Sleep Disturbance Among Individuals with Multiple Myeloma: The Interplay between Physical and Psychosocial Symptoms

Abstract Background: As long-term survival rates for multiple myeloma (MM) improve, and patients receive more prolonged courses of treatment, individuals living with MM experience cumulative physical symptom burden and psychosocial distress. However, the relationship between physical and psychosocial symptoms in MM remains poorly understood. Sleep disturbance is a common symptom in MM, and has been linked to both physical symptoms and psychological issues, including fatigue, mood disturbance, and decreased physical function. We test our hypothesis that the interaction between physical and psychosocial health is associated with sleep disturbance in a national sample of MM patients. Methods: Using data from the Cancer Support Community's Cancer Experience Registry®, our analytic sample includes 288 participants who reported MM as their primary diagnosis and completed the Patient-Reported Outcomes Measurement Information System (PROMIS-29v1.0), a self-reported measure of functioning in 7 domains (depression, anxiety, satisfaction with social roles, physical function, pain interference, fatigue, and sleep disturbance). The dependent variable in all analyses was the continuous T-score on the PROMIS sleep disturbance subscale. Our independent variables include psychosocial distress, operationalized using a continuous T-score on the PROMIS depression subscale, and physical symptom burden, which we calculate using patient-reported data on daily interference from peripheral neuropathy, bone pain, GI toxicity, and infection. Using multivariate regression, we predicted sleep disturbance from psychosocial distress and physical symptom burden, controlling for gender, age, race/ethnicity, time since diagnosis, and a dichotomous indicator of ever having received a stem cell transplant. Next, we calculated an interaction term (physical symptom burden X distress) to evaluate whether sleep disturbance is associated with the concurrent presentation of physical and psychosocial symptoms. Results: Overall, 17% of our sample reported levels of psychosocial distress that were more than one standard deviation above the national average on the PROMIS depression subscale. Approximately 6% fell above the national average for sleep disturbance. Our sample was 54% female, 86% White, and averaged 63 years of age (SD = 9), with a mean time since diagnosis of 4 years. Results of the multivariate analyses revealed that physical symptom burden and psychosocial distress were independently and positively associated with sleep disturbance (p < .05). In other words, greater physical symptom burden and higher levels of distress were linked to elevated sleep disturbance, after controlling for sociodemographic and clinical variables. Additionally, the interaction between physical symptom burden and psychosocial distress on sleep disturbance was statistically significant (p = .05). That is, the degree to which MM symptom burden is linked to sleep disturbance depends on psychological distress. Specifically, sleep disturbance is intensified for individuals living with MM when physical symptom burden is accompanied by distress. Overall, our results point to the important interplay of physical and psychological health for sleep. Conclusion: In the presence of physical symptom burden, sleep disturbance is exacerbated for individuals with psychosocial distress. Clinicians should consider screening for and addressing psychosocial distress when addressing sleep disturbance, particularly among those patients who also report physical symptoms. Indeed, assessing both physical and psychosocial symptoms will inform more comprehensive symptom management. We recommend referrals to inter-disciplinary teams with specialists that address both physical and psychosocial concerns. Disclosures Birhiray: Genomic Health: Patents & Royalties; Norvatis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eli-Lilly: Speakers Bureau; Alexion: Consultancy; Takeda: Research Funding, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Tessaro: Speakers Bureau; Pharmacyclics: Speakers Bureau; AstraZeneca: Speakers Bureau; Pfizer: Speakers Bureau; Excelis: Speakers Bureau; Puma: Research Funding, Speakers Bureau; Clovis Oncology: Speakers Bureau; Sanofi Oncology: Speakers Bureau; Incyte: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Helsinn: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees.

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Patient-Reported Outcome Results from the U.S. Life after Stopping TKIs (LAST) Study in Patients with Chronic Myeloid Leukemia

Blood ◽

10.1182/blood-2019-126002 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 705-705 ◽

Cited By ~ 1

Author(s):

Kathryn E Flynn ◽

Kevin P. Weinfurt ◽

Li Lin ◽

Jerald P. Radich ◽

Charles A. Schiffer ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Sleep Disturbance ◽

Board Of Directors ◽

Withdrawal Syndrome ◽

Myeloid Leukemia ◽

Research Funding ◽

Advisory Board ◽

Advisory Committees ◽

Patient Reported ◽

Tki Discontinuation

Background: Treatment of chronic myeloid leukemia (CML) with a tyrosine kinase inhibitor (TKI) offers significant improvements over previous treatments in terms of survival and toxicity yet has been associated with reduced health-related quality of life and very high cost. Discontinuing TKIs with regular monitoring is safe, but little is known about the impact of discontinuation on patient-reported outcomes (PROs). In the largest U.S. study to date, we evaluated molecular recurrence of CML and PROs after TKI discontinuation. Methods: The Life After Stopping TKIs (LAST) study was a prospective single-group longitudinal study. Key inclusion criteria were age > 18 years, patient on TKI therapy (imatinib, dasatinib, nilotinib, or bosutinib) for > 3 years with documented BCR-ABL < 0.01% by PCR for > 2 years, and no previous TKI resistance. We monitored disease outcome (PCRs by central lab) and PROs (PROMIS computerized adaptive tests via REDCap) monthly for the first 6 months, every 2 months until 24 months, then every 3 months until 36 months. Molecular recurrence was defined as > 0.1% BCR-ABL IS by central lab (loss of major molecular response [MMR]). We considered 3 points to be clinically meaningful and hypothesized that by 6 months after TKI discontinuation, fatigue, depression, sleep disturbance, and diarrhea would improve by at least 3 points each, corresponding to a standardized effect size of 0.3. Given reports of a withdrawal syndrome of musculoskeletal pain in some patients after discontinuation, pain was an additional outcome of particular interest. For each PRO domain, we estimated a polynomial piecewise linear mixed effects model that specified one nonlinear trajectory after TKI discontinuation and, for those with molecular recurrence, another trajectory after TKI restart. The models included patient-level random effects for the intercepts and linear slopes. Results: From 12/2014 to 12/2016, 172 patients enrolled from 14 U.S. sites. Median age was 60 years (range 21-86) and 89 (52%) were female. The median time on TKI prior to enrollment was 81 months (IQR 54-123). With a minimum follow-up of 24 months, 107 (62%) patients remained in a treatment free remission (TFR). Reasons for restarting therapy were: loss of MMR by central (n=56) or local (n=2) lab, patient decision (n=4), and withdrawal syndrome (n=3). Missing PRO data was minimal (< 5%) with > 2000 assessments completed. For patients in TFR at 6 months, the average estimated improvement in fatigue was 2.6 points (95% CI 2.5-2.7), depression was 1.9 points (95% CI 1.8-1.9), sleep disturbance was 0.9 points (95% CI 0.8-1.0), and diarrhea was 2.7 points (95% CI 2.6-2.7). The average estimated worsening in pain interference (i.e., the extent to which pain affects daily life) was 0.4 points (95% CI 0.3-0.5). The figure shows the distribution of estimated change for each domain at 6 months. All patients showed improvements in depression, diarrhea, and fatigue. About 1 in 6 patients (17%) experienced a clinically meaningful (i.e., at least 3 points) improvement in fatigue and/or diarrhea at 6 months. Conclusion: The LAST study is the largest US TKI discontinuation study to date, and the first to include comprehensive PRO measurement. For patients in TFR at 6 months, TKI discontinuation conferred modest benefits in fatigue and diarrhea on average, with a negligible increase in pain interference. Some patients experienced more notable improvements in fatigue and diarrhea. Planned secondary analyses will include change over time up to 3 years and evaluation of additional PRO domains, including anxiety, physical function, social function, and sexual function. Our results provide important new evidence to support shared patient-provider clinical decision making regarding TKI discontinuation for patients with CML. Figure. Disclosures Radich: Novartis: Other: RNA Sequencing; TwinStrand Biosciences: Research Funding. Mauro:Pfizer: Consultancy; Takeda: Consultancy; Novartis Oncology: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy. Pinilla Ibarz:Sanofi: Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Teva: Consultancy; Janssen: Consultancy, Speakers Bureau; Novartis: Consultancy; Takeda: Consultancy, Speakers Bureau; Bayer: Speakers Bureau; TG Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy. Larson:Celgene: Consultancy; Novartis: Honoraria, Other: Contracts for clinical trials; Agios: Consultancy. Oehler:Blueprint Medicines: Consultancy; NCCN: Consultancy; Pfizer Inc.: Research Funding. Deininger:Humana: Honoraria; Incyte: Honoraria; Blueprint: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Research Funding; Ascentage Pharma: Consultancy, Honoraria; TRM: Consultancy; Sangoma: Consultancy; Fusion Pharma: Consultancy; Adelphi: Consultancy; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Sangamo: Consultancy. Shah:Bristol-Myers Squibb: Research Funding. Ritchie:Tolero: Other: Advisory board; Celgene: Other: Advisory board; Celgene, Novartis: Other: travel support; Jazz Pharmaceuticals: Research Funding; Celgene, Incyte, Novartis, Pfizer: Consultancy; AStella, Bristol-Myers Squibb, Novartis, NS Pharma, Pfizer: Research Funding; Ariad, Celgene, Incyte, Novartis: Speakers Bureau; Genentech: Other: Advisory board; Pfizer: Other: Advisory board, travel support; agios: Other: Advisory board. Silver:PharmEssentia: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Cortes:Sun Pharma: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; BiolineRx: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Biopath Holdings: Consultancy, Honoraria; Immunogen: Consultancy, Honoraria, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding. Atallah:Jazz: Consultancy; Helsinn: Consultancy; Pfizer: Consultancy; Takeda: Consultancy, Research Funding; Jazz: Consultancy; Helsinn: Consultancy; Novartis: Consultancy.

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Improvements in Health-Related Quality of Life for Patients Treated with LentiGlobin for Sickle Cell Disease (bb1111) Gene Therapy

Blood ◽

10.1182/blood-2020-136193 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 10-10

Author(s):

Julie Kanter ◽

John F. Tisdale ◽

Markus Y Mapara ◽

Janet L. Kwiatkowski ◽

Lakshmanan Krishnamurti ◽

...

Keyword(s):

Sleep Disturbance ◽

Pain Intensity ◽

Physical Function ◽

Board Of Directors ◽

Sickle Cell ◽

Research Funding ◽

Pain Interference ◽

Advisory Committees ◽

Patient Reported ◽

Population Norm

Background In patients with sickle cell disease (SCD), health-related quality of life (HRQoL) is worse than in the general population and comparable or worse than in patients with other chronic or painful diseases such as cystic fibrosis or cancer. Targeting SCD pathophysiology may significantly improve HRQoL in addition to clinical outcomes. In the ongoing phase 1/2 HGB-206 Study (NCT02140554), which evaluates the safety and efficacy of LentiGlobin for SCD (bb1111) gene therapy (GT), the most recently treated cohort of patients (Group C) have demonstrated improvements in laboratory assessments, including a trend toward normalization in key hemolysis markers and improvements in total hemoglobin values, and near resolution of vaso-occlusive crises and acute chest syndrome (ACS), suggesting a fundamental effect on sickle cell pathophysiology. Patient-reported HRQoL outcomes through 12 months post-treatment are presented here. Methods Patients (≥12 and ≤50 years of age) with SCD and history of stroke or severe vaso-occlusive events, including acute episodes of pain and ACS, were enrolled. CD34+ cells collected by plerixafor mobilization/apheresis were transduced with BB305 lentiviral vector. LentiGlobin was infused following myeloablative busulfan conditioning. In addition to laboratory and clinical assessments, patients were monitored for patient-reported outcomes (PROs) using the PRO Measurement Information System (PROMIS)-57. PROMIS-57 assesses HRQoL using collection of short forms containing 8 questions for each of the 7 PROMIS domains (Depression, Anxiety, Pain Interference, Fatigue, Sleep Disturbance, in which a lower score denotes improvement, and Physical Function, Satisfaction with Participation in Social Roles, in which a higher score denotes improvement) and a 0-10 Pain Intensity numeric rating scale (NRS). PROMIS-57 has been validated in patients with SCD. Data were analyzed for ten Group C patients who had at least 12 months of follow-up and had completed PROMIS-57 assessments as of March 3, 2020. For each domain, patients were stratified into 2 sub-groups based on baseline scores and population norm (i.e., baseline scores "better" than or near the population norm and baseline scores "worse" than the population norm). The stratification was built upon the premise that patients with baseline scores "better" or near the population norm would not be expected to improve. The US general population norm was 2.6 for Pain Intensity and a T-score of 50 for all other domains. The minimal clinically importance difference (2-point difference for pain intensity NRS and 5-point difference for other domains) was selected based on the PROMIS guidelines and literature. Results Patients who had baseline scores "worse" than the population norm reported improvements in all domains at Month 6, which were sustained through Month 12. These patients reported clinically meaningful improvement in 6/8 domains; mean T-scores at baseline and Month 12 were 6 and 2.4 for Pain Intensity (n=5); 63 and 48 for Pain Interference (n=7); 62 and 48 for Anxiety (n=3); 62 and 44 for Depression (n=4); 39 and 60 for Satisfaction with Social Roles (n=5); and 40 and 56 for Physical Function (n=4), respectively. Only 1 patient was included in the analysis of Fatigue and Sleep Disturbance domains, thereby limiting the conclusions in these 2 domains (Figure 1). Patients who had baseline scores that were "better" or near than the population norm reported clinically meaningful improvements in the Physical Function (n=6) and Fatigue domains (n=9); mean scores at baseline and Month 12 were 49 and 55 for Physical Function and 50 and 43 for Fatigue, respectively. Among patients in this sub-group, Pain Intensity (n=5) and Pain Interference (n=3) scores were stable from Month 6 through Month 12; there was no clinically meaningful change for the Anxiety (n=7) and Depression (n=6) domains, however, worsening was observed in the Satisfaction with Social Role (n=4) and Sleep Disturbance (n=9) domains (Figure 1). Summary LentiGlobin for SCD GT improved HRQoL in all domains of PROMIS-57 for patients whose baseline scores were "worse" than the population norm, including clinically meaningful improvements in all evaluable (6/8) domains. Larger sample sizes are required to clarify the impact of LentiGlobin for SCD for some PROMIS-57 domains. Disclosures Kanter: SCDAA Medical and Research Advisory Board: Membership on an entity's Board of Directors or advisory committees; AGIOS: Membership on an entity's Board of Directors or advisory committees; BEAM: Membership on an entity's Board of Directors or advisory committees; Jeffries: Honoraria; Cowen: Honoraria; Wells Fargo: Honoraria; NHLBI Sickle Cell Advisory Board: Membership on an entity's Board of Directors or advisory committees; bluebird bio, inc: Consultancy, Honoraria; Novartis: Consultancy; Sanofi: Consultancy; Medscape: Honoraria; Guidepoint Global: Honoraria; GLG: Honoraria. Kwiatkowski:Terumo Corp: Research Funding; Imara: Consultancy; Celgene: Consultancy; Agios: Consultancy; bluebird bio, Inc.: Consultancy, Research Funding; Novartis: Research Funding; Sangamo: Research Funding; Apopharma: Research Funding; Bristol Myers Squibb: Consultancy. Chen:bluebird bio, Inc.: Consultancy. Gallagher:bluebird bio, Inc.: Current Employment, Other: Ownership Interest and Salary. Ding:bluebird bio, Inc.: Current Employment, Other: Salary. Goyal:bluebird bio, Inc.: Current Employment, Other: Ownership Interest and Salary. Paramore:bluebird bio, Inc.: Current Employment, Other: Ownership Interest and Salary. Thompson:bluebird bio, Inc.: Consultancy, Research Funding; BMS: Consultancy, Research Funding; CRISPR/Vertex: Research Funding; Baxalta: Research Funding; Biomarin: Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Walters:AllCells, Inc: Consultancy; Veevo Biomedicine: Consultancy; Editas: Consultancy.

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To Treat or Not to Treat? Understanding Treatment Patterns in Patients with Lower-Risk Myelofibrosis at the Time of Enrollment in the MOST Study

Blood ◽

10.1182/blood-2020-134958 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 49-51

Author(s):

Rami S. Komrokji ◽

Brady L. Stein ◽

Robyn M. Scherber ◽

Patricia Kalafut ◽

Haobo Ren ◽

...

Keyword(s):

Board Of Directors ◽

Lower Risk ◽

Research Funding ◽

Symptom Burden ◽

Risk Groups ◽

Treatment Patterns ◽

Low Risk ◽

Publicly Traded ◽

Advisory Committees ◽

Therapy Initiation

Background: Myelofibrosis (MF) is a chronic Philadelphia chromosome-negative myeloproliferative neoplasm (MPN) characterized by extramedullary hematopoiesis, bone marrow fibrosis, splenomegaly, constitutional symptoms, and diminished quality of life. Treatment decisions may involve a variety of factors including prognosis and symptomatology. Data regarding real-world disease and demographic factors that contribute to therapy initiation and choice in pts with lower risk MF are limited. This analysis of data from the ongoing Myelofibrosis and Essential Thrombocythemia Observational STudy (MOST; NCT02953704) assessed whether these factors differ for lower risk pts who were treated vs untreated at enrollment. Methods: MOST is a longitudinal, noninterventional, prospective, observational study in pts with MF or essential thrombocythemia enrolled at clinical practices within the US. Pts included in the analysis (≥18 y), had low risk MF by the Dynamic International Prognostic Scoring System (DIPSS; Blood. 2010;115:1703), or intermediate-1 (INT-1) risk by age >65 y alone. Pt data were entered into an electronic case report form during usual-care visits over a planned 36-month observation period. Pt-reported symptom burden was assessed using the MPN-Symptom Assessment Form (MPN-SAF); Total Symptom Score (TSS) was calculated (0 [absent] to 100 [worst imaginable]; J Clin Oncol. 2012;30:4098). Data were analyzed with basic descriptive and inferential statistics. Results: Of 233 pts with MF enrolled at 124 sites between 11/29/2016 and 03/29/2019, 205 were included in this analysis; 28 were excluded for being INT-1 risk for reasons other than age. Of the 205 pts, 85 (41.5%) were low- and 120 (58.5%) were INT-1 risk; 56.5% (48/85) and 59.2% (71/120), respectively, were being treated at enrollment. Pt characteristics are listed in Table 1A. Fewer low- vs INT-1 risk pts were JAK2 V617F or MPL positive, and more were CALR positive. The proportion of pts with palpable splenomegaly was similar for treated low- and INT-1 risk pts. In low risk pts, the proportion of pts with palpable splenomegaly was higher in untreated vs treated pts; whereas, in INT-1 risk pts, the opposite was observed (ie, lower proportion in untreated vs treated pts). Blood counts were generally similar across cohorts, except median leukocytes were lower for low risk treated pts and platelet counts were elevated in low- vs INT-1 risk pts. The proportion of pts with comorbidities was similar across cohorts, except for fewer cardiovascular comorbidities in low- vs INT-1 risk pts. Mean TSS was lower in low- vs INT-1 risk pts, but the proportion of pts with TSS ≥20 was greater in treated vs untreated pts in both low- and INT-1 risk groups. Fatigue was the most severe pt-reported symptom in all cohorts. Differences in mean TSS and individual symptom scores between risk groups were not significant (P > 0.05), except itching was worse among INT-1 risk pts (P=0.03). Physician-reported signs and symptoms were generally more frequent for untreated vs treated pts, irrespective of risk (all P > 0.05). Most low risk (69.4%) and INT-1 risk pts (61.2%) who were currently untreated at enrollment had not received any prior MF-directed treatment (Table 1B); the most common prior treatment among currently untreated pts was hydroxyurea (HU) in both risk groups. Of currently treated pts, HU was the most common MF-directed monotherapy at enrollment in low-risk pts, and ruxolitinib was most common in INT-1 risk pts. No low risk pts and few INT-1 risk pts were currently receiving >1 MF-directed therapy at enrollment. Conclusion: These real-world data from pts with MF enrolled in MOST show that a substantial proportion of both low- and INT-1 risk pts who had received treatment before enrollment were not being treated at the time of enrollment. Although watch-and-wait is a therapeutic option, the finding that many of these lower risk pts had in fact received prior therapies suggests an unmet need for effective and tolerable second-line treatment options. Treated pts had greater pt-reported symptom burden vs untreated pts, which suggests that high symptom burden may contribute to the decision for treatment. Prospective studies are needed to evaluate symptom burden change with therapy initiation. In this regard, future analyses of data from MOST are planned to assess the longitudinal evolution of the clinical characteristics, treatment patterns, and management of pts with MF. Disclosures Komrokji: Geron: Honoraria; Agios: Honoraria, Speakers Bureau; AbbVie: Honoraria; Incyte: Honoraria; Novartis: Honoraria; BMS: Honoraria, Speakers Bureau; JAZZ: Honoraria, Speakers Bureau; Acceleron: Honoraria. Stein:Incyte: Research Funding; Kartos: Other: educational content presented; Constellation Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Pharmaessentia: Membership on an entity's Board of Directors or advisory committees. Scherber:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Kalafut:Incyte: Current Employment, Current equity holder in publicly-traded company. Ren:Incyte: Current Employment, Current equity holder in publicly-traded company. Verstovsek:Incyte Corporation: Consultancy, Research Funding; Roche: Research Funding; Genentech: Research Funding; Blueprint Medicines Corp: Research Funding; CTI Biopharma Corp: Research Funding; NS Pharma: Research Funding; ItalPharma: Research Funding; Celgene: Consultancy, Research Funding; Gilead: Research Funding; Protagonist Therapeutics: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; PharmaEssentia: Research Funding; AstraZeneca: Research Funding; Promedior: Research Funding.

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Baseline Characteristics and Symptom Burden in RESPONSE: A Randomized, Open-Label, Phase 3 Study of Ruxolitinib In Polycythemia Vera Patients Resistant to or Intolerant of Hydroxyurea

Blood ◽

10.1182/blood.v122.21.4071.4071 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4071-4071 ◽

Cited By ~ 7

Author(s):

Alessandro M. Vannucchi ◽

Jean-Jacques Kiladjian ◽

Martin Griesshammer ◽

Tamás Masszi ◽

Simon Durrant ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Symptom Burden ◽

Open Label ◽

Phase 3 ◽

Advisory Committees ◽

Jak2 Inhibitor ◽

Open Label Phase ◽

Night Sweats ◽

Equity Ownership

Abstract Background Polycythemia vera (PV) is the most common of the myeloproliferative neoplasms and is characterized by elevated hematocrit requiring phlebotomy, splenomegaly, a variety of symptoms and increased thrombotic risk. Ruxolitinib, a JAK1/JAK2 inhibitor, was well tolerated and achieved rapid and durable clinical responses in a phase 2 study of patients (pts) with PV who were resistant to or intolerant of hydroxyurea (HU). Pts experienced phlebotomy independence, resolution of splenomegaly, and improvements in white blood cell (WBC) counts, platelet (PLT) counts, and disease-related symptoms. Here, we describe the baseline (BL) characteristics and symptom burden of pts in a phase 3 study of ruxolitinib in pts with PV who are resistant to or intolerant of HU. Methods RESPONSE is a randomized (1:1), open-label, phase 3 study (NCT01243944) comparing the efficacy and safety of ruxolitinib with best available therapy (BAT) in pts with PV who are resistant to or intolerant of HU (modified European LeukemiaNet criteria), have splenomegaly, and require phlebotomy for inadequate hematocrit (Hct) control. Fourteen disease-related symptoms were assessed on a scale of 0 (absent) to 10 (worst imaginable) using the modified Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF). Blinded data are presented here. Results BL demographic data are available for the 222 enrolled pts (Table). Apart from HU, other common prior medications for PV included interferons (15%), PLT aggregation inhibitors (10%), alkylating agents (3.6%), alkyl sulfonates (3.2%), pyrimidine analogues (1.8%), and nitrosoureas (1.4%). The majority of pts (54.5%) had 1 phlebotomy within 12 weeks prior to screening; 23.9% had 2 and 17.1% had 3 or more phlebotomies. RESPONSE BL demographics are generally similar in terms of age (60 years vs 57-67); sex (66% male vs 58%-68%); Hct (44% vs 45%-48%); and platelets (419 x 109/L vs 320-429 x 109/L) to other PV studies including trials of givinostat (Finazzi BJH 2013) and AOP2014 (Gisslinger ASH 2012) and the ECLAP-PV (Marchioli JCO 2005) and CYTO-PV studies (Marchioli NEJM 2012). At the time of writing, BL symptom data from the MPN-SAF were available for 164 pts (Table). Pts in this study reported a similar symptom burden as PV pts from a large study of pts with MPNs (Emanuel JCO 2012; N = 1425; PV, n = 538), including similar mean scores for early satiety, abdominal discomfort, concentration problems, night sweats, itching, and tiredness/fatigue. In addition, prior therapy may have adversely affected BL symptom burden, as many of these symptoms (concentration problems, night sweats, fatigue) have been shown to be worsened by the use of conventional therapy to strictly control Hct (< 45%) and cardiovascular risk (Emanuel EHA 2013). BL MPN-SAF symptom data for all 222 pts will be presented. In addition, correlations between BL EORTC QLQ-C30 and MPN-SAF scores will be presented. Summary/Conclusions Demographic and BL symptom data from the RESPONSE study demonstrated that pts with HU refractory or intolerant PV have a significant disease burden that includes a variety of symptoms. These findings are consistent with those of Emanuel (JCO 2012), which showed that pts with PV have a significant symptom burden and a reduced quality of life. Pts with PV in the RESPONSE study are representative of those who have been studied in other clinical trials for the treatment of PV. Disclosures: Vannucchi: Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Off Label Use: Ruxolitinib, a JAK1/JAK2 inhibitor, has been approved by the US Food and Drug Administration for the treatment of intermediate- or high-risk MF and by the European Commission and Health Canada for the treatment of disease-related splenomegaly or symptoms in adult patients with MF. Here, we describe the baseline (BL) characteristics and symptom burden of patients in a phase 3 study of ruxolitinib in patients with PV who are resistant to or intolerant of HU. Kiladjian:Novartis: Honoraria; Shire: Honoraria. Durrant:Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Sanofi: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Pane:Novartis: Consultancy, Honoraria; Shire: Honoraria. Harrison:Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; YM Bioscience: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Celgene: Honoraria; Shire: Speakers Bureau; SBio: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity’s Board of Directors or advisory committees. He:Incyte: Employment. Leopold:Incyte: Employment, Stock options Other. Li:Novartis: Employment, Equity Ownership. Pirron:Novartis: Employment, Equity Ownership. Lawniczek:Novartis: Employment. Verstovsek:Incyte: Research Funding.

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A 3-Part, Phase 2 Study of Bezuclastinib (CGT9486), an Oral, Selective, and Potent KIT D816V Inhibitor, in Adult Patients with Nonadvanced Systemic Mastocytosis (NonAdvSM)

Blood ◽

10.1182/blood-2021-147072 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3642-3642

Author(s):

Frank Siebenhaar ◽

Jason Gotlib ◽

Michael W. Deininger ◽

Daniel J. DeAngelo ◽

Francis Payumo ◽

...

Keyword(s):

Mast Cell ◽

Board Of Directors ◽

Research Funding ◽

Systemic Mastocytosis ◽

Symptom Burden ◽

Phase 2 ◽

Advisory Committees ◽

Management Committee ◽

Study Management ◽

Kit D816v

Abstract Systemic mastocytosis (SM) is characterized by mast cell infiltration of ≥ 1 extracutaneous organs and encompasses a spectrum of diagnoses that can range from a non-advanced to advanced disease (Shomali et al, 2018). There are two nonadvanced variants of SM: indolent systemic mastocytosis (ISM), which accounts for approximately 85% and smoldering systemic mastocytosis (SSM), which includes about 5% of the general SM population (Cohen et al, 2014, Jennings et al, 2014). ISM is characterized by 0 or 1 B-findings and SSM by 2 or more B findings and absence of organ damage or an associated hematologic neoplasm (Gotlib et al, 2018). There are currently no approved therapies to treat the underlying disease of ISM or SSM. Although anti-mediator therapies (e.g. anti-H1 and H2 antihistamines, leukotriene receptor antagonists, cromolyn sodium, corticosteroids) are used to control symptoms such as anaphylaxis, GI intolerance, and flushing to improve quality of life, their effectiveness and tolerability are variable. Many patients experience a persistently high symptom burden despite maximized anti-mediator therapies. Because the molecular pathogenesis of SM is driven by KIT D816V mutations in 95% of patients (Garcia-Montero et al, 2006, Jara-Acevedo et al, 2015, Vaes et al, 2017), other agents targeting this mutated kinase have been used to treat the spectrum of SM variants; however, toxicities such as cognitive impairment, GI effects, intracranial hemorrhage, and edema may limit dosing and thus efficacy. In addition to targeting KIT D816V, bezuclastinib was designed to avoid other closely related kinases with known liabilities, such as PDGFRα, PDGFRβ, wild-type KIT, VEGFR2 (KDR), and CSF1R (FMS). Furthermore, bezuclastinib has demonstrated minimal brain penetration and no CNS toxicities have been identified in preclinical studies. Preliminary clinical activity with bezuclastinib has been observed in patients with advanced solid tumors or locally advanced, unresectable, or metastatic gastrointestinal stromal tumor (GIST). A reduction in KIT exon 17 mutational burden was observed in patients treated with bezuclastinib. This reduction was temporally associated with a reduction in tumor burden supporting bezuclastinib as an active therapy in KIT-driven diseases (Wagner et al, 2018). This is a multi-center, Phase 2, double blind, placebo-controlled, 3-part clinical study to evaluate the safety, efficacy, and biomarker correlates (e.g. bone marrow mast cell percentage, serum tryptase level, and KIT D816V mutation burden) of the KIT inhibitor bezuclastinib in patients with ISM and SSM. This study will enroll patients with SSM and moderate-to-severe ISM who have inadequate control of their symptoms despite at least 2 anti-mediator treatments. Part 1 of the study is intended to determine the recommended dose of bezuclastinib in Part 2. Subjects will be randomized to placebo or 1 of 3 doses of bezuclastinib which will be administered in combination with a baseline regimen of best supportive care (BSC). Part 2 will evaluate the efficacy of bezuclastinib at the selected dose as compared with placebo. Efficacy will be measured by the reduction of symptom burden as assessed by the mastocytosis activity score (MAS), a disease specific patient reported outcome tool (Siebenhaar et al, 2018). In Part 3, patients who have completed treatment in Part 1 or Part 2 of the study, including those initially randomized to placebo, may participate in a long-term extension and receive open-label bezuclastinib in combination with BSC. The study will enroll approximately 138 subjects. Data from this study will support further development of bezuclastinib in SM. Disclosures Gotlib: Cogent Biosciences: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Chair for the Eligibility and Central Response Review Committee, Research Funding; PharmaEssentia: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kartos: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Deciphera: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Allakos: Consultancy; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Blueprint Medicines: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Deininger: Novartis: Consultancy, Research Funding; SPARC, DisperSol, Leukemia & Lymphoma Society: Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Part of a Study Management Committee, Research Funding; Blueprint Medicines Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Part of a Study Management Committee, Research Funding; Fusion Pharma, Medscape, DisperSol: Consultancy; Sangamo: Consultancy, Membership on an entity's Board of Directors or advisory committees. DeAngelo: Incyte: Consultancy; Jazz: Consultancy; Novartis: Consultancy, Research Funding; Pfizer: Consultancy; Servier: Consultancy; Takeda: Consultancy; Abbvie: Research Funding; Forty-Seven: Consultancy; Autolus: Consultancy; Amgen: Consultancy; Agios: Consultancy; Blueprint: Research Funding; Glycomimetrics: Research Funding. Payumo: Cogent Biosciences, Inc: Current Employment. Mensing: Cogent Biosciences, Inc.: Current Employment. Jolin: Cogent Biosciences: Current Employment. Sachs: Cogent Biosciences: Current Employment. George: Bristol Meyers Squibb: Consultancy; Blueprint Medicines: Consultancy; Celgene: Consultancy; Incyte Corporation: Consultancy. OffLabel Disclosure: study of investigational agent

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Rationale and Design of a Phase 3 Study to Evaluate the Efficacy and Safety of ION-682884 in Patients with Transthyretin-Mediated Amyloid Cardiomyopathy (ATTR-CM)

Blood ◽

10.1182/blood-2019-129269 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5764-5764 ◽

Cited By ~ 1

Author(s):

Rodney H Falk ◽

Morie A Gertz ◽

Merrill D Benson ◽

Gustavo Buchele ◽

Michela Brambatti ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Parent Compound ◽

Controlled Study ◽

Efficacy And Safety ◽

Phase 3 ◽

Advisory Committees ◽

Study Visit ◽

Clinical Events ◽

Patient Reported

Background: Transthyretin amyloidosis cardiomyopathy (ATTR-CM) is a life-threatening, irreversible condition, which can lead to heart failure (HF) and, ultimately, heart transplant or death. Despite the recent approval in United States of a TTR stabilizer (VYNDAQEL®-tafamidis meglumine;VYNDAMAX™-tafamidis) for the treatment of ATTR-CM, disease progression still occurs. This study aims to determine if treatment with AKCEA-TTR-LRx (ION-682884), an antisense oligonucleotide (ASO), is safe and superior to placebo in reducing the risk of cardiovascular (CV) death or CV clinical events in patients with hereditary (hATTR-CM) or wild-type ATTR-CM (wtATTR-CM). Study Design and Methods: AKCEA-TTR-LRx (ION-682884) is a follow-on compound that incorporates the Ligand-Conjugated Antisense (LICA) technology; in this case, a triantennary N-acetyl galactosamine (GalNAc) moiety which targets the asialoglycoprotein receptors (ASGPR) expressed abundantly on the hepatocyte cell surface. In comparison to inotersen, its parent compound, ION-682884 requires a lower dose and frequency of administration (27-fold smaller; 45mg SC Q4W) to achieve a similar reduction in ATTR, providing greater patient convenience. ION-682884-CS2 (EudraCT No: 2019-002835-27) is a Phase 3 global, double-blind, randomized, placebo-controlled study assessing the efficacy and safety of AKCEA-TTR-LRx (ION-682884) in hATTR-CM or wtATTR-CM patients receiving available background standard of care (SoC) therapy. Approximately 750 patients with a history of HF due to ATTR-CM will be randomized 1:1 to receive AKCEA-TTR-LRx (ION-682884) or placebo administered by subcutaneous injection once every 4 weeks. The main inclusion criteria include confirmed diagnosis of ATTR-CM by tissue biopsy or positive PYP/DPD scan, end-diastolic interventricular septum thickness of >12mm, NT-proBNP >600 pg/mL, NYHA class I-III and 6-minute walk distance (6MWD) >150 m. The main exclusion criteria include estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73m2, platelet count below the low limit of normality and urine protein/creatinine ratio (UPCR) ≥ 1000 mg/g. Patients are allowed to concomitantly receive tafamidis/tafamidis meglumine as SoC for ATTR-CM, if locally approved and available, per physician's discretion. The study consists of a 120-week Treatment Period and a 20-week Post-Treatment Evaluation Period. During each study visit, subjects will undergo laboratory tests, cardiac assessments (echocardiography), and functional evaluations. Patient-reported outcomes (PRO) will also be collected. Primary efficacy endpoint is the composite of CV mortality and frequency of CV clinical events (HF-related urgent visits requiring administration of IV diuretics and/or CV-related hospitalizations) at Week 120 study visit, analyzed by the Finkelstein-Shoenfeld method. This test is based on the principle of each patient in the study being compared with every other patient in a pairwise manner in hierarchical fashion. Secondary endpoints include the change from baseline in the 6MWD, Kansas City Cardiomyopathy Questionnaire score, rate of CV mortality, CV clinical events, and all-cause of mortality at Week 120. Additional exploratory endpoints include a change from baseline in cardiac imaging parameters, renal function, biomarkers, and PROs questionnaires and disease scores. An interim analysis on change from baseline in 6MWD is also planned at Week 60. All deaths and CV clinical events will be adjudicated by an independent, blinded Clinical Adjudication Committee, using predefined endpoint criteria. Conclusions: Despite recent advances, there is still a need for more efficacious, safe and convenient treatment options for ATTR-CM. The ION-682884-CS2 is a large Phase 3 trial designed to evaluate the clinical efficacy and safety of AKCEA-TTR-LRx (ION-682884) compared to placebo for the treatment of ATTR-CM. Figure Disclosures Falk: Ionis Pharmaceuticals: Consultancy. Gertz:Ionis/Akcea: Consultancy; Alnylam: Consultancy; Proclara: Membership on an entity's Board of Directors or advisory committees; Prothena Biosciences Inc: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Spectrum: Consultancy, Research Funding; Annexon: Consultancy; Appellis: Consultancy; Amgen: Consultancy; Medscape: Consultancy, Speakers Bureau; Physicians Education Resource: Consultancy; Abbvie: Other: personal fees for Data Safety Monitoring board; Research to Practice: Consultancy; Teva: Speakers Bureau; Johnson and Johnson: Speakers Bureau; DAVA oncology: Speakers Bureau; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; i3Health: Other: Development of educational programs and materials; Springer Publishing: Patents & Royalties; Amyloidosis Foundation: Research Funding; International Waldenstrom Foundation: Research Funding. Benson:Ionis Pharmaceuticals: Research Funding. Buchele:Ionis Pharmaceuticals: Employment. Brambatti:Ionis Pharmaceuticals: Employment. Tsimikas:Ionis Pharmaceuticals: Employment. Viney:Ionis Pharmaceuticals: Employment. Tai:Ionis Pharmaceuticals: Employment. Monteiro:Ionis Pharmaceuticals: Employment. Yang:Ionis Pharmaceuticals: Employment. O'Dea:Akcea Therapeutics: Employment. Karwatowska-Prokopczuk:Akcea Therapeutics: Employment. Schneider:Ionis Pharmaceuticals: Employment. Geary:Ionis Pharmaceuticals: Employment. Monia:Ionis Pharmaceuticals: Employment.

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Elipsis: A Longitudinal Study of Electronic Patient-Reported Outcomes, Actigraphy and Biomarkers to Identify and Assess at-Home Vaso-Occlusive Crises in Adults and Adolescents with Sickle Cell Disease

Blood ◽

10.1182/blood.v130.suppl_1.973.973 ◽

2017 ◽

Vol 130 (Suppl_1) ◽

pp. 973-973

Author(s):

Michael U. Callaghan ◽

Patrick C. Hines ◽

Debra D Pittman ◽

David Beidler ◽

Denis Rybin ◽

...

Keyword(s):

Clinical Trials ◽

Board Of Directors ◽

Research Funding ◽

Patient Reported Outcomes ◽

Clinical Laboratory ◽

Advisory Committees ◽

Pain Scores ◽

Patient Reported ◽

Platelet Aggregates ◽

At Home

Abstract Clinical trials in sickle cell disease (SCD) continue to have challenges achieving clinical endpoints. Most SCD clinical trials have focused on painful vaso-occlusive crisis (VOC) episodes because they are prevalent, debilitating and often lead to medical contact. However with VOC as a clinical endpoint: there are no objective, quantifiable biomarkers of pain; pain may not be specific to VOC; the threshold for medical contact varies between patients; VOCs occurring at home without medical contact are not captured; other components of VOC (e.g., fatigue, functioning) are poorly assessed. We therefore undertook the present non-interventional, longitudinal study to test novel tools for the identification of VOCs occurring in SCD patients with varying degrees of medical contact. During 6 months of evaluation, longitudinal measures of pain, fatigue, function, activity (by actigraphy), clinical laboratory and biomarker samples from SCD patients (+/- hydroxyurea therapy) in steady state to VOC were studied. A novel electronic patient-reported outcome tool (ePRO) enabled patients to self-report daily pain, fatigue, function, and medication use. It was also used to report VOC in real time, triggering an alert to a mobile phlebotomy team. Blood collections were taken within 24 and 48 hours of self-reported VOC onset (either at home, emergency department [ED], or hospital). Follow-up blood samples were collected 2 days after resolution of the VOC. Baseline blood samples were drawn at home every 3 weeks during stable, non-VOC periods. Biomarker assays included leukocyte-platelet aggregates and circulating microparticles measured by flow cytometry, cell adhesion in microfluidic flow-based assays to immobilized vascular cell adhesion molecule or P-selectin, and a panel of soluble adhesion molecules, cytokines, inflammatory mediators and coagulation factors. Patients wore a Phillips Actiwatch Spectrum™ actigraphy device to track sleep and activity. Patient-reported outcomes, activity, and biomarkers on non-VOC days were compared to those on VOC days using a mixed model approach and results are reported as means with 95% confidence intervals (95%CI). In this study 27 of 35 patients experienced a total of 286 days with VOC >4 hr (VOC days), of which only 58 days (20%) resulted in healthcare utilization such as contacting provider, visiting ED and/or hospitalization. VOC days had significantly higher pain scores (scale: 0-10) with worst pain score increased by 4.5 (95% CI 4.3-4.7) compared to non-VOC days. VOCs requiring medical contact had significantly higher worst pain scores compared to at-home VOCs. Similar changes observed with reported least, average and pain right now. VOC days had significantly higher fatigue scores by 2.3 (95% CI 2.1-2.5) points (scale: 0-10). However, fatigue scores during at-home VOCs were not different from VOCs requiring medical contact. VOC days were associated with significantly decreased functional scores (physical, social, self-care and role activity), with significantly greater decreases during VOCs requiring medical contact compared to at-home VOCs. Different activity profiles were identified for non-VOC, at-home VOC and medical contact VOC days by actigraphy monitoring. At-home VOC days exhibited increased (34%, 95% CI 9%-64%) daytime resting compared to non-VOC days. Medical contact VOCs had decreased average and peak activity, and increased daytime resting compared to non-VOC days. A sleep fragmentation index trended up for both at-home (16%) and medical contact VOC days (18%). Significant changes during VOC days were observed in a subset of clinical laboratory and biomarker measures. Examples include: C-reactive protein (54% increase) and nucleated RBC (34% increase) in the clinical laboratory panel; monocyte-platelet aggregates (25% increase) and neutrophil-platelet aggregates (35% increase) in the biomarker panel. This innovative at-home study design demonstrates the feasibility of monitoring out of hospital pain and use of patient-reported VOC day as a potential endpoint for clinical trials. Electronic patient-reported outcomes, actigraphy and clinical laboratory and biomarkers may enable improved identification and assessment of at-home VOCs for further clinical studies. Disclosures Callaghan: CSL Behring: Membership on an entity's Board of Directors or advisory committees; Grifols: Membership on an entity's Board of Directors or advisory committees; Biogen: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Other: Site PI; Baxalta: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche/Genentech: Membership on an entity's Board of Directors or advisory committees, Other: Site PI, Speakers Bureau; Octapharma: Membership on an entity's Board of Directors or advisory committees; Alnylam Pharmaceuticals, Inc: Other: Owns stock, stock options, or bonds ; Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer HealthCare; Pfizer Inc.; Roche; Shire: Consultancy; Sancillio: Other: Site PI; Bayer: Membership on an entity's Board of Directors or advisory committees; Pfizer Inc.: Membership on an entity's Board of Directors or advisory committees, Other: Site PI, Research Funding; Roche; Shire: Speakers Bureau; Novo Nordisk: Speakers Bureau. Pittman: Pfizer: Employment. Beidler: Pfizer: Employment. Rybin: Pfizer: Employment. Liu: Functional Fluidics: Employment. Pleil: Pfizer: Employment. Barsdorf: Pfizer: Employment. David: Pfizer: Employment. Simmons: Pfizer: Employment. Frelinger: Baxalta: Research Funding; Ionis: Research Funding; Sysmex: Research Funding; Pfizer: Research Funding; Ironwood: Research Funding; GLSynthesis: Research Funding. Michelson: Eisai: Research Funding; Ionis: Research Funding; Ironwood: Research Funding; Pfizer: Research Funding; Sysmex: Research Funding; GLSynthesis: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Instrumentation Laboratory: Consultancy; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Elsevier: Patents & Royalties; Baxalta: Research Funding. Clarke: Pfizer: Employment. Charnigo: Pfizer: Employment.

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Symptom Burden in "Low Risk PV" Frequently Is Problematic and May Justify Earlier Intervention with Cytoreductive Therapy: An MPN-QOL Study Group Study

Blood ◽

10.1182/blood-2020-134583 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 47-48

Author(s):

Ruben Mesa ◽

Heidi E. Kosiorek ◽

Alessandra Carobbio ◽

Tiziano Barbui ◽

Amylou C. Dueck

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Treatment Guidelines ◽

Symptom Burden ◽

Low Risk ◽

Study Group ◽

Advisory Committees ◽

Specific Symptom ◽

Hemorrhagic Events ◽

The Impact

Background: Historical treatment guidelines for the myeloproliferative neoplasm, polycythemia vera (PV), have generally not recommended cytoreductive therapy for "low risk" PV (age <60 and no prior thrombo-hemorrhagic events (TH)) on the hypothesis that decreasing the risk of TH events is the only goal of therapy for PV. The MPN-QOL Study Group has previously reported on the presence of PV associated symptoms, sometime severe, in PV including "low risk" PV patients. Recently, data from the ongoing "Low PV" interventional trial of RoPEG Interferon (INF) vs. Phlebotomy alone suggests an advantage in symptom control and event free survival in "low risk" PV patients treated on the RoPEG INF cytoreductive arm (LBA EHA 2020). Given this latter trial might alter the approach to managing "low risk" PV patients we sought to assess the symptom burden (with or without cytoreductive treatments) in that population. Methods: MPN patient data was collected prospectively amongst an international cohort of PV patients including symptom burden, demographics, and disease features collected by IRB approved de-identified survey questionnaires (N=2,017, of which 698 had PV). We analyzed data from a subgroup consistent with "low risk PV" (age <60, no prior thrombo-hemorrhagic events). All participants completed the MPN-specific symptom burden questionnaire (MPN-SAF TSS [MPN-10]) and had no prior history of splenectomy. Surveyed symptoms on the MPN-10 included the patient's perceptions of common MPN-related symptoms and overall quality of life (QOL) on a 0 (absent) to 10 (worst imaginable) scale. Results: A total of 211 "low risk" PV patients were identified, of which 140 (66.4%) had received some form of cytoreductive therapy (hydroxyurea = 54%; pegylated interferon = 44%; and anagrelide = 2%), with those patients not on cytoreductive therapy being statistically significantly younger (M=48.2±8.74 years vs. M=50.6±7.41 years), having a shorter duration of an MPN diagnosis (M=4.6±4.82 years vs. M=6.7±6.00 years), and higher hemoglobin (M=16.9±3.26 vs. M=15.2±2.37), higher hematocrit (M=50.6±9.83 vs. M=45.5±7.10), higher leukocyte (M=10.8±4.25 vs. M=7.5±4.72), and higher platelet counts (M=508.1±317.19 vs. M=327.8±190.52) at the time of MPN symptom assessment (Table 1). The entire cohort was quite symptomatic with 87% (n=184/211) of patients endorsing fatigue, but overall the PV patients on cytoreduction were more symptomatic (mean MPN-10 of 24.7 (cytoreduction) vs 18.5 (no cytoreduction) p=0.01) with significantly higher levels of fatigue (p=0.04), bone pain (p=0.04), fever (p=0.001) and weight loss (p=0.04) in cytoreductive group (Table 2). Conclusions: "Low risk" PV patients are frequently symptomatic, and an unselected series from the MPN-QOL Study Group demonstrates significant symptomatic unmet needs in this population potentially supporting the need and potential benefit of cytoreductive therapy. "Low risk" PV patients (even before the impact of the Low PV Study is realized) also have frequently been receiving cytoreductive therapies, even though they have not been included in treatment guidelines, and typically have higher symptom burden despite lower counts, are older, and have longer duration of MPNs. Drivers of the decision to use cytoreductive therapy was not captured, but it is possible longer duration of disease, higher symptom burden, intolerance of phlebotomy might all be contributing factors. These results show there is both unmet need, and frequent heterogeneity amongst "low risk" PV patients, the final results of the Low PV Study are anticipated with great interest. Disclosures Mesa: Novartis: Consultancy; LaJolla Pharmaceutical Company: Consultancy; Samus Therapeutics: Research Funding; Sierra Oncology: Consultancy; Genentech: Research Funding; Incyte: Research Funding; AbbVie: Research Funding; CTI BioPharma: Research Funding; Promedior: Research Funding; Bristol Myers Squibb: Research Funding. Barbui:Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; AOP: Membership on an entity's Board of Directors or advisory committees.

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Being Present-CML: A Distress Reduction Intervention for Patients with Chronic Myeloid Leukemia Taking Tyrosine Kinase Inhibitors

Blood ◽

10.1182/blood-2021-152076 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4051-4051

Author(s):

Kelly L. Schoenbeck ◽

Anand Dhruva ◽

Albert Lee ◽

Neha G. Goyal ◽

Adrienne K. Yang ◽

...

Keyword(s):

General Population ◽

Sleep Disturbance ◽

Myeloid Leukemia ◽

Research Funding ◽

Mindfulness Meditation ◽

Kinase Inhibitors ◽

Median Number ◽

Pain Interference ◽

Advisory Committees ◽

Patient Reported

Abstract Background: Tyrosine kinase inhibitors (TKIs) enable patients with chronic phase chronic myeloid leukemia (CP-CML) to achieve similar overall survival to the general population, but can cause side effects that negatively impact quality of life (QOL) and contribute to distress. Since most CP-CML patients remain on TKIs indefinitely, there is a need to develop targeted interventions to address their physical and psychosocial complications. Mindfulness meditation interventions have improved QOL and decreased distress, depression, anxiety, fatigue, and pain in patients with solid tumors; however, such interventions have not previously been evaluated in patients with CP-CML. In Being Present-CML, we sought to determine if a mindfulness meditation-based program is feasible and acceptable to patients with CP-CML, and to explore its preliminary efficacy. Methods: Being Present-CML is a prospective, single-arm clinical trial of an 8-week, online mindfulness meditation-based intervention effective in patients with gastrointestinal cancers (Atreya, et al. PLoS One, 2018). Participants were recruited from a single academic institution. Eligibility included adult patients with CP-CML taking TKIs. Participants were instructed to independently play audio-guided meditations at least 5 times per week on a secure website and to participate in once weekly, instructor-led meditation classes on Zoom in assigned cohorts. Qigong was incorporated into the classes to target fatigue, a common TKI side effect. Class content was recorded and uploaded to the website for those unable to attend live. Feasibility was assessed through measurement of recruitment and attrition. Adherence was determined by web capture. Acceptability was determined by feedback from study surveys and qualitative interviews. Preliminary efficacy was evaluated using patient-reported outcome measures (PROMs) at baseline (week 0) and post-intervention (week 8) using the NCCN Distress Thermometer (DT) and Patient-Reported Outcomes Measurement Information System (PROMIS) short forms for anxiety, depression, fatigue, pain interference, and sleep disturbance. A DT score ≥4 is consistent with moderate to severe distress. PROMIS scores use T-scores where the mean score for the general population is 50 (standard deviation [SD] +/-10); higher scores indicate worse symptoms. Descriptive statistics and two-tailed paired t-tests (p <0.05) were used to summarize the data. Results: Between October 2020-April 2021, 98 eligible participants were approached to participate in the study; 88 (89.8%) patients agreed to learn more, and 37 (37.8%) patients provided consent. The median age was 51 (range 23-72), 51.5% (n=19/37) were male, and 89.1% (n=33/37) were non-Hispanic White. At time of study start, 83.7% (n=31/37) had a BCR-ABL1 PCR transcript ≤1% and a median time since diagnosis of 71 months (range 2-234) (Table 1). Of 37 participants, 29 (78.4%) completed end of study procedures; 4 (10.8%) dropped out, and 4 (10.8%) did not complete week 8 surveys. The median number of audio meditations listened to per participant was 34 with an average of 4.3 per week. The median number of weekly classes attended and/or recordings viewed per participant was 7 (range 1-8). At baseline, participants had a median DT score of 5 (range 2-8). Average baseline PROMIS scores were slightly worse than the general population in depression (51.4, SD 8.8), anxiety (55.9, SD 7.8), sleep disturbance (51.8, SD 6.9), fatigue (53.9, SD 10.6), and pain interference (52.2, SD 9.9). By week 8, the median DT score improved to 3 (p=0.003) (Figure 1). Post-study PROMIS scores improved in sleep disturbance (p=0.001) and depression (p=0.01) (Figure 2), but not anxiety (p=0.12), fatigue (p=0.10), or pain interference (p=0.98). Of those who conducted post-study interviews, 77% (n=20/26) reported their symptoms during the study were not influenced by the COVID-19 pandemic. Nearly all participants found the study helpful (Figure 3) and would recommend it to others (median score of 8 on a 1-10 scale; 10=extremely likely). Conclusions: Patients with CP-CML taking TKIs found the mindfulness meditation-based intervention to be feasible and acceptable. PROM results suggest promise of clinical benefit in this patient population, including patients with well-controlled disease and a long history of CML. A randomized controlled trial is being planned to validate these findings. Figure 1 Figure 1. Disclosures Smith: Astellas Pharma: Consultancy, Research Funding; FUJIFILM: Research Funding; Daiichi Sankyo: Consultancy; Revolutions Medicine: Research Funding; AbbVie: Research Funding; Amgen: Honoraria. Shah: Bristol-Myers Squibb: Research Funding. Atreya: Guardant Health: Research Funding; Pionyr Immunotherapeutics: Membership on an entity's Board of Directors or advisory committees; Array Biopharma: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Bristol-Meyers Squibb: Research Funding; Gossamer Bio: Research Funding; Novartis: Research Funding.

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Symptom Burden and Health-Related Quality Of Life (HRQoL) In Patients With Myelofibrosis (MF) Treated With Fedratinib (SAR302503) In a Phase III Study (JAKARTA)

Blood ◽

10.1182/blood.v122.21.4061.4061 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4061-4061 ◽

Cited By ~ 1

Author(s):

Ruben A. Mesa ◽

Jorge E. Cortes ◽

Francisco Cervantes ◽

Donald Milligan ◽

Tamás Masszi ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Symptom Burden ◽

Phase Iii ◽

Spleen Volume ◽

Advisory Committees ◽

Night Sweats ◽

Symptom Response ◽

Phase Iii Study ◽

Ecog Ps

Abstract Introduction Fedratinib (SAR302503), a JAK2-selective inhibitor, has demonstrated clinical improvements in splenomegaly and constitutional symptoms in patients with MF in Phase I/II trials (J Clin Oncol 2011;29:789. Haematologica 2013;98:S1113). The aim of this primary analysis was to determine the effect of fedratinib on key MF symptom burden and global assessment of HRQoL in the JAKARTA trial (NCT01437787). Methods JAKARTA is a double-blind, placebo-controlled, international, 3-arm, Phase III study, in which patients ≥18 years of age with intermediate- or high-risk MF, platelet count ≥50 × 109/L, and splenomegaly were randomized (1:1:1) to receive placebo or fedratinib at a dose of 400 or 500 mg, orally, once daily, in consecutive 4-week cycles. Total symptom score (TSS), a key efficacy end point (TSS: averaged daily total score of 6 item measures over 1 week: night sweats, pruritus, abdominal discomfort, early satiety, pain under ribs on left side, and bone or muscle pain), was assessed through a daily electronic eDiary using the modified Myelofibrosis Symptom Assessment Form (MFSAF; Cancer 2011;117:4869. Blood 2011;118:401), with symptom response defined as a ≥50% reduction in TSS at the end of Cycle 6 (EOC6). HRQoL was assessed using the EuroQOL (EQ)-5D instrument that was completed at baseline and EOC6. Patient performance was assessed using the Eastern Cooperative Oncology Group Performance Scale (ECOG PS). Spleen volume was measured by MRI or CT at baseline and EOC6. Results In JAKARTA, a total of 289 patients were randomized: median age 65 years; 59% male; 63% primary MF; 48% high-risk MF; 67% JAK2V617F positive; 16% platelet count <100 × 109/L. The symptom evaluable population comprised 261 patients (placebo [n=82]; 400 mg [n=89]; 500 mg [n=90]). The mean (SD) baseline TSS was 14.6 (11.9), 17.6, (13.5), and 16.9 (11.9) in the placebo, 400 mg, and 500 mg groups, respectively. At Week 24 (EOC6), the proportion of patients with a symptom response was significantly higher (p<0.0001) in the 400 and 500 mg groups versus placebo (Table). Symptom responses with fedratinib were also higher than placebo in the subgroup of patients with baseline platelets <100 × 109/L (Table). For individual symptoms, the greatest improvements were seen for night sweats and early satiety (Table). Baseline HRQoL (EQ-5D, mean [SD]) was similar in the three groups (placebo: 62.5 [21.2]; 400 mg: 61.3 [22.2]; 500 mg: 60.1 [20.1]). Fedratinib treatment led to improvements in HRQoL from baseline to Week 24, whereas placebo treatment led to slight worsening of HRQoL (Table). At Week 24, the degree of improvement in TSS was greatest in patients with ≥35% reduction in spleen volume from baseline (Figure). Mean TSS improvement was correlated with improvement in HRQoL (TSS reductions were greater in EQ-5D improvers versus non-improvers), and ECOG PS (TSS reductions were greater in patients with ECOG PS 1 or 2 score improvement versus those with ECOG PS worsening). Conclusions Fedratinib treatment over 24 weeks led to significant improvements in MF symptoms versus placebo. Patients treated with fedratinib also experienced substantial improvements in HRQoL versus placebo. Symptom improvements were associated with spleen responses. This study was sponsored by Sanofi. Disclosures: Mesa: Incyte, Genentech, Lilly, MS Pharma, Gilead: Research Funding. Cortes:Incyte, Sanofi: Consultancy; Incyte, Sanofi: Research Funding. Cervantes:Novartis: Speakers Bureau; Novartis and Sanofi: Membership on an entity’s Board of Directors or advisory committees. Jourdan:Sanofi: Honoraria. Vannucchi:Novartis: Membership on an entity’s Board of Directors or advisory committees. Drummond:TargeGen, Novartis: Speakers Bureau; Sanofi, Novartis, Celgene: Honoraria; Sanofi, Novartis, Celgene: Consultancy. Passamonti:Novartis, Celgene, Incyte, Sanofi, Roche: Honoraria. Neumann:Sanofi: Employment. Joulain:Sanofi: Employment. Iqbal:Sanofi: Employment. Harrison:Novartis: Research Funding; Novartis, Sanofi, YM Bioscience, Celgene, SBio, Gilead: Honoraria; Novartis, Sanofi, Shire: Speakers Bureau; Novartis, Sanofi, YM Bioscience, SBio, Gilead: Membership on an entity’s Board of Directors or advisory committees.

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