 .

Jaktinib in patients (pts) with myelofibrosis (MF) who were intolerant to ruxolitinib (RUX): An open-label, single-arm phase 2b study.

7061 Background: As the first approved Janus kinase inhibitor (JAKi) for pts with symptomatic MF, RUX showed superiority in spleen volume reduction with increased anemia and thrombocytopenia. However, there are few treatment options after RUX intolerance. Jaktinib, an oral novel JAK and ACVR1 inhibitor showed promising efficacy in Jaki-naïve pts with intermediate or high risk MF with mild side effects. Here we present the results of MF pts who were intolerant to RUX and received jaktinib 100 mg bid from a phase 2b study. Methods: Pts who had primary or post-ET/PV MF and were previously treated with RUX for ≥28 days who either required RBC transfusions or required more frequent transfusions on RUX, or had grade 3/4 anemia, thrombocytopenia or hematoma when receiving RUX, and with palpable spleen ≥5 cm were included. The primary endpoint was the proportion of pts with spleen volume reduction of ≥ 35% from baseline (SVR35) at week (wk) 24, assessed centrally on the basis of MRI/CT images. Secondary endpoints included the best spleen response rate (defined as achieving SVR35 at any time), the proportion of pts with ≥ 50% reduction in MPN Symptom Assessment Form Total Symptom Score (MPN-SAF TSS), anemia response, safety, etc. Results: A total of 45 patients received jaktinib 100 mg bid. The full analysis set (FAS) for efficacy included 44 pts who had completed the 24-week treatments and evaluations or terminated prior to wk 24, and excluded one pt because of incorrect diagnosis of MF. The median baseline TSS was 9.5, hemoglobin (Hb) was 79.5 g/L, and platelets was 132.5×109/L. While on RUX, 21 pts (48%) required RBC transfusion and all pts experienced those grade 3 hematological toxicities. In FAS, the SVR35 rate at wk 24 was 43% (19/44). Over the study phase, the best spleen response rate was 55% (24/44). The median time to achieve the first SVR35 was 12 weeks. Response was maintained in 80% pts for at least 24 weeks and median duration was not reached. At wk 24, 62% of the evaluable pts achieved a ≥ 50% improvement in TSS from baseline. Of 31 pts with baseline Hb ≤ 100 g/L, 13 (42%) had a ≥20 g/L Hb increase. Of 19 pts who required RBC transfusion at baseline, 11 (58%) had a 50% decrease in RBC infusion frequency. Of 9 transfusion-dependent pts at baseline, one became transfusion-independent. In the safety set (n = 45), the median jaktinib exposure time was 280 days. The most common grade ≥3 TEAEs were anemia (31%), thrombocytopenia (22%), pneumonia (18%), neutropenia (16%) and leukopenia (16%). Treatment discontinuation due to TEAEs occurred in five pts (11%). A dose reduction or temporary interruption due to TEAEs were reported in 12 pts (27%). Conclusions: Jaktinib demonstrated promising activities in MF pts who was intolerant to RUX by substantially reducing spleen volume, ameliorating MF-related symptom burdens, and elevating Hb levels. Jaktinib could be a viable treatment for MF pts with anemia in this setting. Clinical trial information: NCT04217993 .

Jaktinib in patients (pts) with myelofibrosis (MF) who were refractory to or relapsed after ruxolitinib: A single-arm, open-label, multicenter, phase 2 study.

7062 Background: Currently, ruxolitinib is the only marketed Janus kinase inhibitor (JAKi) for pts with MF in China, which demonstrated symptomatic and splenic benefit with increased cytopenias. However, at least 50% of pts develop resistance or intolerance to ruxolitinib in the long-term follow up, for whom life expectancy is largely reduced. There are few therapeutic options after ruxolitinib failure. Jaktinib, an oral novel JAK and AVCR1 inhibitor showed promising activity in Jaki-naïve pts with intermediate or high risk MF with mild side effects. Here we present the results of jaktinib in MF pts who were refractory or relapsed to prior ruxolitinib therapy. Methods: Pts who had primary or post-ET/PV MF and were previously treated with ruxolitinib for at least 3 months and with either inadequate efficacy response (defined as &lt; 10% spleen volume reduction [SVR] by MRI/CT or &lt; 30% decrease in spleen size by palpation from baseline) or spleen regrowth to &lt; 10% SVR or &lt; 30% decrease in spleen size from baseline following an initial response were recruited to receive jaktinib 100 mg twice daily. The primary endpoint was the proportion of pts with SVR ≥ 35% from baseline (SVR35) at week (wk) 24, measured by MRI/CT images and assessed by Independent Review Committee. Secondary endpoints included the best spleen response rate (defined as achieving SVR35 at any time), the proportion of pts with ≥ 50% reduction in MPN Symptom Assessment Form Total Symptom Score (MPN-SAF TSS), improvement of anemia and safety. Results: A total of 34 pts were enrolled. The median duration of previous ruxolitinib treatment was 18.6 months (range 3.4-70.1). The median baseline TSS was 19.5 (range 1-55), hemoglobin (Hb) was 101.5 g/L (range 61-149), and platelets was 159×109/L (range 66-951). 11 pts (32.4%) achieved SVR35 at wk 24. The best spleen response rate was 38.2% (13/34). The median time to achieve the first SVR35 was 8.1 weeks, and the median duration of response was not reached. At wk 24, 13 pts (46.4%) achieved a ≥ 50% improvement in TSS from baseline. Of 16 transfusion-independent pts with Hb ≤ 100 g/L at baseline, 8 (50.0%) had a ≥20 g/L Hb increase by wk 24. Of 6 pts who required RBC transfusion at baseline, 2 had a 50% decrease in RBC infusion by wk 24. The median jaktinib exposure time was 231 days (range 96-371). 23 pts (67.6%) had one or more grade ≥3 treatment emergent adverse events (TEAEs). The most common grade ≥3 TEAEs were anemia (32.4%, n = 11), thrombocytopenia (32.4%, n = 11), leukocytosis (20.6%, n = 7) and leukopenia (11.8%, n = 4). Treatment discontinuation due to TEAEs occurred in 2 pts (5.9%). A dose reduction or temporary interruption due to TEAEs were reported in 9 pts (26.5%). Conclusions: MF pts who were refractory/relapsed to ruxolitinib attained substantial spleen response, and reduction in MF-related symptom burden with jaktinib, which could be a new option for MF pts who have failed ruxolitinib. Clinical trial information: NCT04851535 .

Analysis of Predictive Factors for Early Response to Ruxolitinib in 320 Patients with Myelofibrosis From the Polish Adult Leukemia Group (PALG) Registry.

Ruxolitinib is widely used in myelofibrosis (MF). However, some patients do not optimally respond and require more efficacious treatment. Our analysis aimed to establish predictors of ruxolitinib response. We designed a multicenter, retrospective analysis of the efficacy of ruxolitinib treatment in patients with MF in 15 Polish hematology centers. As responses to ruxolitinib occur within the first 6 months, we used this point to evaluate the efficacy of treatment. Symptoms response was defined as ≥50% reduction of the MF constitutional symptoms assessed by Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS). Spleen response was defined as ≥50% reduction of the difference between the spleen's baseline length and the upper limit norm measured by ultrasonography. 320 MF patients were enrolled. At 6 months of therapy, the spleen response was detected in 140 (50%) patients, and symptoms response in 241 patients (76%). Multivariable analysis identified leukocytosis <25 G/L (OR 2.06, 95%CI: 1.12-3.88, P=.0200), and reticulin fibrosis MF 1 (OR 2.22, 95%CI: 1.11-4.46, P=.0249) contributed to better spleen response. The time interval between MF diagnosis and ruxolitinib administration shorter than 3 months, and platelets ≥150 G/L (OR 1.69, 95% CI 1.01-2.83, P=.0466) influenced symptoms response. Establishing predictive factors for ruxolitinib response is particularly important given the potential for new therapies in MF. In patients with a low likelihood of responding to ruxolitinib, using other JAK inhibitors or adding a drug with a different mechanism of action to ruxolitinib may be of clinical benefit.

Efficacy and Safety of Ruxolitinib for Treatment of Symptomatic Chronic Myelomonocytic Leukemia (CMML): Results of a Multicenter Phase II Clinical Trial

Introduction CMML is a myelodysplastic/myeloproliferative neoplasm (MDS/MPN) with poor overall survival (OS). Like primary myelofibrosis, a large subset of CMML patients suffer from disease-related symptoms and splenomegaly that contribute to morbidity. We have demonstrated that CMML is molecularly characterized by hematopoietic stem and progenitor cell hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF). As the sentinel kinase required for GM-CSF signaling, JAK2 represents a rational therapeutic target in CMML and pharmacologic inhibition has demonstrated activity in preclinical models and in a phase I/II clinical trial. The overall response rate in that trial was 38% by MDS/MPN IWG criteria and 43% of patients (pts) with baseline splenomegaly achieved a spleen response by palpation. However, that clinical trial did not systematically or objectively measure symptom burden or radiographic splenomegaly. Here, we report results of our second phase II clinical trial with ruxolitinib for treatment of CMML objectively measuring spleen responses and symptom improvement. Methods This was a phase II prospective multicenter study. Key eligibility criteria included confirmed diagnosis of CMML and having either symptomatic splenomegaly and/or a myeloproliferative neoplasms symptom assessment form (MPN-SAF) total score (TSS) >17, ANC ≥ 250/ul, and platelets ≥35,000 u/l. Ruxolitinib was administered at 20 mg po BID at the previously identified RP2D. Dose adjustments/holding occurred for both hematological and non-hematological parameters. The primary endpoint was clinical benefit or better response per International Working Group (IWG) criteria for MDS/MPNs and symptom improvement was assessed using the MPN-SAF TSS. Pts were treated at least for 16 weeks if no clear progression and those deriving a clinical benefit could continue on study. Serial blood counts, chemistry and bone marrow assessment were conducted to assure safety and assess efficacy. Spleen volume was measured by CT imaging and the percentage of spleen volume reduction (SVR) was captured. Daily measurements of the MPN-SAF were performed for up to 17 weeks while on study. Results A total of 29 pts were enrolled at 4 centers (Moffitt, John Hopkins, Cleveland Clinic and Dana Farber) between September 2019 and June 2022. The median age was 74 (63-87) years. The majority were white (93%) and male (62%) consistent with the known demographics of CMML. Most pts had CMML-0 (62%) and proliferative CMML (69%) by the French American British group criteria. Fifty nine percent were high risk by the Mayo Clinic CMML risk model. Two patients had prior hypomethylating agent treatment and two had prior hydroxyurea. The most common somatic mutations at baseline were TET2 (79%), SRSF2 (68%) and ASXL1(48%). NRAS (21%), CBL (37%), and JAK2 (21%) were seen at higher proportions than previously reported likely due to study inclusion criteria. The median duration of follow up was 16 months and at the data cut off 8 pts remains on treatment. The median duration on treatment was 4 mo (.5-23 mo). Treatment-related adverse events and reasons for discontinuation are similar to that reported in the initial phase 1/2 study. The overall response rate by MDS/MPN IWG criteria was 17%: 10% (3) partial response and 7% (2) marrow response; 69% (20) had stable disease and 14% (4) were not yet evaluable. In addition, a clinical benefit was achieved in 66% of pts (19/29). Among 20 pts evaluable for spleen response, 30% (6/20) achieved ≥ 35% SVR measured by CT scan and 10/20 (50%) had 10% or more SVR (Figure 1a). Fifty four percent of patients achieved MPN-SAF TSS >50% reduction at 60 days and all but four patients demonstrated an improvement in MPN-SAF TSS (Figure 1b). The estimated median overall survival was 24 months (95% CI 9-39). Conclusions Ruxoltinib demonstrated meaningful clinical activity in CMML patients with splenomegaly and/or high disease symptom burden. Two thirds of patients achieved clinical benefit, 33% had ≥ 35% SVR, and 54% had a reduction in TSS>50%. The overall survival compares favorably to historical data among higher risk CMML and the magnitude of symptomatic benefit is similar to that observed in primary myelofibrosis. Collectively, our data suggests that ruxolitinib is a viable therapeutic for patients with symptomatic CMML. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Safety and Effectiveness of Ruxolitinib in Real-World Patients with Myelofibrosis: A 2-Year Observational Study from Taiwan

Introduction Ruxolitinib (RUX) is an approved JAK1/JAK2 inhibitor for the treatment of intermediate or high-risk myelofibrosis, including primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (PPV-MF), and post-essential thrombocythemia myelofibrosis (PET-MF), but real-world safety and efficacy of RUX in Taiwan are not well understood. This study was conducted to evaluate the safety and efficacy of treatment with RUX with intermediate-2 or high risk PMF, PPV-MF or PET-MF in routine clinical practice. Method This 2-year, single-arm, multicenter, post-marketing surveillance registry collected data on the safety, tolerability, efficacy, and other clinical information of adult patients (pts) aged ≥20 years with a confirmed diagnosis of intermediate-2 or high-risk PMF, PPV-MF, or PET-MF who either received RUX or starting RUX in accordance with the general clinical practice in Taiwan. Primary endpoint included collection of adverse events (AEs), AE of special interest (AESIs; anemia, thrombocytopenia, leukocytosis, hepatitis B virus (HBV) infection or reactivation, tuberculosis (TB) infection, and other infections), and serious adverse events (SAEs) throughout the study. Key secondary endpoints included treatment duration, discontinuation rates, dosage of prescribed RUX, Myeloproliferative Neoplasm symptom assessment form (MPN-10) score after study entry and change in spleen size, specifically in naïve patients who were eligible for spleen response evaluation. Results A total of 99 (51% PMF, 22.4% PPV-MF, and 26.5% PET-MF) pts were recruited, of which 38 (38.4%) pts discontinued due to consent withdrawal (n=11), death (n=10), discontinued prescription of RUX for 3 months (n=4), AEs (n = 2), unsatisfactory therapeutic effect (n=2), administrative problems (n=1), disease progression (n=1), required immediate stem cell transplantation (n=1), and others (n=6). Median age was 68.1 (range: 38.3-87.2) years and gender ratio was balanced, with 97 Taiwanese pts (98.0%). Median disease duration was 13.9 months (range: 0-967.6 months) and 70.7% and 28.3% of pts were identified with the risk of intermediate-2 or high using IPSS/DIPSS risk assessment, respectively. Majority of the recruited pts were RUX pre-treated (n=75; 75.8%) and 24.2% (n=24) pts were RUX-naïve at baseline. During the study, 88 pts (89.8%) had 673 AEs, and 44 (44.9%) experienced 159 SAEs. Half of the pts (55.1%) had moderate or severe SAEs and 39 pts recovered. Over 80% of SAEs (n=131) were not related to RUX. Major AESIs were anemia (29.6%) and thrombocytopenia (20.4%). There were no HBV infection or reactivation reported; 2% of pts had TB while 3% of pts had herpes zoster infections. The major reported infection was pneumonia (20.4%). Key safety data are summarized in Table 1. Most pts had their AEs resolved (77.6%), while 10 deaths occurred due to AEs (10.2%). Majority of the pts (41.8%) received a daily dose of RUX 20 mg at the enrolment, with an average mean daily dose of 22.7±9.2 mg (Figure 1). For naïve pts, mean initial dose was 18.8 ± 8.50 mg and gradually titrated up to 22.3 ± 8.69 mg at 3 months and to 24.0 ± 9.17 mg at 6 months. Among 98 pts, 13.3% pts whose platelet counts between 100-200×103/μL and 21.4% pts whose platelet counts were >200×103/μL were treated with RUX 5-10 mg twice daily. Among 27 RUX pre-treated patients (mean RUX duration before study entry: 17.0 ± 20.98 months), spleen size by palpation was relatively stable throughout the study period. For the 7 RUX naïve pts, the mean spleen size change from baseline was -15.9 %± 28.72 at 12 weeks, -30.8% ± 31.28 at 24 weeks, -54.2% ± 41.93 at 48 weeks and -52.0% ± 36.41 at 96 weeks. However, it should be interpreted with caution due to the small pt pool. A total of 65 pts (65.7%) had >50% improvement in the symptom response by MPN-10 during 2-year study period. . Conclusion This is the first real-world study in Taiwan to evaluate safety and efficacy with RUX in patients with MF. It was observed that physicians employed a conservative strategy for a lower starting dose with gradual titration resulting in comparable safety profile, but lower incidences of thrombocytopenia compared to published clinical trials. The majority of pts reported continuous symptomatic improvement and a small number of RUX naïve pts had pronounced spleen size reduction. Further investigations are required to evaluate whether optimal dose of RUX or titration speed would improve spleen response. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal