Modified Myelofibrosis Symptom Assessment Form Research Articles

P1057: REAL-WORLD UTILIZATION OF FEDRATINIB FOR MYELOFIBROSIS FOLLOWING RUXOLITINIB FAILURE

Background: In August 2019, fedratinib (FEDR) became the second treatment, after ruxolitinib (RUX), to be approved for intermediate (Int)- or high-risk (HR) primary or secondary myelofibrosis (MF). Aims: To characterize real-world patient characteristics and treatment patterns for patients with MF receiving FEDR after RUX therapy in US clinical practices. Methods: Adults with Int- or HR MF initiating FEDR on or after August 16, 2019 (FEDR approval date) after discontinuing RUX were identified from community oncology practices. Eligible patients had ≥90 days of follow-up from FEDR initiation, completed ≥1 FEDR cycle, and had a spleen size assessment at FEDR initiation. Treating physicians completed electronic case report forms for the selected eligible patients, capturing patient characteristics at time of MF diagnosis and during RUX and FEDR therapy, including bone marrow fibrosis grade, biomarkers, risk score, performance status score, spleen size (cm above the costal margin), symptoms (per Modified Myelofibrosis Symptom Assessment Form version 4.0), and complete blood count data. Providers reported treatment dosing and modifications and dates/rationale for RUX treatment failure (defined a priori, including refractory or suboptimal response, disease progression [PD], or intolerance). Results: Among 150 eligible patients, the median age at diagnosis was 68 years; 55% were male, 68% were non-Hispanic White, 85% had primary MF, 55% were JAK2 V617F-positive, and 9% were JAK2/MPL/CALR-negative. RUX initiation dosage was ≥20 mg twice/daily (bid) for approximately 50% of patients. At RUX initiation, 65% had ECOG scores of 0/1, and 90% had palpable spleen (Table). A total of 19 patients (13%) had RUX dosage reductions due to neutropenia (7), thrombocytopenia (6), other adverse event (AE)/toxicity (3), patient request (2), and anemia (1); 4 patients (3%) had treatment interruptions due to thrombocytopenia (2), neutropenia (1), other AE/toxicity (1), and patient request (1); and 18 patients (12%) had dosage increases due to titration (13) and persistent MF symptoms (5). Primary reasons for RUX discontinuation were PD (70%), refractory or suboptimal response (25%), or intolerance (5%). RUX discontinuation due to PD was most often attributed to MF symptom return (65%), increased spleen size to >50% vs best achieved response (23%), and other reasons (12%). Median RUX duration was 4.0 months (IQR, 3.0–6.1) for refractory or intolerant patients and 11.7 months (IQR, 6.5–17.1) for those with PD. FEDR was initiated at 400 mg daily for 74% of patients. At FEDR initiation, 43% had International Prognostic Scoring System (IPSS)/Dynamic IPSS HR, 37% Int-2 risk, and 88% had palpable spleen; mean spleen size was 16.0 cm, and median platelet count was 98.0×109/L (Table). Symptoms reported at FEDR initiation included fatigue (72%), abdominal discomfort (51%), night sweats (44%), early satiety (25%), bone pain (18%), itching (13%), and pain under the left rib (13%). At the end of follow-up, 44 patients (29.3%) were deceased, and mean time to death among deceased patients was 6.5 (standard deviation, 2.7) months from initiation of FEDR. Image:Summary/Conclusion: This study showed a short duration of RUX therapy for real-world patients with MF, and poorer clinical status at FEDR initiation than at RUX initiation. Patients at risk of early failure of RUX should be considered for earlier FEDR interventional treatment.

Real-World Utilization of Fedratinib for Myelofibrosis Post-Ruxolitinib: Patient Characteristics, Treatment Patterns, and Characterization of Ruxolitinib Failure

Real-World Utilization of Fedratinib for Myelofibrosis Post-Ruxolitinib: Patient Characteristics, Treatment Patterns, and Characterization of Ruxolitinib Failure

An Open-Label, Phase II Study Of The JAK1 Inhibitor INCB039110 In Patients With Myelofibrosis

An Open-Label, Phase II Study Of The JAK1 Inhibitor INCB039110 In Patients With Myelofibrosis

Fedratinib Improves Myelofibrosis-related Symptoms and Health-related Quality of Life in Patients with Myelofibrosis Previously Treated with Ruxolitinib: Patient-reported Outcomes from the Phase II JAKARTA2 Trial.

Myelofibrosis symptoms compromise health-related quality of life (HRQoL). Ruxolitinib can reduce myelofibrosis symptom severity, but many patients discontinue ruxolitinib due to loss of response or unacceptable toxicity. Fedratinib is an oral, selective JAK2 inhibitor approved in the United States for treatment of patients with intermediate-2 or high-risk myelofibrosis. The single-arm, phase II JAKARTA2 trial assessed fedratinib 400 mg/d (starting dose) in patients with myelofibrosis previously treated with ruxolitinib. Patient-reported changes in myelofibrosis symptom severity using the modified Myelofibrosis Symptom Assessment Form (MFSAF), and overall HRQoL and functional status using the EORTC QLQ-C30, were evaluated at each cycle. Clinically meaningful changes from baseline HRQoL scores were based on effect sizes. Ninety patients were MFSAF-evaluable. Myelofibrosis symptoms were mild-to-moderate at baseline. Patients showed statistically significant and clinically meaningful improvements in total symptom scores from baseline on the MFSAF at all post baseline visits through the end of cycle 6 (EOC6). Baseline global health status/QoL and functional domain scores on the EORTC QLQ-C30 were meaningfully worse than in the general population. At EOC6, 44% of patients reported clinically meaningful improvements in global health status/QoL, and 30%–53% of patients experienced clinically meaningful improvement in QLQ-C30 functional domains across post baseline timepoints. Over 80% of ongoing patients perceived fedratinib as beneficial on the Patient’s Global Impression of Change questionnaire. Fedratinib effects were consistent among prognostically relevant patient subgroups. Patients with myelofibrosis previously treated with ruxolitinib experienced clinically meaningful improvements in myelofibrosis symptom burden, overall HRQoL, and functional status in the first 6 months of fedratinib treatment.

Patient-reported Effects of Fedratinib, an Oral, Selective Inhibitor of Janus Kinase 2, on Myelofibrosis-related Symptoms and Health-related Quality of Life in the Randomized, Placebo-controlled, Phase III JAKARTA Trial.

Patients with myelofibrosis (MF) experience an array of symptoms that impair health-related quality of life (HRQoL). Fedratinib, an oral, selective Janus-kinase 2 (JAK2) inhibitor, was investigated in the randomized, placebo-controlled, phase III JAKARTA study in adult patients with intermediate- or high-risk JAK-inhibitor-naïve MF. The effect of fedratinib 400 mg/d on patient-reported MF symptoms and HRQoL in JAKARTA was assessed. Participants completed the modified Myelofibrosis Symptom Assessment Form (MFSAF v2.0), which evaluates 6 key MF symptoms (night sweats, early satiety, pruritus, pain under ribs on the left side, abdominal discomfort, bone/muscle pain). The modified MFSAF v2.0 was completed during the first 6 treatment cycles and at end of cycle 6 (EOC6). Symptom response was a ≥50% improvement from baseline in total symptom score (TSS). Overall HRQoL was assessed by EQ-5D-3L health utility index (HUI) score. The MFSAF-evaluable population comprised 91/96 patients randomized to fedratinib 400 mg and 85/96 patients randomized to placebo. Mean baseline TSS was 17.6 and 14.7 for fedratinib and placebo, respectively, and mean EQ-5D-3L HUI was 0.70 and 0.72. Fedratinib elicited statistically significant and clinically meaningful improvements in TSS from baseline versus placebo at all postbaseline visits. Symptom response rates at EOC6 were 40.4% with fedratinib and 8.6% with placebo (OR 7.0 [95% CI, 2.9-16.9]; P < 0.001), and a significantly higher proportion of fedratinib-treated patients achieved clinically meaningful improvement from baseline on the EQ-5D-3L HUI at EOC6 (23.2% versus 6.5%; P = 0.002). Fedratinib provided clinically meaningful improvements in MF symptoms and overall HRQoL versus placebo in patients with JAK-inhibitor-naïve MF.

Treatment with Imetelstat Improves Myelofibrosis-Related Symptoms and Other Patient-Reported Outcomes in Patients with Relapsed or Refractory Higher-Risk Myelofibrosis

Treatment with Imetelstat Improves Myelofibrosis-Related Symptoms and Other Patient-Reported Outcomes in Patients with Relapsed or Refractory Higher-Risk Myelofibrosis

Fedratinib, an Oral, Selective Inhibitor of Janus Kinase 2 (JAK2), in Patients with Intermediate-2 or High-Risk Myelofibrosis (MF): Updated Results from the Randomized, Placebo-Controlled, Phase III JAKARTA Trial

Fedratinib, an Oral, Selective Inhibitor of Janus Kinase 2 (JAK2), in Patients with Intermediate-2 or High-Risk Myelofibrosis (MF): Updated Results from the Randomized, Placebo-Controlled, Phase III JAKARTA Trial

Health-Related Quality of Life (HRQoL) with Fedratinib, a Selective, Oral Inhibitor of Janus Kinase 2 (JAK2), in the Phase II JAKARTA2 Study in Patients with Intermediate- or High-Risk Myelofibrosis Previously Treated with Ruxolitinib

Health-Related Quality of Life (HRQoL) with Fedratinib, a Selective, Oral Inhibitor of Janus Kinase 2 (JAK2), in the Phase II JAKARTA2 Study in Patients with Intermediate- or High-Risk Myelofibrosis Previously Treated with Ruxolitinib

Health-Related Quality of Life (HRQoL) in Patients with Myelofibrosis Treated with Fedratinib, an Oral, Selective Inhibitor of Janus Kinase 2 (JAK2), in the Randomized, Placebo-Controlled, Phase III JAKARTA Study

Health-Related Quality of Life (HRQoL) in Patients with Myelofibrosis Treated with Fedratinib, an Oral, Selective Inhibitor of Janus Kinase 2 (JAK2), in the Randomized, Placebo-Controlled, Phase III JAKARTA Study

Fedratinib Induces Spleen Responses and Reduces Symptom Burden in Patients with Myeloproliferative Neoplasm (MPN)-Associated Myelofibrosis (MF) and Low Platelet Counts, who were Either Ruxolitinib-Naïve or were Previously Treated with Ruxolitinib

Fedratinib Induces Spleen Responses and Reduces Symptom Burden in Patients with Myeloproliferative Neoplasm (MPN)-Associated Myelofibrosis (MF) and Low Platelet Counts, who were Either Ruxolitinib-Naïve or were Previously Treated with Ruxolitinib

Practical Measures of Clinical Benefit with Ruxolitinib Therapy: An Exploratory Analysis of COMFORT-I

Background: In 2 phase III studies comparing the Janus kinase (JAK) 1 and JAK2 inhibitor ruxolitinib with placebo (Controlled Myelofibrosis Study with Oral JAK Inhibitor Treatment I [COMFORT-I]) or best available therapy (COMFORT-II), ruxolitinib treatment was associated with rapid and durable reductions in spleen volume, improved myelofibrosis (MF)-related symptoms and quality of life measures, and prolonged survival. However, the key measures of efficacy used in the COMFORT studies—magnetic resonance imaging/computed tomography (MRI/CT) to measure change in spleen volume and the modified Myelofibrosis Symptom Assessment Form v2.0 to assess change in MF-related symptoms—are not commonly used in clinical practice. Therefore, we analyzed the efficacy of ruxolitinib in COMFORT-I using practical, community-based measures of clinical benefit (spleen palpation and the Patient Global Impression of Change [PGIC] questionnaire).Methods: In COMFORT-I, patients (N = 309) with primary MF, post–polycythemia vera MF or post–essential thrombocythemia MF were randomized to receive ruxolitinib (n = 155) or placebo (n = 154). For this analysis, patients were divided into groups by degree of palpable spleen reduction and symptom improvement at week 12 as follows: patients with clinically relevant reductions in palpable spleen as defined by the International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European LeukemiaNet (ELN) consensus criteria (SPL), patients with “much improved” or “very much improved” symptoms as measured by the PGIC (PGIC), or patients who did not achieve SPL or PGIC (Neither). The Neither group encompassed patients with “minimally improved” symptoms with no worsening in palpable spleen or patients who achieved 10% reduction in palpable spleen with no worsening in symptoms (Minor), and patients who did not achieve any palpable spleen reduction or PGIC-assessed symptom improvement (None). Nonevaluable patients (4/155 for ruxolitinib and 13/154 for placebo) were not included in the analysis. Additional measures of clinical benefit assessed at week 12 included changes in spleen volume and changes in white blood cell (WBC) count. Durability of all measures of clinical benefit with longer-term ruxolitinib therapy was also evaluated.Results: At week 12, the majority (91.4%) of patients randomized to ruxolitinib achieved some clinical benefit as measured by palpable spleen reduction and/or PGIC-assessed symptom improvement, vs 31.9% of those assigned to placebo (Figure 1). Benefits in palpable spleen length reduction and PGIC-assessed symptom improvement achieved at week 12 with ruxolitinib were sustained at week 24. Benefits in palpable spleen length reduction were sustained with longer-term ruxolitinib therapy (median follow-up: 149 weeks). At week 12, ruxolitinib treatment was associated with meaningful reductions in spleen volume by MRI or CT and WBC count in patients who achieved SPL and PGIC criteria, while worsening spleen volume and WBC count was observed with placebo (Figure 2); these effects were durable with longer-term therapy. Patients who achieved neither SPL nor PGIC criteria by week 12 (n = 47; 31.1%) achieved a clinically meaningful reduction in spleen volume by MRI or CT (mean change, −25.6%) and decreased WBC counts (mean change, −7.4%) at week 12 (Figure 2). Patients who did not achieve any palpable spleen reduction or PGIC-assessed symptom improvement (n = 13; 8.6%) were generally older, more likely to have high-risk MF as assessed by the International Prognostic Scoring System, and had higher WBC counts, lower platelet counts, and worse fibrosis grade at baseline compared with those achieving defined palpable spleen length reduction and/or PGIC-assessed symptom improvement with ruxolitinib.Conclusions: Nearly all patients treated with ruxolitinib achieved some clinical benefit as assessed by practical measures of assessing efficacy (ie, palpable spleen reduction or PGIC-assessed symptom improvement) within 12 weeks of treatment initiation. Meaningful reductions in spleen volume and WBC count were observed in patients receiving ruxolitinib whether or not they achieved palpable spleen reduction by IWG-MRT/ELN consensus criteria or PGIC symptom improvement (“much improved” or “very much improved”) at week 12; these reductions were durable with long-term ruxolitinib therapy. [Display omitted] [Display omitted] DisclosuresMiller:Incyte Corporation: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Komrokji:Incyte Corporation: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Mesa:CTI: Research Funding; NS Pharma: Research Funding; Gilead: Research Funding; Incyte Corporation: Research Funding; Celgene: Research Funding. Sun:Incyte Corporation: Employment. Montgomery:Incyte Corporation: Employment. Verstovsek:Incyte Corporation: Research Funding.

Primary Analysis Results from an Open-Label Phase II Study of INCB039110, a Selective JAK1 Inhibitor, in Patients with Myelofibrosis

Primary Analysis Results from an Open-Label Phase II Study of INCB039110, a Selective JAK1 Inhibitor, in Patients with Myelofibrosis

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

IntroductionFedratinib (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). MethodsJAKARTA 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. ResultsIn 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). [Display omitted] ConclusionsFedratinib 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.

Efficacy and Safety Of Fedratinib (SAR302503/TG101348) In Patients With Intermediate- Or High-Risk Myelofibrosis (MF), Post-Polycythemia Vera (PV) MF, Or Post-Essential Thrombocythemia (ET) MF Previously Treated With Ruxolitinib: Interim Results From a Phase II Study (JAKARTA-2)

▪ BackgroundThe JAK1/JAK2 inhibitor ruxolitinib (RUX) is approved for treatment of myelofibrosis (MF). However, some patients do not respond to RUX, while others lose responsiveness or develop intolerance to RUX over time. Preclinical data also suggest that certain JAK2 mutations (eg the gatekeeper mutation M929I) may confer resistance to RUX (Leukemia 2012;26:708). Options for these RUX resistant/intolerant patients, particularly with regard to further JAK inhibitor therapy, are unclear. Fedratinib (SAR302503) is a JAK2-selective inhibitor which has demonstrated clinically meaningful reductions in splenomegaly and symptom burden in patients with MF, with an acceptable and consistent safety profile (J Clin Oncol 2011;29:789. Haematologica 2013;98:S1113). Fedratinib sensitivity in vitro is unaffected by the M929I mutation. This pre-specified interim analysis of the JAKARTA-2 study (NCT01523171) investigated the efficacy and safety of fedratinib in MF patients previously treated with RUX. MethodsJAKARTA-2 is a Phase II, multicenter, open-label, single-arm study of patients who previously received RUX for MF. Patients ≥18 yrs with splenomegaly and platelet count ≥50 ×109/L received fedratinib 400 mg orally, once daily for consecutive 4-wk cycles (permitted dose adjustment to 200–600 mg daily). Eligible patients had received ≥14 d RUX treatment, and had discontinued RUX for ≥14 d prior to starting fedratinib. Although there is no consensus definition of RUX resistance/intolerance, for the purpose of this study patients were classed (investigator assessment) as resistant (lack or loss of response) or intolerant to RUX. Primary endpoint for the interim analysis: spleen response rate (RR) (≥35% reduction in spleen volume from baseline at Wk 12 [MRI/CT blinded central review]) in the per-protocol (PP) population. Secondary endpoints: symptom RR (≥50% reduction in total symptom score [TSS: modified Myelofibrosis Symptom Assessment Form] from baseline to Wk 12) and safety. ResultsAt the cut-off date for this interim analysis, 27 patients had received fedratinib treatment (median RUX exposure 10.7 months [range 1.9–34.4]): median age 69 yrs; 56% male; 67% primary MF; 63% high-risk MF; 67% JAK2V617F positive; 41% platelet count <100 × 109/L; baseline median spleen volume 3190 mL [1072–7815]; baseline median TSS 19.6 [4.9–46.0]. Eighteen patients were considered resistant by the treating physician (8 lack of response, 3 disease progression, 7 loss of response; median RUX exposure 11.1 months [range 1.9–34.4]) and 9 intolerant (6 hematologic, 3 non-hematologic toxicity; median RUX exposure 9.2 months [2.9–33.2]) to RUX. Median fedratinib exposure to cut-off date: 4 cycles (range 1–10); 19 patients remain on treatment. Spleen RRs were 40% (8/20 PP patients) and 43% (3/7) in patients with baseline platelet count <100 ×109/L. Overall, 19% (5/26 evaluable patients) had a symptom response by Wk 12 (Table). The majority of patients had a reduction in TSS at Wk 12 (Figure). [Display omitted] The most common non-hematologic treatment-emergent adverse events (AEs) were gastrointestinal (nausea 67%; diarrhea 56%; vomiting 48%). Grade 3/4 diarrhea occurred in 2 patients; no Grade 3/4 vomiting or nausea. Anemia was the most common hematologic AE (all grades, 93%; Grade 3, 41%; Grade 4, 0%). Thrombocytopenia (all grades) occurred in 19 (70%) patients; Grade 3 in 6 patients and Grade 4 in 2 patients. One patient had Grade 3 AST elevations and 1 patient had Grade 3 hyperbilirubinemia. Seven patients (26%) discontinued treatment due to AEs. There were 2 deaths on study, both due to disease progression. ConclusionsInterim results from the JAKARTA-2 study indicate that once-daily fedratinib provides clinical benefit, through reduced splenomegaly and symptom burden, in MF patients previously treated with RUX. The safety profile was acceptable and manageable, with safety results to date consistent with those reported in previous trials of fedratinib. Sponsored by Sanofi. Disclosures: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. Jourdan:Sanofi: Honoraria. Kiladjian:Novartis, Celgene, AOP Orphan: Research Funding; Novartis, Sanofi, AOP Orphan: Honoraria; Novartis, Sanofi, AOP Orphan: Membership on an entity's Board of Directors or advisory committees. Cervantes:Novartis: Speakers Bureau; Novartis and Sanofi: Membership on an entity's Board of Directors or advisory committees. Niederwieser:Novartis Pharma: Consultancy. Cortes:Incyte, Sanofi: Consultancy; Incyte, Sanofi: Research Funding. Passamonti:Novartis, Celgene, Incyte, Sanofi, Roche: Honoraria. Reiter:Sanofi: Honoraria. Heidel:Novartis Inc.: Honoraria; Novartis Inc.: Research Funding; Novartis Inc.: Membership on an entity's Board of Directors or advisory committees. Silver:Sanofi: Consultancy; Sanofi: Research Funding; Sanofi: Honoraria. Winton:Sanofi: Research Funding. Gupta:Incyte, Novartis: Consultancy; Incyte, Novartis: Research Funding; Novartis: Honoraria. Gisslinger:AOP Orphan Pharmaceuticals, Novartis, Sanofi, Shire, Celgene, Janssen: Membership on an entity's Board of Directors or advisory committees; AOP Orphan Pharmaceuticals, Novartis, Sanofi, Shire, Celgene, Janssen: Honoraria. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees. Talpaz:Novartis, Bristol-Myers Squibb, Ariad, Deciphera: Research Funding; Novartis, Bristol-Myers Squibb, Ariad, Deciphera: Speakers Bureau. Zhang:Sanofi: Employment. Shi:Sanofi: Employment. Mesa:Incyte, Genentech, Lilly, MS Pharma, Gilead: Research Funding.

Results Of a Randomized, Double-Blind, Placebo-Controlled Phase III Study (JAKARTA) Of The JAK2-Selective Inhibitor Fedratinib (SAR302503) In Patients With Myelofibrosis (MF)

▪ BackgroundFedratinib (SAR302503) is a JAK2-selective inhibitor that has provided clinically meaningful reductions in MF-associated splenomegaly and symptoms in Phase I and II studies (J Clin Oncol 2011;29:789. Haematologica 2013;98:S1113). Here, we present efficacy and safety data from the Phase III JAKARTA study of fedratinib versus placebo in patients with MF (NCT01437787). MethodsIn this international double-blind, placebo-controlled, 3-arm study, patients aged ≥18 years with IPSS intermediate-2 or high-risk MF, platelet count ≥50 × 109/L, and splenomegaly were randomized (1:1:1) to receive placebo or fedratinib 400 mg or 500 mg, orally, once daily, in consecutive 4-week cycles. Patients who received placebo were eligible to cross-over to fedratinib (randomized 1:1 to 400 mg or 500 mg) following 6 cycles of treatment, or prior to Cycle 6 if the patient had disease progression. The primary endpoint was spleen response rate (RR) (≥35% reduction in spleen volume from baseline measured by MRI or CT at Week 24, and confirmed 4 weeks later). Secondary endpoints included symptom RR (≥50% reduction in total symptom score from baseline at Week 24, measured through a daily electronic eDiary using the modified Myelofibrosis Symptom Assessment Form [Cancer 2011;117:4869. Blood 2011;118:401]), and safety of fedratinib. ResultsA 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; median baseline spleen volume 2568 mL (range 316–8244); median baseline total symptom score 14.7 (0–57). Median (range) exposures for placebo, 400 mg and 500 mg groups were 24 (2–34), 30 (1–55) and 28 (1–60) weeks, respectively. Spleen RRs at Week 24 (placebo 1%; 400 mg 47%; 500 mg 49%), and confirmed at Week 28 (placebo 1%; 400 mg 36%; 500 mg 40%), were significantly (p<0.0001) higher in both fedratinib groups compared with placebo (Table). Nineteen patients had a spleen response at Week 24 not confirmed 4 weeks later (spleen reduction 25–35% [n=10]; image not available/evaluable [n=8]; image taken outside time window [n=1]). Spleen RRs by baseline platelet level are shown in the table. Patients treated with fedratinib had significantly (p<0.0001) greater improvements in MF symptoms compared with placebo (Table).The most common all grade non-hematologic treatment-emergent adverse event (TEAE) was diarrhea (16%, 66% and 56% of patients in the placebo, 400 mg and 500 mg groups, respectively). Grade 3/4 diarrhea was reported in 5% of patients in both the 400 mg and 500 mg dose groups. The most common hematologic TEAE was anemia (any grade 91%, 99% and 98%; Grade 3/4 25%, 43% and 60% in the placebo, 400 mg and 500 mg groups, respectively). Rates of Grade 3/4 thrombocytopenia were 9% (placebo), 17% (400 mg), and 27% (500 mg). Incidences of Grade 3/4 liver function tests (placebo/400 mg/500 mg) were: bilirubin, 2%/2%/1%; ALT, 0%/3%/3%; and AST, 1%/2%/2%. Overall treatment discontinuation rates up to 24 weeks of treatment were 25% (placebo), 22% (400 mg) and 32% (500 mg). Twenty-five patients died during the study (10, 5 and 10 in the placebo, 400 mg and 500 mg groups, respectively); the most common causes of death: disease progression (placebo [n=5]; 400 mg [n=3]; 500 mg [n=4]) and adverse events (placebo [n=4]; 400 mg [n=1]; 500 mg [n=4]). ConclusionsIn this Phase III, randomized, placebo-controlled, 3-arm study of 289 MF patients, treatment with fedratinib 400 mg or 500 mg once-daily demonstrated clinically meaningful and statistically significant reductions in splenic volume and MF-associated symptom burden versus placebo. Fedratinib had an acceptable safety profile, with the adverse events reported consistent with those observed in previous studies. This study was sponsored by Sanofi. Disclosures:Pardanani:Sanofi, Bristol Myers Squibb, PharmaMar and JW Pharma: Clinical trial support Other. 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. 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. Mesa:Incyte, Genentech, Lilly, MS Pharma, Gilead: Research Funding. Jourdan:Sanofi: Honoraria. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees. Drummond:Sanofi, Novartis, Celgene: Honoraria; TargeGen, Novartis: Speakers Bureau; Sanofi, Novartis, Celgene: Consultancy. Passamonti:Novartis, Celgene, Incyte, Sanofi, Roche: Honoraria. Neumann:Sanofi: Employment. Gao:Sanofi: Employment.

Long-Term Outcomes Of Ruxolitinib Therapy In Patients With Myelofibrosis: 3-Year Update From COMFORT-I

Long-Term Outcomes Of Ruxolitinib Therapy In Patients With Myelofibrosis: 3-Year Update From COMFORT-I

Progressive burden of myelofibrosis in untreated patients: Assessment of patient-reported outcomes in patients randomized to placebo in the COMFORT-I study

Patient-reported outcomes (PROs) and spleen size in patients not receiving therapy (N=154) in COMFORT-I, a randomized, double-blind study of the JAK1/JAK2 inhibitor ruxolitinib in patients with intermediate-2 or high-risk myelofibrosis were evaluated. Baseline PROs indicated considerable disease burden. European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 scores, modified Myelofibrosis Symptom Assessment Form v2.0 Total Symptom Score, and Patient Reported Outcome Measurement Information System Fatigue scores worsened from baseline through week 24. At weeks 4 and 24, 18.3 and 40.2% of patients evaluated their condition as having worsened from baseline on the Patient Global Impression of Change questionnaire. Spleen volume and palpable length increased in most patients. These results demonstrate the progressive and debilitating effects of myelofibrosis. The consequences of delayed intervention should be assessed in the management of patients with myelofibrosis and treatment should be considered as clinically indicated for symptomatic relief or splenomegaly control.

Effect of Ruxolitinib Therapy on Myelofibrosis-Related Symptoms and Other Patient-Reported Outcomes in COMFORT-I: A Randomized, Double-Blind, Placebo-Controlled Trial

To assess the effects of ruxolitinib on symptom burden and quality of life (QoL) and to evaluate the ability of the modified Myelofibrosis Symptom Assessment Form (MFSAF) v2.0 to measure meaningful changes in myelofibrosis-related symptoms in patients with myelofibrosis. COMFORT-I (Controlled Myelofibrosis Study With Oral JAK Inhibitor Treatment-I) is a double-blind, placebo-controlled phase III study evaluating ruxolitinib in patients with intermediate-2 or high-risk myelofibrosis. Exploratory analyses were conducted on the following patient-reported outcomes (PROs) assessments: modified MFSAF v2.0 (individual symptoms and Total Symptom Score [TSS]), European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30), Patient Reported Outcomes Measurement Information System (PROMIS) Fatigue Scale, and Patient Global Impression of Change (PGIC). Patients receiving ruxolitinib experienced improvements in individual myelofibrosis-related symptoms, although patients receiving placebo experienced worsening (P < .001). The majority (91%) of ruxolitinib-treated patients designated as ≥ 50% TSS responders (≥ 50% TSS improvement) self-reported their condition as either "Much improved" or "Very much improved" on the PGIC. These patients achieved significant improvements in the EORTC QLQ-C30 functional domains and Global Health Status/QoL versus patients receiving placebo, who experienced worsening on these measures (P ≤ .0135). Ruxolitinib-treated patients with a lesser degree of symptom improvement (< 50% TSS responders) also achieved improvements over placebo on these measures. The degree of spleen volume reduction with ruxolitinib correlated with improvements in TSS, PGIC, PROMIS Fatigue Scale, and EORTC Global Health Status/QoL. Ruxolitinib-treated patients who achieved a ≥ 35% reduction in spleen volume experienced the greatest improvements in these PROs. Ruxolitinib-treated patients achieved clinically meaningful improvements in myelofibrosis-related symptoms and QoL, but patients receiving placebo reported worsening of symptoms and other PROs.

Long-Term Outcome of Ruxolitinib Treatment in Patients with Myelofibrosis: Durable Reductions in Spleen Volume, Improvements in Quality of Life, and Overall Survival Advantage in COMFORT-I

Long-Term Outcome of Ruxolitinib Treatment in Patients with Myelofibrosis: Durable Reductions in Spleen Volume, Improvements in Quality of Life, and Overall Survival Advantage in COMFORT-I

Clinical Benefits of Ruxolitinib Therapy in Myelofibrosis Patients with Varying Degrees of Splenomegaly and Symptoms

AbstractAbstract 1727 Background:Myelofibrosis (MF) is characterized by cytopenias, splenomegaly, and burdensome symptoms that may worsen over time. Ruxolitinib (RUX) has been shown to reduce splenomegaly and improve MF-associated symptoms in 2 phase III studies, including COMFORT-I, a randomized, double-blind, placebo (PBO)-controlled trial, which also showed prolonged survival in favor of RUX. Purpose:In this post hoc analysis of COMFORT-I, the efficacy of RUX in patients with varying degrees of splenomegaly and symptom severity at baseline was evaluated to assess the potential effects of earlier versus later intervention in this progressive disease. Methods:COMFORT-I participants randomized to RUX (n=155) or PBO (n=154) had MF with an International Prognostic Scoring System (IPSS) score ≥2 and a platelet count of ≥100 × 109/L. Patients with protocol-defined worsening splenomegaly were permitted to cross over from PBO to RUX. The primary endpoint was the percentage of patients with ≥35% reduction in spleen volume (SV) at week (wk) 24. Change in Total Symptom Score (TSS) was a secondary endpoint. TSS was the sum of 6 symptom scores (night sweats, itching, abdominal discomfort, pain under ribs on left side, early satiety, muscle/bone pain) assessed with the modified MF Symptom Assessment Form (MFSAF) v2.0 on a scale of 0 (“absent”) to 10 (“worst imaginable”).Patients were stratified by palpable spleen length (SL) (≤ 10 cm, <10 to 20 cm, >20 cm) and TSS tertile (≤11.1, >11.1 to 22.0, >22.0) at baseline. SV and TSS stratified by baseline values as described were summarized over time. To account for PBO crossover, modeling was performed to predict SV after crossover using a nonlinear mixed model that best predicted individual patient data. Last observation carried forward was used to impute missing TSS data. Results:Mean absolute SV and TSS worsened over time in the PBO group regardless of baseline SL and TSS, demonstrating the progressive nature of MF. In patients treated with RUX, mean absolute SV and TSS at wk 24 were lower for patients with smaller SL and less severe TSS at baseline, respectively (Table); absolute differences with PBO were significant within each subgroup. Therefore, patients who initiated RUX therapy with more advanced MF were less likely to achieve the same clinical status experienced by patients initiating therapy with less advanced MF. Notably, even after 24 wks of RUX treatment, SV and TSS reductions in the cohorts with larger SL or greater TSS at baseline did not achieve levels equivalent to baseline of the next lesser baseline severity group (Table; Figure).Although the severity of splenomegaly and symptoms at baseline influenced the absolute SV and TSS achieved at wk 24, RUX treatment resulted in similar percent reductions in SV and improvements TSS across all subgroups, with the exception of the lower TSS tertile (where there is less room for improvement). In contrast, PBO treatment resulted in increases in SV and worsening of symptoms and patients with less severe SV and TSS at baseline experienced the greatest percent increases in SV and TSS at wk 24. Conclusions:RUX therapy was associated with SV reduction and symptom improvement regardless of spleen size or symptom severity at baseline, whereas patients on PBO experienced disease progression across all subgroups. Patients receiving RUX with less advanced disease achieved an overall better clinical status, as defined by lower absolute SV and symptom scores. This analysis suggests that initiation of RUX in patients with less severe splenomegaly and symptoms may contribute to improved patient outcomes.TableRuxolitinib Efficacy by Baseline Palpable Spleen Size and Symptom SeveritySV (cm3)≤10 cm>10–20 cm>20 cmRUXPBORUXPBORUXPBOn=32n=27n=89n=89n=34n=37Baseline, mean ± SEM1602 ± 1071568 ± 1482672 ± 982580 ± 1224015 ± 2244218 ± 176Wk 24, mean ± SEM1208 ± 93*1810 ± 1351751 ± 82‡2903 ± 952851 ± 207‡4454 ± 167% change from baseline at Wk 24 ± SEM–26.1 ± 3.317.7 ± 4.3–34.7 ± 2.013.3 ± 1.8–29.9 ± 2.87.3 ± 3.0TSSLowerMiddleUpperRUXPBORUXPBORUXPBOn=46n=57n=49n=49n=54n=45Baseline, mean ± SEM5.8 ± 0.65.6 ± 0.416.6 ± 0.516.4 ± 0.530.2 ± 0.731.8 ± 1.1Wk 24, mean ± SEM4.3 ± 0.7†9.4 ± 0.98.5 ± 1.2‡21.4 ± 1.516.2 ± 1.5‡x33.4 ± 1.7% change from baseline at Wk 24 ± SEM–25.8 ± 10.498.4 ± 26.2–49.6 ± 6.732.3 ± 10.1–45.6 ± 5.26.1 ± 4.5PBO, placebo; RUX, ruxolitinib; SEM, standard error of the mean.P-value for RUX vs PBO: *<0.05; †<0.01; ‡<0.001. [Display omitted] Disclosures:Mesa:Incyte: Research Funding; Lilly: Research Funding; Sanofi: Research Funding; NS Pharma: Research Funding; YM Bioscience: Research Funding. Gotlib:Incyte: Consultancy. Kantarjian:Incyte: grant support Other. Sun:Incyte: Employment. Verstovsek:Incyte Corporation: Research Funding.