Myelofibrosis Symptom Assessment Form Research Articles

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

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

Phase 2 Study to Assess the Safety and Efficacy of Bomedemstat (MK3543) in Combination with Ruxolitinib in Patients with Myelofibrosis

Background Approximately 50% of patients with myelofibrosis (MF) discontinue ruxolitinib after 3 years, mostly due to disease progression, suboptimal response or cytopenia. Outcome after ruxolitinib discontinuation is poor with a median overall survival (OS) of approximately 14 months. Lysine-specific demethylase-1 (LSD1) is a histone demethylase critical for self-renewal of malignant hematopoietic stem cells and for maturation of progenitor cells. Bomedemstat is an oral LSD1 inhibitor clinically active in patients with myeloproliferative neoplasms (MPN) and has shown clinical activity as a single-agent in patients with MF. Aims This is an ongoing, open-label, Phase 2 study of the combination of bomedemstat and ruxolitinib in treatment-naïve patients with MF or those with a sub-optimal response to ruxolitinib. The objectives of this are to evaluate the safety and tolerability of the combination, the optimal dosing of bomedemstat in this regimen, and to assess the efficacy of the combination as assessed by spleen size reduction and symptom reduction using the Myelofibrosis Symptom Assessment Form (MFSAF). Methods Cohort A is comprised of patients with a sub-optimal response to an adequate trial of ruxolitinib defined as splenomegaly not reduced by >35% from baseline or symptoms scores that have not improved by >50%. Cohort A patients must have been on a stable dose of ruxolitinib for ≥8wks. Cohort B is comprised of treatment-naïve patients with MF who require treatment per guidelines. Patients in Cohort A remain on the entry dose of ruxolitinib while Cohort B patients received a starting ruxolitinib dose of 10 mg BID throughout the study. All patients received concomitantly, a starting dose of bomedemstat of 0.4mg/kg/d. Dose adjustments up were allowed every 4 weeks to achieve a target platelet count of 50 x 10 9/L (40-90 x 10 9/L range) Down titrations could be made at any time in the interest of patient safety. Results At the data cut-off of 30 June 2023, 16 men and 16 women with a median age of 64 (range: 47-81) years were enrolled. Case distribution was PMF, N=19 (59.4%); PPV-MF, N=7 (21.9%); and PET-MF, N=6 (18.8%). Mutational profile of driver genes was JAK2 V617F, N=24 (75%); JAK2 exon 12, N=1 (3.1%); and CALR mutations, N=7 (21.9%). Six patient (18.8%) harbored high-molecular risk (HMR) mutations ( ASXL N =4; EZH2, N=2). At enrollment, the median white blood cell count (WBC), hemoglobin (Hb), platelet count, and lactate dehydrogenase (LDH) were 10.21 x 10 9/L (2.4-50.8 x 10 9/L), 9.4 g/dL (6.7-12.1g/dL), 215 x 10 9/L (100-906 x 10 9/L) and 504 IU/L (107-2174 UL), respectively. Ten patients (31.2%), 19 patients (59.4%) and 3 patients (9.4%) belonged to the Dynamic International Prognostic Scoring System (DIPSS) high, intermediate-2 and intermediate-1 risk categories, respectively. The median spleen size was 5cm (5-16cm) below left costal margin (BLCM). Twenty-four patients were enrolled in Cohort A with a median treatment duration of ruxolitinib of 128 (13-668) weeks. Cohort B has enrolled 8 patients. The median duration of ruxolitinib + bomedemstat was 12 (1-26) weeks. In 20 evaluable patients at Week 12 (Cohort A, N=17; Cohort B, N=3), 12 patients (60%) had stable ( ∆<± 1.0 g/dL) or improved Hb (>1.0 g/dL) (Cohort A: 11/17, 64.7%; Cohort B: 1/3, 33.3%), 5 patients (25%) had ≥50% reduction in MF-SAF Total Symptom Score (TSS) (Cohort A: 4/17, 23.5%; Cohort B: 1/3, 33.3%) and 18 patients (65%) had ≥ 30% spleen length reduction (Cohort A: 15/17, 88.2%; Cohort: 3/3, 100%) (Figure 1A-C). In six patients evaluable for molecular responses by droplet-digital polymerase chain reaction at Week 12, 4 patients (67%) had reductions in JAK2 V617F allele frequencies with 1 patient (17%) having ≥50% reduction. The most common non-hematologic adverse events (AEs) were diarrhea (Grade 1-2, N=16; Grade 3-4, N=0); malaise (Grade 1-2, N= 6; Grade 3-4, N=0); oedema (Grade 1-2, N=7; Grade 3-4, N=0) and dysgeusia (Grade 1-2, N=5; Grade 3-4, N=0). There were no safety signals, dose-limiting toxicities, or deaths related to drug. Conclusions These early results suggest that the addition of bomedemstat to a ruxolitinib regimen is well tolerated, improves splenomegaly and symptom scores, and stabilizes hemoglobin both in the frontline and second-line setting. Enrollment in ongoing.

A Global, Phase 3, Randomized, Double-Blind Study to Evaluate Safety and Efficacy of Selinexor, an XPO-1 Inhibitor, in Combination with Ruxolitinib in JAK Inhibitor-Naïve Myelofibrosis (XPORT-MF-034)

Background and Significance: Myelofibrosis (MF) is a myeloproliferative neoplasm that commonly harbors somatic gene driver mutations in Janus kinase 2 ( JAK2), calreticulin ( CALR), and myeloproliferative leukemia virus ( MPL) genes. Selinexor is an investigational oral XPO1 inhibitor that may inhibit MF-relevant pathways including STAT, extracellular signal-regulated kinase (ERK), protein kinase B (AKT) and p53. Furthermore, in vivo preclinical studies have shown potential synergy between selinexor and ruxolitinib treatment. The Phase 3 trial was initiated based on data from the Phase 1 portion of XPORT-MF-034 evaluating the combination of selinexor and ruxolitinib in JAKi-naïve patients with MF. Previously we reported that the combination of selinexor and ruxolitinib was generally tolerable and manageable and that the 60 mg selinexor dose cohort showed 71% and 79% of the intent-to-treat (ITT) population achieving a ≥35% reduction in spleen volume from baseline (SVR35) at Week 12 and Week 24, respectively; SVR35 rates were consistent across subgroups, including gender and regardless of ruxolitinib starting dose. Robust symptom improvement was also observed with 58% of the ITT achieving a ≥50% reduction in total symptom score from baseline (TSS50) at Week 24 (Ali et al., ASCO 2023; Ali et al., AACR 2023). These data provided strong support to further evaluate selinexor (60 mg) and ruxolitinib in patients with JAKi-naïve MF. Study Design and Methods: The XPORT-MF-034 (NCT04562389) trial includes a global, Phase 3 randomized, double-blind, placebo-controlled study designed to evaluate the combination of 60 mg selinexor and ruxolitinib. Patients will be randomized 2:1 to receive oral selinexor 60 mg or placebo once weekly (28-day cycle) and twice daily ruxolitinib. Select eligibility criteria include patients ≥18 years of age, with a spleen volume of ≥450 cm 3 by MRI or CT, dynamic international prognostic scoring system (DIPSS) of intermediate-1, intermediate-2, or high-risk, active symptoms of MF as determined by presence of at least 2 symptoms with a score ≥3 or total score of ≥10 at screening using the MFSAF v4.0, currently not eligible for stem cell transplantation, ECOG PS ≤2, platelet count ≥100 x 10 9/L, and creatinine clearance >15mL/min. Patients will be excluded if more than 10% blasts are present in peripheral blood or bone marrow; received previous treatment with JAK inhibitors for MF, or previous treatment with selinexor or other XPO1 inhibitors. The co-primary study endpoints are SVR35 at Week 24 as measured by MRI or CT scan and TSS50 at Week 24 as measured by the Myelofibrosis Symptom Assessment Form (MFSAF) V4.0. The key secondary endpoint is anemia response as per the International Working Group Myeloproliferative Neoplasms Research and Treatment and European Leukemia Network (IWG-MRT and ELN) criteria at Week 24. Results: TheXPORT-MF-034 Phase 3 trial is currently open for enrollment; a total of 306 JAKi-naïve MF patients will be enrolled and the study was initiated on June 28, 2023.

Efficacy and Safety of Fedratinib in Patients with Myelofibrosis Previously Treated with Ruxolitinib: Results from the Phase 3 Randomized FREEDOM2 Study

Introduction Patients (pts) with myelofibrosis (MF) treated with the Janus kinase inhibitor (JAKi) ruxolitinib (RUX) show spleen volume reduction (SVR) and symptom reduction. However, most develop RUX intolerance or relapsed/refractory (R/R) disease and survival rates after RUX discontinuation are poor. Fedratinib (FEDR) delivered SVR and symptom reduction in the JAKARTA2 and FREEDOM studies (C Harrison et al. Am J Hematol 2020; V Gupta et al. Blood 2022). FREEDOM2 (NCT03952039) was a phase 3, open-label, randomized study to evaluate the safety and efficacy of FEDR compared with best available therapy (BAT) in pts with MF previously treated with RUX. Methods Pts aged ≥ 18 years with primary, post-polycythemia vera, or post-essential thrombocythemia MF with Dynamic International Prognostic Scoring System (DIPSS) score ≥ intermediate-2, splenomegaly (≥ 450 cm 3), platelets ≥ 50 x 10 9/L, peripheral blood myeloblasts < 5%, and normal baseline thiamine, R/R or intolerant to RUX, were randomized 2:1 to FEDR 400 mg/day or BAT in 28-day cycles, with stratification by spleen size, platelet count, and RUX R/R vs intolerant. Crossover to FEDR was permitted for progressive disease or after cycle 6 (EOC6) response assessment. Pts were treated until intolerance or lack of efficacy and followed-up every 3 months until death, withdrawal of consent, or study closure. The primary endpoint was SVR ≥ 35% (SVR35) at EOC6; secondary endpoints included symptom response (≥ 50% reduction in total symptom score measured by Myelofibrosis Symptom Assessment Form), SVR ≥ 25% (SVR25), durability of SVR and symptom response, and safety. Results Overall, 201 pts were initially randomized and treated, 134 and 67 pts in the FEDR and BAT arms, respectively; subsequently, 46 (68.7%) pts from the BAT arm crossed over to FEDR. Median (interquartile range) age was 70 (64-74) years, 52.2% were male, and most had primary MF (54.7%) and intermediate-2 DIPSS risk (76.1%). Assessed by aggregated group, most pts in the BAT arm received RUX (70.1%), hydroxyurea (10.4%), or RUX plus hydroxyurea (7.5%). At the data cutoff of December 27, 2022 (median follow-up, 15 months), pts receiving FEDR had significantly higher rates of SVR35 at EOC6 compared with BAT (35.8% vs 6.0%; P < 0.0001), as well as superior SVR25 at EOC6 and SVR35 during the full treatment course ( Table, Figure). SVR35 benefit with FEDR was observed across subgroups. The FEDR arm also showed higher rates of symptom response at EOC6 compared with BAT (34.1% vs 16.9%; P = 0.0033; Table). Median treatment duration was 43 weeks of FEDR and 24.7 weeks of BAT. During the first 6 cycles in the safety population: 70 (52.2%) pts on FEDR and 20 (29.9%) pts on BAT had dose interruption/reduction; median time to first reduction/interruption was 44.0 days for FEDR and 56.5 days for BAT. Treatment-emergent adverse events (TEAEs) leading to permanent treatment discontinuation occurred in 13 (9.7%) and 4 (6.0%) pts in the FEDR and BAT arms, respectively, during the first 6 cycles. During the first 6 cycles, 132 (98.5%) pts on FEDR and 65 (97.0%) pts on BAT had ≥ 1 TEAE; treatment-related AEs (TRAEs) occurred in 109 (81.3%) and 23 (34.3%) pts in the FEDR and BAT arms, respectively. The most frequently occurring TRAEs with FEDR were diarrhea (38.1% FEDR vs 0.0% BAT) and nausea (32.1% FEDR vs 1.5% BAT); most cases were grade 1/2. Grade 3/4 TRAEs occurred in 52 (38.8%) pts in FEDR and 8 (11.9%) pts in BAT arms, most frequently thrombocytopenia (11.9% FEDR vs 3.0% BAT) and anemia (9.0% FEDR vs 9.0% BAT). In the FEDR arm, 22 (16.4%) pts had thiamine levels below normal range, compared with 2 (3.0%) pts receiving BAT; most cases occurred prior to the study amendment of prophylactic thiamine supplementation. There was a single grade 1 case of suspected Wernicke's encephalopathy in the FEDR arm during cycle 3, which resolved fully 24 hours after thiamine supplementation (0 cases in BAT arm). Two pts each in FEDR and BAT arms had TRAEs of infection. Conclusions In this phase 3 randomized study in pts with MF and prior RUX treatment, FEDR demonstrated superior SVR and symptom response rates compared with BAT. Most pts on BAT received RUX, highlighting a clinical need for an alternative JAKi. Differences in AE and discontinuation rates in the first 6 cycles are consistent with other studies comparing JAKi with BAT. AE mitigation strategies were effective and no new safety concerns for FEDR were identified. Study support Bristol Myers Squibb

Longitudinal Assessment of Transfusion Intensity in Patients with JAK Inhibitor-Naive or -Experienced Myelofibrosis Treated with Momelotinib in the Phase 3 Simplify-1 and Momentum Trials

Introduction: Anemia is a cardinal feature of myelofibrosis (MF), along with splenomegaly and constitutional symptoms. Red blood cell (RBC) transfusions, often used to manage anemia in patients (pts) with MF, are a negative prognostic factor for overall survival and are associated with diminished quality of life and increased healthcare-related economic burden. Momelotinib (MMB), a Janus kinase (JAK) 1/JAK2/activin A receptor type 1 inhibitor, has demonstrated clinically meaningful and durable improvements in anemia, splenomegaly, and symptoms. Prespecified anemia endpoints in MMB phase 3 studies prioritized achievement of a strict transfusion independence response, defined as no transfusions for ≥12 wk immediately before the end of wk 24, with all hemoglobin levels ≥8 g/dL. Longitudinal analysis of transfusion intensity (units per 28 days) in a phase 2 trial of MMB in pts with transfusion-dependent MF demonstrated a reduction in transfusion burden in most (85%) pts (Harrison C, et al. EHA 2023). Here, we further characterize the impact of MMB and comparators on transfusion burden in pts with JAK inhibitor-naive and -experienced MF from the phase 3 SIMPLIFY-1 and MOMENTUM trials. Methods: This analysis evaluated time-dependent transfusion burden in pts enrolled in the phase 3 SIMPLIFY-1 (NCT01969838) and MOMENTUM (NCT04173494) trials. SIMPLIFY-1 included pts with JAK inhibitor-naive MF randomized (1:1) to receive MMB or ruxolitinib (RUX). In MOMENTUM, pts with symptomatic (Myelofibrosis Symptom Assessment Form Total Symptom Score ≥10), anemic (hemoglobin <10 g/dL), JAK inhibitor-experienced MF were randomized (2:1) to receive MMB or danazol (DAN). All RBC units transfused were collected during the 24-wk randomized treatment period of each study and during the 84 days before receipt of randomized treatment on study for baseline assessment. Time-dependent transfusion burden was quantified by number of RBC units administered, in a tabular display of baseline- and treatment-period intensity. Pts were grouped jointly based on the baseline- and treatment-period intensity of RBC units per 28 days into ordinal bins: exactly zero units, >0 to 1 unit, >1 to 2 units, >2 to 3 units, >3 to 4 units, and >4 units. Results: In SIMPLIFY-1 (JAK inhibitor-naive pts), 150 of 213 evaluable pts (70%) in the MMB arm and 163 of 216 evaluable pts (76%) in the RUX arm required zero units of RBC transfusion per 28 days at baseline. Of pts who required zero units of transfusion at baseline, a higher proportion in the MMB arm (142 of 150 [95%]) maintained a requirement of zero RBC transfusions during randomized treatment of 24 wks vs the RUX arm (93 of 163 [57%]). Overall, the mean RBC transfusion burden per 28 days declined 0.10 units (SD, 0.701) from baseline to randomized treatment in the MMB arm and increased 0.39 units (SD, 1.016) in the RUX arm. Using ordinal bins, 87% of pts in the MMB arm maintained (144 [67.6%]) or improved (41 [19.2%]) RBC transfusion intensity during randomized treatment compared with baseline vs 54% in the RUX arm (maintained, 94 [43.5%]; improved, 23 [10.6%]) (Figure). In MOMENTUM (JAK inhibitor-experienced pts), most pts had some transfusion requirement at baseline, with 26 of 130 (20%) in the MMB arm and 11 of 65 (17%) in the DAN arm requiring zero units of RBC transfusion per 28 days. During randomized treatment, a higher proportion of pts in the MMB arm (46 of 130 [35%]) required zero units of RBC transfusion vs the DAN arm (11 of 65 [17%]), including a higher proportion of those who had zero RBC transfusion requirement at baseline who maintained zero RBC transfusion requirement during randomized treatment (MMB, 92%; DAN, 64%). The mean RBC transfusion burden per 28 days declined 0.86 units (SD, 1.748) from baseline to randomized treatment in the MMB arm and declined 0.28 units (SD, 1.584) in the DAN arm. Using ordinal bins, 85% of pts in the MMB arm maintained (25 [19.2%]) or improved (85 [65.4%]) RBC transfusion intensity compared with baseline vs 63% in the DAN arm (maintained, 7 [10.8%]; improved, 34 [52.3%]). Conclusions: These data demonstrate that MMB was associated with better maintenance of RBC transfusion intensity and zero RBC transfusion status vs RUX in pts with MF who were JAK inhibitor naive and showed greater reduction in RBC transfusion burden from baseline vs DAN in pts with MF who were JAK inhibitor experienced. Across both trials, ≥85% of pts treated with MMB maintained or improved transfusion intensity.

Patient-reported Outcomes and Quality of Life in Anemic and Symptomatic Patients With Myelofibrosis: Results From the MOMENTUM Study.

Myelofibrosis (MF) is a chronic myeloproliferative neoplasm that typically manifests with debilitating symptoms that progressively worsen, negatively impacting patients' quality of life. Fatigue is a multifactorial and burdensome MF-related symptom due to its severity, persistence, and prevalence, with anemia a contributing factor and major unmet need. Clinical trials of the Janus kinase (JAK)1/JAK2/activin A receptor type 1 inhibitor momelotinib have shown consistent anemia benefits, in addition to improvements in MF-related symptoms. The phase 3 MOMENTUM trial in symptomatic and anemic patients met its primary end point, with a greater proportion having a Myelofibrosis Symptom Assessment Form (MFSAF) Total Symptom Score (TSS) reduction ≥50% at week 24 with momelotinib versus danazol. To support the positive primary end point result, we conducted longitudinal, responder, and time-to-event analyses of patient-reported outcomes from MOMENTUM, as measured by the MFSAF, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), and Patient-Reported Outcomes Measurement Information System (PROMIS) assessments. These analyses demonstrated rapid and durable response benefits with momelotinib, with achievement of first TSS response by day 29 and continued improvement over time. Improvements favored momelotinib versus danazol for each MFSAF individual item, and greater improvements were observed for disease- and cancer-related fatigue and physical functioning at week 24, with significant results for multiple items/domains across the 3 assessments. These findings are consistent in demonstrating that momelotinib provides substantial symptom benefit.

Momelotinib versus danazol in symptomatic patients with anaemia and myelofibrosis previously treated with a JAK inhibitor (MOMENTUM): an updated analysis of an international, double-blind, randomised phase 3 study

The MOMENTUM study met all key endpoints at week 24, demonstrating symptom, spleen, and anaemia benefits with momelotinib versus danazol in patients with myelofibrosis. In this updated analysis, we report duration of week 24 responses and new responses with momelotinib through week 48. MOMENTUM is an international, double-blind, randomised, phase 3 study done at 107 sites across 21 countries. Patients were 18 years or older with primary, post-polycythaemia vera, or post-essential thrombocythaemia myelofibrosis, previously treated with an approved Janus kinase (JAK) inhibitor for 90 days or more (≥28 days with haematological complications), and had an Eastern Cooperative Oncology Group performance status of 2 or less. Patients were randomly assigned (2:1) to either the momelotinib group (200 mg orally once per day) or danazol group (300 mg orally twice per day) through week 24 via non-deterministic biased coin minimisation and an interactive response system. Stratification factors were Total Symptom Score (TSS; <22 vs ≥22), spleen size (<12 cm vs ≥12 cm), transfusion burden (0 units vs 1-4 units vs ≥5 units), and study site. After week 24, all patients initially randomly assigned to either group who remained on the study received open-label momelotinib. The primary endpoint, which has already been reported, was Myelofibrosis Symptom Assessment Form TSS response rate at week 24. Predefined secondary endpoints were duration of week 24 TSS and transfusion independence responses, safety, and survival, which are summarised post hoc at the week 48 data cutoff (May 17, 2022). TSS, transfusion independence, and splenic responses at week 48 were defined post hoc and assessed in all evaluable patients who entered the open-label period and provided sufficient data. The timing of this updated analysis was defined post hoc after all patients had the opportunity to complete their week 48 assessments, as most patients entered an extended access study (NCT03441113) after week 48. This study is registered with ClinicalTrials.gov, number NCT04173494, and is now complete. Between April 24, 2020, and Dec 3, 2021, a total of 195 patients were randomised (130 [67%] in the momelotinib group and 65 [33%] in the danazol group). 93 (72%) of 130 patients in the momelotinib group and 41 (63%) of 65 in the danazol group entered the momelotinib open-label extension period. Median follow-up was 48·4 weeks (IQR 40·6-55·7). Among TSS-evaluable patients at week 48, 30 (45%) of 67 patients in the momelotinib group who continued treatment and 15 (50%) of 30 in the danazol group who crossed over were responders. TSS responders at any time during the open-label period by week 48 were 46 (61%) of 75 evaluable patients in the momelotinib group who continued and 19 (59%) of 32 in the danazol group who crossed over, including most week 24 responders plus new responders after week 24. No new safety signals emerged with long-term follow-up. The most common non-haematological treatment-emergent adverse events in momelotinib-treated patients over the entire study period as of the data cutoff were diarrhoea (45 [26%] of 171) and asthenia (28 [16%]); the most common grades 3-4 treatment-emergent adverse events were thrombocytopenia (33 [19%]) and anaemia (19 [11%]). Serious treatment-emergent adverse events were reported in 79 (46%) of 171 patients, and fatal treatment-emergent adverse events were reported in 30 (18%); two fatal treatment-emergent adverse events were considered possibly related to momelotinib (rotaviral enteritis and Staphylococcus pneumonia). Momelotinib was associated with durable symptom, spleen, and anaemia benefits, late responses after week 24, and favourable safety through week 48. These results highlight the potential benefits of treatment with momelotinib in patients with myelofibrosis, particularly those with anaemia. Sierra Oncology, a GSK company.

Momelotinib versus danazol in symptomatic patients with anaemia and myelofibrosis (MOMENTUM): results from an international, double-blind, randomised, controlled, phase 3 study

Janus kinase (JAK) inhibitors approved for myelofibrosis provide spleen and symptom improvements but do not meaningfully improve anaemia. Momelotinib, a first-in-class inhibitor of activin A receptor type 1 as well as JAK1 and JAK2, has shown symptom, spleen, and anaemia benefits in myelofibrosis. We aimed to confirm the differentiated clinical benefits of momelotinib versus the active comparator danazol in JAK-inhibitor-exposed, symptomatic patients with anaemia and intermediate-risk or high-risk myelofibrosis. MOMENTUM is an international, double-blind, randomised, controlled, phase 3 study that enrolled patients at 107 sites across 21 countries worldwide. Eligible patients were 18 years or older with a confirmed diagnosis of primary myelofibrosis or post-polycythaemia vera or post-essential thrombocythaemia myelofibrosis. Patients were randomly assigned (2:1) to receive momelotinib (200 mg orally once per day) plus danazol placebo (ie, the momelotinib group) or danazol (300 mg orally twice per day) plus momelotinib placebo (ie, the danazol group), stratified by total symptom score (TSS; <22 vs ≥22), spleen size (<12 cm vs ≥12 cm), red blood cell or whole blood units transfused in the 8 weeks before randomisation (0 units vs 1-4 units vs ≥5 units), and study site. The primary endpoint was the Myelofibrosis Symptom Assessment Form (MFSAF) TSS response rate at week 24 (defined as ≥50% reduction in mean MFSAF TSS over the 28 days immediately before the end of week 24 compared with baseline). MOMENTUM is registered with ClinicalTrials.gov, number NCT04173494, and is active but not recruiting. 195 patients were randomly assigned to either the momelotinib group (130 [67%]) or danazol group (65 [33%]) and received study treatment in the 24-week randomised treatment period between April 24, 2020, and Dec 3, 2021. A significantly greater proportion of patients in the momelotinib group reported a 50% or more reduction in TSS than in the danazol group (32 [25%] of 130 vs six [9%] of 65; proportion difference 16% [95% CI 6-26], p=0·0095). The most frequent grade 3 or higher treatment-emergent adverse events with momelotinib and danazol were haematological abnormalities by laboratory values: anaemia (79 [61%] of 130 vs 49 [75%] of 65) and thrombocytopenia (36 [28%] vs 17 [26%]). The most frequent non-haematological grade 3 or higher treatment-emergent adverse events with momelotinib and danazol were acute kidney injury (four [3%] of 130 vs six [9%] of 65) and pneumonia (three [2%] vs six [9%]). Treatment with momelotinib, compared with danazol, resulted in clinically significant improvements in myelofibrosis-associated symptoms, anaemia measures, and spleen response, with favourable safety. These findings support the future use of momelotinib as an effective treatment in patients with myelofibrosis, especially in those with anaemia. Sierra Oncology.

The Impact of Momelotinib on Patient Reported Quality of Life for Symptomatic and Anemic Patients with Myelofibrosis: Results from the Phase 3 Momentum Study

Introduction Disease-related inflammation, anemia and splenomegaly contribute to a host of burdensome symptoms in patients with myelofibrosis (MF), including fatigue, bone pain, night sweats, and others, which can negatively impact health-related quality of life (HRQoL). There are no approved treatments for patients with intermediate- and high-risk MF that specifically target anemia, and approved MF therapies for splenomegaly and symptoms often exacerbate anemia. Momelotinib (MMB) is a Janus kinase (JAK) 1, JAK2, and activin A receptor type 1 (ACVR1) inhibitor with demonstrated symptom, spleen, and anemia benefits in patients with MF. MOMENTUM, a phase 3 study in symptomatic, anemic patients with MF who were previously treated with a JAKi, showed that MMB significantly improved disease-related symptoms compared to danazol (DAN) (24.6% vs 9.2%) as measured by achieving at least a 50% reduction in total symptom score (TSS50) at week 24 compared to baseline. Herein we report the results of patient-reported health status and HRQoL analyses, including impact on fatigue and physical function, for patients treated with MMB compared to DAN in the MOMENTUM study. Methods Patient-reported outcome (PRO) analyses were performed for the following assessments in the intent-to-treat (ITT) population: Myelofibrosis Symptom Assessment Form (MFSAF) v4.0 TSS and individual items, European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30)-derived scales and items, and Patient-Reported Outcomes Measurement Information System (PROMIS) short form physical function total score 10b and additional PROMIS bank items. Analyses of PRO response were summarized by corresponding meaningful change threshold (MCT) for each PRO. Longitudinal change from baseline scores were analyzed using mixed model for repeated measures (MMRM). Longitudinal responder analyses were performed by generalized estimating equation (GEE) after multiple imputation for missing scores. Odds ratio (OR) for response, 95% confidence interval (CI), and p-value were presented as the treatment effect (MMB vs DAN). Time to first response was analyzed using the Kaplan-Meier method. A stratified log-rank test was performed to compare treatment arms, and hazard ratios (HR) were estimated from a stratified Cox regression model. Results Proportionally greater improvements in MF-related symptoms, physical function, and global quality of life were observed with MMB versus DAN as measured at week 24 by the MFSAF, PROMIS, and EORTC QLQ-C30 questionnaires, respectively. Improvements in all MFSAF individual item scores from baseline at week 24 were greater in the MMB group than in the DAN group based on median scores (Figure 1) and MMRM analysis (Table 1), with the greatest treatment differences noted for night sweats, abdominal discomfort, bone pain, and rib pain, favoring MMB. Longitudinal MFSAF TSS response analysis indicated a higher likelihood of response for patients in the MMB group: an overall OR of 2.50 throughout the 24-week randomized treatment period. HRs for response were greater than 1 (ranging from 1.47 - 3.82) in the time to first response analysis for MFSAF TSS and individual items, excluding itching (0.77), indicating a faster symptom response for more patients in the MMB group for TSS and 6 of 7 individual items. Responder analyses showed that the proportion improved for fatigue was greater in the MMB group based on MFSAF fatigue (18.5% MMB, 9.2% DAN) and EORTC QLQ-C30 fatigue (41.5% MMB, 21.5% DAN), where missing data was considered nonresponse. Consistent with these results, responder analysis using the PROMIS assessments related to physical function also favored MMB (17.7% MMB, 4.6% DAN). This trend was supported by shorter times to first response for physical function in more patients in the MMB group versus the DAN group (HR = 1.93, 95% CI 0.95, 3.91). Improvement in global quality of life as measured by EORTC QLQ-C30 was also greater in the MMB group with a proportion difference of 14.6% between MMB and DAN (95% CI: 1.5-27.7%; p = 0.04). Conclusions Consistent with the positive primary endpoint (TSS50) result of the MOMENTUM study, these responder, longitudinal, and time-to-event analyses demonstrate that MMB provides comprehensive improvements in disease-related symptoms with associated improvement in physical function and overall HRQoL compared with DAN in patients with MF. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Pelabresib (CPI-0610) As Add-on to Ruxolitinib in Myelofibrosis: Durability of Response and Safety Beyond Week 24 in the Phase 2 MANIFEST Study

Background: Myelofibrosis (MF) is largely characterized by bone marrow (BM) fibrosis, splenomegaly and cytopenias. Progressive BM fibrosis results from aberrant megakaryopoiesis and proinflammatory cytokine expression, two processes that are tightly regulated by bromodomain and extraterminal domain (BET) protein-mediated expression of genes (eg NF-κB target genes, MYC and BCL-2) and often lead to myeloproliferation and cytopenias. Although the current standard of care for MF is treatment with the Janus kinase inhibitor (JAKi) ruxolitinib (RUX), many patients (pts) experience a suboptimal response to RUX monotherapy or must discontinue treatment due to cytopenias and therefore there is a significant unmet need for new therapies in this population. Pelabresib (CPI-0610; PELA) is an oral, small-molecule, investigational BET inhibitor that downregulates NF-κB signaling and other relevant genes involved in MF disease pathways (Mascarenhas J, et al. HemaSphere 2022;6:99-100). Aims: In the ongoing, open-label Phase 2 MANIFEST study (NCT02158858), PELA is under investigation as monotherapy and in combination with RUX in pts with MF. In Arm 2 of MANIFEST, pts with suboptimal/lost response to RUX are treated with PELA as 'add-on’ to RUX. In this abstract we will discuss results from the September 2021 data cut; updated data with longer follow-up on efficacy (≥35% reduction in spleen volume from baseline [BL; SVR35], ≥50% total symptom score reduction from BL [TSS50], duration of response and BM fibrosis improvement) and safety data from the planned July 2022 data cut will be presented. Methods: Pts in Arm 2 are stratified as transfusion dependent (TD; Arm 2A) and nontransfusion dependent (non-TD; Arm 2B). The primary endpoints are conversion from TD to transfusion independence (TI) in Arm 2A (TD cohort) and SVR35 at Week (Wk) 24 for Arm 2B (non-TD cohort). The secondary endpoints include TSS50 per MF Symptom Assessment Form v4.0 at Wk 24 and SVR35 at Wk 24 in Arm 2A (TD cohort). BM biopsies to assess BM fibrosis, durability of responses and safety data are evaluated. Data reported here are from the September 2021 data cut. Results: At Wk 24 in Arm 2 (N=86), 20% (16/81) of pts achieved SVR35 (Figures 1 and 2); 17% for Arm 2A (TD cohort) and 26% for Arm 2B (non-TD cohort). SVR35 at any time was achieved by 30% (24/81) of pts. At Wk 24, 27% (22/81) pts achieved ≥25% reduction in spleen volume from BL (SVR25); 26% (14/54) pts in Arm 2A (TD cohort) and 30% (8/27) pts in Arm 2B (non-TD cohort). Median spleen volume reduction for the full Arm 2 cohort was -18% at Wk 24. Durable (up to Wk 60) spleen volume reductions were observed as depicted in mean spleen volume change over time, and spleen volume reduction deepened over time (Figure 1). Twenty percent (16/80) pts had SVR35 response at Wk 48. In Arm 2A (TD cohort), the TD to TI rate was 16% (6/38). TSS50 at Wk 24 was 37% (30/81); 36% for Arm 2A (TD cohort) and 39% for Arm 2B (non-TD cohort). A total of 54% (46/86) of pts achieved TSS50 at any time. Median total symptom score reduction was -47% at Wk 24. As of data cut off, the median follow-up time was 24.4 (23.0-30.7) months and median treatment duration was 14.0 (8.4-20.6) months. After 24 wks of treatment, BM fibrosis improvement by ≥1 grade was achieved in 26% of evaluable pts by central pathology review; 50% of pts maintained the improvement at the next available assessment or longer. A total of 39% of pts achieved ≥1 grade improvement at any time (best response). The two most common hematologic treatment-emergent adverse events (TEAEs) of any grade were thrombocytopenia, reported in 52% (Grade ≥ 3: 33%) pts, and anemia, reported in 27% (Grade ≥ 3: 19%) pts. Low-grade gastrointestinal TEAEs and respiratory infections were observed but rarely a reason for treatment discontinuation. A total of 20 pts (23%) reported TEAEs that led to PELA discontinuation. Serious adverse events reported in ≥3 pts were anemia (6 pts), respiratory tract infections (4 pts) and urinary tract infections (3 pts). Conclusions: Based on these preliminary Phase 2 data, PELA as 'add-on’ to RUX in pts with a suboptimal/lost response to RUX monotherapy resulted in durable splenic and symptom responses, deepening of spleen responses over time, and was generally well tolerated. Additionally, improvement in BM fibrosis, as a marker of disease modification, was observed in 39% of treated pts. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Pelabresib (CPI-0610) Combined with Ruxolitinib for JAK Inhibitor Treatment-Naïve Patients with Myelofibrosis: Durability of Response and Safety Beyond Week 24

Background: Myelofibrosis (MF) is characterized by progressive bone marrow (BM) fibrosis, splenomegaly and cytopenias resulting from aberrant megakaryopoiesis and proinflammatory cytokine expression. These processes are heavily regulated by bromodomain and extraterminal domain (BET) protein-mediated gene expression (eg NF-κB target genes, MYC and BCL-2) and lead to myeloproliferation and cytopenias. The current standard of care for patients (pts) with MF is the Janus kinase inhibitor (JAKi) ruxolitinib (RUX); however, the depth and durability of responses, along with the percentage of pts that achieve ≥35% spleen volume reduction from baseline (BL; SVR35) and ≥50% total symptom score reduction (TSS) from BL (TSS50) with RUX monotherapy are limited. Pelabresib (CPI-0610; PELA) is an oral, small-molecule, investigational BET inhibitor that downregulates NF-κB signaling and other relevant genes involved in MF disease pathways (Mascarenhas J, et al. HemaSphere 2022;6:99-100). In the ongoing Phase 2 MANIFEST study (NCT02158858), PELA is under investigation as monotherapy and in combination with RUX in pts with MF. Here, we present results from Arm 3 of MANIFEST (in which JAKi-naïve pts with MF receive PELA in combination with RUX). Aims: The primary endpoint of MANIFEST Arm 3 is SVR35 after 24 weeks (wks) of treatment. Secondary endpoints include TSS50, duration of splenic response, pharmacokinetics and safety. Exploratory endpoints include transfusion independence and changes from BL in BM fibrosis. In this abstract we will discuss results from the September 2021 data cut; longer-term data from the July 2022 data cut will be presented. Methods: Spleen volume was assessed by computed tomography or magnetic resonance imaging every 12 wks; TSS per Myelofibrosis Symptom Assessment Form v4.0; and BM fibrosis by biopsies at Wk 24 and Wk 48. Duration of splenic response and safety data are also evaluated. Data presented are from the September 2021 data cut; a more mature data set will be presented at the conference. Results: Eighty-four pts received ≥1 dose of PELA and RUX. Median age was 68 years (range 37-85); 24%, 61% and 16% had Dynamic International Prognostic Scoring System intermediate-1, intermediate-2 or high risk, respectively. Pts who did not reach Wk 24 were counted as nonresponders. At Wk 24 and Wk 48, 68% (57/84) and 60% (47/79) of pts, respectively, achieved SVR35. SVR35 at any time was achieved by 80% pts (67/84), and 87% (58/67) pts with SVR35 maintained response at the time of data cutoff. Median spleen volume change was -50% (range -84.4% to 27.9%) at Wk 24. Median time to SVR35 response was 12 wks (first on-treatment assessment of splenic response); durable spleen volume reductions were observed as depicted in mean spleen volume change over time in Figure 1. TSS50 was achieved by 56% (46/82) pts at Wk 24 and 43% (34/79) at Wk 48. TSS50 at any time was achieved by 81% pts (68/84). The median change in TSS was −59% (range −100% to 225%) at Wk 24. Mean TSS change over time is shown in Figure 2, indicating sustained reduction in symptom burden. Median follow up for Arm 3 was 21.8 (range 21.2-22.5) months; median treatment duration was not reached as of data cutoff. BM fibrosis improved by ≥1 grade in 28% (16/57) of evaluable pts at Wk 24 as assessed by central pathology review; 56% maintained the improvement at the next available assessment (Wk 48 or beyond) or longer; and 40% achieved ≥1 grade improvement at any time (best response). The most common hematologic treatment-emergent adverse event (TEAE) of any grade was thrombocytopenia, reported in 52% (Grade ≥3: 12%) of pts. Anemia was reported in 42% (Grade ≥3: 34%). Serious adverse events reported in ≥2 pts were respiratory tract infections (6 pts), pyrexia (3 pts) and anemia, multiorgan failure, fall and pelvic fracture (2 pts each). TEAEs that led to PELA discontinuation occurred in 7 pts (8%). Updated data with longer follow-up, including durability of splenic response and safety data from a more mature data set, will be available for presentation at the conference. Conclusions: The combination of PELA and RUX in JAKi-naïve pts with MF showed durable improvements in spleen volume, total symptom score and BM fibrosis, and was generally well tolerated. The randomized, double-blind, active-controlled Phase 3 MANIFEST-2 study is open for enrollment and evaluating the safety and efficacy of PELA in combination with RUX in JAKi treatment-naïve pts with MF (NCT04603495). Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The Use of Fedratinib for Myelofibrosis As a Potential Bridge to Hematopoietic Stem Cell Transplantation after Ruxolitinib Failure: Real-World Assessment of Treatment Characteristics and Spleen, Symptom, and Hematologic Response

Introduction: Janus kinase (JAK) inhibitors provide therapeutic benefits and symptom control in patients with myelofibrosis (MF) regardless of line of therapy. However, their use as a treatment pathway to hematopoietic stem cell transplantation (HSCT), the only curative option for patients with MF, is poorly understood. In August 2019, the JAK inhibitor fedratinib (FEDR) became the second treatment to be approved in the US for treatment of intermediate- or high-risk primary or secondary MF. We previously observed that 18% (12/67) of patients discontinued FEDR following failure of treatment with ruxolitinib (RUX) to undergo HSCT (Mascarenhas J, et al. Blood 2021;138(Suppl 1):1980). Here we describe patient characteristics, treatment characteristics, spleen and symptom changes, and outcomes following discontinuation of FEDR to undergo HSCT among real-world patients prescribed FEDR after treatment with RUX. Methods: Treating physicians from community oncology practices in the US selected eligible patients and completed electronic case report forms from February to March 2021. Eligible patients were adults with intermediate- or high-risk MF, who were treated with RUX and subsequently initiated FEDR on or after August 16, 2019, with ≥ 90 days of follow-up, and who had completed ≥ 1 cycle of FEDR and had discontinued FEDR prior to data cutoff to undergo HSCT. Physicians abstracted demographic and disease characteristics, RUX and FEDR treatment characteristics, spleen size, symptoms derived from the Myelofibrosis Symptom Assessment Form version 4.0 (MFSAF v.4.0), platelet count, hemoglobin (Hb), white blood cell (WBC) count, peripheral blasts, disease transformation, and death. Descriptive analyses characterized patient demographic and clinical characteristics, as well as disease transformation and death. Mean spleen size (length determined by palpation), symptom count, platelet count, Hb, WBC count, and mean proportion of peripheral blasts at FEDR initiation versus 3 months post-FEDR initiation were compared via paired 2-sided t-tests; P values < 0.05 were considered statistically significant. Results: A total of 12 patients underwent HSCT; 58% were male. At FEDR initiation, mean age was 56 years (interquartile range [IQR], 50-63), 42% of patients had ECOG performance status ≥ 2, and the mean Charlson Comorbidity Index score was 0.3 (standard deviation [SD], 0.6). Median RUX treatment duration prior to FEDR was 10.3 months (IQR, 6.3-25.4), and median time from RUX failure to RUX discontinuation was 23 days (IQR, 7-39). Median time from RUX failure to FEDR initiation was 1.1 months (IQR, 0.9-1.9). All patients received starting FEDR doses of 400 mg once daily; median FEDR treatment duration was 5.3 months (IQR, 4.1-7.9). From FEDR initiation to 3 months post-FEDR initiation, patients showed a statistically significant reduction in mean spleen size and mean number of symptoms (Table). Median follow-up after FEDR initiation was 9.4 months (IQR, 4.4-13.5). Disease transformation to acute myeloid leukemia occurred in 1 patient. No deaths were recorded as of the data cutoff in March 2021. Conclusions: This is the first real-world evidence on baseline characteristics and outcomes of patients with intermediate- or high-risk MF receiving FEDR after RUX failure, as a potential bridge to HSCT. Based on this dataset, HSCT following FEDR appears to be an effective and safe treatment option to consider. Larger prospective studies in patients treated with FEDR prior to HSCT should be conducted to determine efficacy and safety in this setting. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Modulation of TGF-β Superfamily Signaling to Treat Myelofibrosis and Mitigate JAK Inhibitor Toxicity: A Report on the Phase 2 Study of Ker-050 in Participants with Myelofibrosis

Background: Myelofibrosis (MF) is a disorder characterized by unrestrained proliferation of myeloid precursors and dysfunctional Janus kinase (JAK) signaling. Hyperplastic and dysplastic megakaryocyte expansion in MF releases inflammatory cytokines. These cytokines promote fibroblast proliferation, bone remodeling, and marrow fibrosis, disrupting the osteohematopoietic niche and leading to ineffective and extramedullary hematopoiesis (Vainchenker et al. 2017). Clinical manifestations include splenomegaly, anemia, and often disabling constitutional symptoms. JAK inhibitors, such as ruxolitinib, have been shown to improve spleen size and symptoms, but are associated with dose-limiting anemia and thrombocytopenia, reducing their utility for many patients (Verstovsek et al. 2012). KER-050 is an investigational product designed to alter signaling of TGF-β superfamily ligands, restoring balance to the osteohematopoietic niche and promoting differentiation of erythroid and megakaryocytic precursors. It is a modified activin receptor type IIA ligand trap that inhibits TGF-β superfamily ligands, including activins A and B and growth and differentiation factors (GDFs) 8 and 11. Preclinical studies have demonstrated that KER-050 induces erythropoiesis, increases platelet counts, improves bone mass, and prevents fibrosis. A preclinical study previously presented demonstrated that RKER-050 can reverse ruxolitinib-associated reductions in hemoglobin, hematocrit, and red blood cell count, indicating potential for KER-050 to mitigate ruxolitinib toxicity. In two clinical studies, including an ongoing study in participants with myelodysplastic syndromes (MDS), KER-050 has been well-tolerated. Accumulated clinical data demonstrate that KER-050 can stimulate erythropoiesis and thrombopoiesis in both healthy post-menopausal women and MDS participants with ineffective hematopoiesis. Here we present data from the first clinical study of KER-050 in participants with MF (NCT05037760). The objective of this study is to evaluate the potential of KER-050 as monotherapy and in combination with ruxolitinib to treat the underlying pathology of MF and mitigate JAK inhibitor-associated cytopenias. Methods: This ongoing Phase 2 open-label study is evaluating the safety, tolerability, pharmacokinetics PK), pharmacodynamics (PD), and efficacy of KER-050 administered with or without ruxolitinib in participants with primary myelofibrosis (PMF), post-essential thrombocythemia myelofibrosis (post-ET MF), and post-polycythemia vera myelofibrosis (post-PV MF) who have anemia (hemoglobin ≤ 10 g/dL or receiving transfusions). Part 1 involves parallel dose escalation arms (1A: monotherapy, 1B: combination with ruxolitinib) to evaluate the safety and tolerability of KER-050 and identify the dose(s) of KER-050 to be evaluated in Part 2 (Figure 1). Changes in hemoglobin, transfusion burden, spleen size, the Myelofibrosis Symptom Assessment Form Total Symptom Score (MF-SAF-TSS), PK and incidence of accelerated MF and acute myeloid leukemia are assessed as secondary endpoints. This study is also evaluating markers of multilineage hematopoiesis, bone remodeling, iron metabolism, inflammation, and marrow fibrosis. Frequency of ruxolitinib dose modification and quality of life will be explored. Results: Preliminary results from Part 1 will be presented. At the time of this writing, 5 patients have received KER-050 on study, 3 in Arm 1A and 2 in Arm 1B. Three participants have completed the dose-limiting toxicity (DLT) assessment period and no DLTs have been experienced. Data evaluated to date indicate a PD effect consistent with previous preclinical and clinical studies of KER-050. Summary: KER-050 is designed to alter TGF-β superfamily signaling, restoring balance to the osteohematopoietic niche and promoting multilineage hematopoietic differentiation. Here we present data from the first study of KER-050 in participants with MF evaluating the potential for KER-050 to impact key aspects of the MF disease state (anemia, spleen size, symptoms, progression), as monotherapy and in combination with ruxolitinib. The potential for KER-050 to mitigate ruxolitinib toxicity and related dose-reductions is being investigated. Exploratory analyses of the KER-050 impact on inflammation, bone remodeling, iron metabolism, and marrow fibrosis, as available, will be shared. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

P1041: IMPACT OF FEDRATINIB ON SPLEEN VOLUME AND MYELOFIBROSIS SYMPTOMS IN PATIENTS WITH SUBSTANTIAL SPLENOMEGALY: POST HOC ANALYSES FROM THE JAKARTA AND JAKARTA2 TRIALS

Background: In myelofibrosis (MF), splenomegaly is a marker of disease progression, and larger spleen size (SS) is correlated with poorer survival and debilitating symptoms. Fedratinib (FEDR) is an oral, selective Janus kinase 2 (JAK2) inhibitor approved as first-line (1L) treatment (Tx) of patients (pts) with MF and in pts previously treated with ruxolitinib (RUX). In the phase 3, placebo-controlled JAKARTA trial (NCT01437787) and the phase 2, single-arm JAKARTA2 trial (NCT01523171), pts experienced substantial improvements in spleen volume and MF symptoms after receiving 6 FEDR Tx cycles. Given the prognostic impact of splenomegaly, these analyses explore whether these clinical benefits were influenced by pre-Tx SS. Aims: Investigate the efficacy of FEDR 400 mg/d in JAKARTA and JAKARTA2, in pt subgroups defined by baseline (BL) SS. Methods: The JAKARTA trial assessed FEDR 400 mg/d, FEDR 500 mg/d, and placebo in pts with JAK inhibitor-naïve MF, and the JAKARTA2 trial evaluated FEDR 400 mg/d (starting dose) in pts resistant/intolerant to prior RUX. Both studies enrolled pts with intermediate- or high-risk MF, SS >5 cm from the left costal margin by palpation, platelets ≥50×109/L, and ECOG PS ≤2. These post hoc analyses included pts from both studies who were allocated to receive FEDR 400 mg/d (the approved dosage) in continuous 28-d Tx cycles. Pt subgroups were divided according to BL median SS (mSS) in each trial. Changes from BL in spleen volume and Myelofibrosis Symptom Assessment Form (MFSAF) total symptom score (TSS) were measured at the end of cycle 6 (EOC6). Spleen volume was assessed by MRI/CT scan; MFSAF TSS was the sum of 6 MF symptom scores: night sweats, early satiety, pruritus, pain under ribs-left side, abdominal discomfort, and bone/muscle pain. Eligible pts must have had spleen volume and/or TSS data at BL and EOC6. Results: Overall, 96 pts in JAKARTA and 97 pts in JAKARTA2 received FEDR 400 mg/d; mSS (range) at BL was 16 (5–40) cm and 18 (5–36) cm, respectively. In the JAKARTA <mSS and ≥mSS cohorts, median BL spleen volume was 1771 (316–3396) mL and 3329 (983–6430) mL, respectively, and median TSS was 13.0 (0.0–54.9) and 17.2 (0.4–57.0). In JAKARTA2, median BL spleen volume was 1937 (737–4305) mL and 4002 (1821–7815) mL for pts with <mSS and ≥mSS, respectively; BL TSS was 17.2 (0.7–48.0) and 23.6 (1.0–44.0). Overall, 75 (78%) pts in JAKARTA and 51 (53%) pts in JAKARTA2 had spleen volume data available at BL and EOC6; the <mSS and ≥mSS cohorts, comprised 37 and 38 pts, respectively, in JAKARTA, and 31 and 20 pts in JAKARTA2. Median spleen volume reduction (SVR) from BL was similar between the <mSS and ≥mSS cohorts in each trial, and 97% of pts with ≥mSS in both trials achieved some degree of SVR. In JAKARTA, median SVR at EOC6 was −38% (95% CI, −43 to −31) in the <mSS and −40% (95% CI, −40 to −28) in the ≥mSS cohort; in JAKARTA2, median SVR was −37 (95% CI, −43 to −30) in the <mSS and −38.5% (95% CI, −49 to −14) in the ≥mSS cohort. TSS data were available at BL and EOC6 for 71 (74%) pts in JAKARTA and 51 (53%) pts in JAKARTA2. Changes from BL in TSS at EOC6 were similar in the JAKARTA <mSS and ≥mSS cohorts, with median TSS reductions of −49% and −51%, respectively. Median TSS changes at EOC6 in JAKARTA2 were greater for pts with larger spleens, −36% and −49% in the <mSS and ≥mSS cohorts, respectively. Image:Summary/Conclusion: Pts who completed 6 Tx cycles with FEDR 400 mg/d, whether used as 1L MF Tx or after RUX Tx, experienced substantial improvements in spleen volume and MF symptom severity regardless of the extent of splenomegaly at BL.

P1060: REAL-WORLD CLINICAL OUTCOMES AFTER 3 AND 6 MONTHS OF TREATMENT WITH FEDRATINIB FOLLOWING RUXOLITINIB FAILURE

Background: Relief of symptoms and splenomegaly is an important treatment (Tx) goal for patients with myelofibrosis (MF). Fedratinib (FEDR) and ruxolitinib (RUX) are approved in the USA for Intermediate (Int)- or High-risk (HR) primary or secondary MF. Aims: To describe spleen size, and hematologic and MF-specific symptoms, during the first 6 months of FEDR therapy after prior Tx with RUX in US clinical practices. Methods: Adults with Int- or HR MF who initiated FEDR on or after August 16, 2019 (FEDR approval date) and with ≥90 days of follow-up were identified from community oncology practices. Eligible patients were those treated with RUX and then FEDR, who had spleen palpation at FEDR initiation, and who had completed ≥1 cycle of FEDR. Treating physicians completed electronic case report forms for the selected eligible patients, extracting patient characteristics, Tx pattern data, and clinical outcomes such as spleen size, MF-related symptoms per the Myelofibrosis Symptom Assessment Form version 4.0 (MFSAF v4.0), hemoglobin (Hb), and platelet and white blood cell (WBC) counts, at each visit in the first 6 months of FEDR Tx. Data were collected from February to March 2021. Mean spleen size, symptom count, Hb, and platelet and WBC counts at FEDR initiation vs at 3 and 6 months post-FEDR were compared via paired 2-sided t-test. Percentage reduction in spleen size and proportion of transfusion-dependent patients between FEDR initiation and 3 and 6 months post-FEDR were compared via 1-sided chi-square test. Only patients assessed at FEDR initiation (with palpable spleen or complete blood count available) and with a corresponding assessment at 3 or 6 months were included in the comparative analysis. Results: Among 150 eligible patients, the mean age at FEDR initiation was 68 years (range, 36–85). Median duration of RUX Tx prior to FEDR was 7.6 months (range, 0.7–65.5). At FEDR initiation, MF risk was categorized as International Prognostic Scoring System (IPSS)/Dynamic IPSS HR in 43% of patients, Int-2 in 37%, Int-1 in 9%, and unknown in 10%. A total of 74% of patients started FEDR at the recommended dosage of 400 mg daily. Median duration of post-FEDR follow-up was 5.1 months (IQR, 3.0–17.3) for patients initiated at FEDR 400 mg daily and 4.4 months (IQR, 3.0–14.3) for those initiating at <400 mg daily. At data cutoff, 55% of patients were still on FEDR. The primary reason for FEDR discontinuation was disease progression (43%). Mean duration of FEDR Tx was 4.7 months. Of 67 patients who discontinued FEDR, 44 were deceased at data cutoff. At FEDR initiation, 88% of patients had palpable spleen; mean spleen size was 16.0 cm (standard deviation [SD] 5.8) above the costal margin, which decreased to 13.2 cm (SD 7.9) at 3 months (P=0.0001) and 7.2 cm (SD 7.4) at 6 months (P=0.012). Mean number of MF-related symptoms declined significantly at 3 and 6 months; mean platelet count increased significantly at 6 months, from 160×109/L to 186×109/L (Table). Overall, 65.2% of patients experienced spleen size reduction, 18.8% had no change, and 16.0% had an increase. Mean best percentage change in spleen size was −29.2% (median −9.8%); complete resolution of palpable spleen occurred in 21% of patients. Image:Summary/Conclusion: This study illustrates the real-world effectiveness of FEDR after RUX failure in patients with Int- or HR MF. FEDR provided significant reductions in spleen size and reported number of MF-related symptoms after 3 months of Tx, including complete spleen responses. Greater benefits were observed with longer Tx duration.

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.

MOMENTUM: Phase 3 randomized study of momelotinib (MMB) versus danazol (DAN) in symptomatic and anemic myelofibrosis (MF) patients previously treated with a JAK inhibitor.

7002 Background: MMB, an oral JAK1/2 and ACVR1/ALK2 inhibitor, showed clinical activity on MF symptoms, RBC transfusion requirements (anemia), and spleen volume in the SIMPLIFY trials. This pivotal phase 3 study of MF patients (pts) previously treated with a JAK inhibitor (JAKi) tested MMB vs DAN on key symptom, anemia, and spleen volume endpoints at 24 weeks (wks). Methods: Eligibility: Primary or post-ET/PV MF; DIPSS high risk, Int-2, or Int-1; MF Symptom Assessment Form Total Symptom Score (MFSAF TSS) ≥10; Hgb &lt;10 g/dL; prior JAKi for ≥90 days, or ≥28 days if RBC transfusions ≥4 units in 8 wks or Gr 3/4 thrombocytopenia, anemia, or hematoma; palpable spleen ≥5 cm. Stratification: TSS, palpable spleen, and RBC units transfused. JAKi taper and washout was ≥21 days. Randomization: 2:1 to MMB 200 mg QD plus DAN placebo or DAN 600 mg QD plus MMB placebo for 24 wks, after which pts could receive open-label MMB. Assessments: Pt reported symptoms using a daily eDiary and spleen volume by MRI or CT. The primary endpoint was TSS response (≥50% reduction from baseline [BL]) rate at wk 24. Secondary endpoints, assessed sequentially at wk 24, were RBC transfusion independence (TI) rate, splenic response rate (SRR; ≥25% reduction in volume from BL), change from BL in TSS, SRR (≥35% reduction from BL) and rate of zero transfusions since BL. Results: 94 of 130 (72%) MMB pts and 38 of 65 (58%) DAN pts completed the 24-wk randomized treatment (RT) phase. Median BL TSS were 28 (MMB) and 26 (DAN), Hgb were 8.1 (MMB) and 7.9 (DAN) g/dL, and platelets were 97 (MMB) and 94 (DAN) x109/L. BL TI was 13% (MMB) and 15% (DAN). Prior JAKi was ruxolitinib in 195 pts (100%) and fedratinib in 9 pts (5%). All primary and key secondary endpoints were met (Table). Most common Gr ≥3 TEAEs in the RT phase of the study were thrombocytopenia (MMB, 22%; DAN, 12%) and anemia (MMB, 8%; DAN, 11%). Gr ≥3 infections occurred in 15% of MMB and 17% of DAN pts. Peripheral neuropathy occurred in 5 (4%) of MMB (all Gr ≤2) and 1 (2%) of DAN (Gr ≤2) pts in the RT phase, and none discontinued study drug. Overall, TEAEs led to study drug discontinuation in 18% of MMB and 23% of DAN pts in RT phase. A trend toward improved OS up to wk 24 was seen with MMB vs DAN (HR=0.506, p=0.0719). Conclusions: In symptomatic and anemic MF pts, MMB was superior to DAN for symptom responses, transfusion requirements, and spleen responses with comparable safety and favorable survival. MMB may address a critical unmet need, particularly in MF pts with anemia. Clinical trial information: NCT04173494. [Table: see text]

Thrombocytopenic myelofibrosis (MF) patients previously treated with a JAK inhibitor in a phase 3 randomized study of momelotinib (MMB) versus danazol (DAN) [MOMENTUM

7061 Background: MMB, an oral JAK1/2 and ACVR1/ALK2 inhibitor, showed clinical activity on MF symptoms, RBC transfusion requirements (anemia), and spleen volume in the SIMPLIFY trials, including in MF patients (pts) with thrombocytopenia. MOMENTUM is a pivotal phase 3 study of symptomatic and anemic MF pts previously treated with a JAK inhibitor (JAKi) testing MMB vs DAN. This analysis evaluated MOMENTUM pts with baseline (BL) platelet counts (PLT) ≤150 x 109/L. Methods: Eligibility: Primary or post-ET/PV MF; DIPSS high risk, Int-2, or Int-1; MF Symptom Assessment Form Total Symptom Score (MFSAF TSS) ≥10; Hgb &lt;10 g/dL; prior JAKi for ≥90 days, or ≥28 days if RBC transfusions ≥4 units in 8 weeks (wks) or Gr 3/4 thrombocytopenia, anemia, or hematoma; palpable spleen ≥5 cm; PLT ≥25 x 109/L. JAKi taper and washout was ≥21 days. Randomization: 2:1 to MMB 200 mg QD plus DAN placebo or DAN 600 mg QD plus MMB placebo for 24 wks. Primary endpoint: TSS response (≥50% reduction from BL) rate at wk 24. Key secondary endpoints, assessed sequentially at wk 24: RBC transfusion independence (TI) rate, splenic response rate (SRR; ≥25% reduction in volume from BL), change from BL in TSS, SRR (≥35% reduction from BL) and rate of zero transfusions since BL. Results: 60 (74%) of 81 MMB pts and 25 (58%) of 43 DAN pts with BL PLT ≤150 x 109/L completed the 24-week randomized treatment (RT) phase. Median BL TSS were 29 (MMB) and 24 (DAN), Hgb were 7.9 (MMB) and 8.0 (DAN) g/dL, and PLT were 67 x 109/L (MMB) and 64 x 109/L (DAN). Prior JAKi was ruxolitinib in 124 pts (100%) and fedratinib in 6 pts (5%). Efficacy results are in Table. These results are consistent with the overall ITT analysis set (N=195). Most common Gr ≥3 TEAEs in the RT phase were thrombocytopenia (MMB, 31%; DAN, 16%) and anemia (MMB, 7%; DAN, 14%); Gr ≥3 bleeding events occurred in 9% of MMB and 5% of DAN pts. TEAEs led to study drug discontinuation in 15% of MMB and 19% of DAN pts in RT phase. A trend toward improved OS up to wk 24 was seen with MMB vs DAN [HR (95% CI)=0.490 (0.195, 1.235)]. Additional analyses of pts with BL PLT &lt;100 x 109/L (N=100) and BL PLT &lt;50 x 109/L (N=31) show similar treatment effects of MMB vs DAN. Conclusions: In thrombocytopenic MF pts who were symptomatic and anemic, MMB was superior to DAN for symptom responses, transfusion requirements, and spleen responses and showed comparable safety and favorable survival. MMB may address a critical unmet need in thrombocytopenic MF pts. Clinical trial information: NCT04173494. [Table: see text]

Addition of navitoclax to ongoing ruxolitinib treatment in patients with myelofibrosis (REFINE): a post-hoc analysis of molecular biomarkers in a phase 2 study

Primary analyses of cohort 1a of the REFINE trial showed that addition of navitoclax to ruxolitinib induced a 35% or greater reduction in spleen volume (SVR35) and reduced symptoms in patients with myelofibrosis no longer benefiting from ruxolitinib. Here, we report the exploratory post-hoc biomarker analyses from cohort 1a. REFINE is a phase 2, multicentre, open-label trial designed to assess the activity and safety of navitoclax alone or in combination with ruxolitinib in patients with primary or secondary (post-polycythaemia vera or post-essential thrombocythaemia) myelofibrosis. Cohort 1a of the study included patients who had disease progression or suboptimal response on stable ruxolitinib monotherapy. Patients in cohort 1a, who had previously received ruxolitinib for 12 weeks or more, continued their current stable dose, and navitoclax was orally administered at 50 mg per day and escalated weekly to a maximum of 300 mg per day, based on tolerability. The primary activity endpoint was SVR35 at week 24 from baseline. Secondary endpoints were a 50% or greater reduction in total symptom score (TSS50) at week 24 from baseline as measured by the Myelofibrosis Symptom Assessment Form (version 4.0), anaemia response assessed according to International Working Group-Myeloproliferative Neoplasms Research and European LeukemiaNet criteria, and change in grade of bone marrow fibrosis according to the European consensus grading system; and exploratory endpoints included overall survival and changes in inflammatory cytokines. Exploratory analyses investigated potential prognostic biomarkers of the benefit of navitoclax-based combination treatment, including bone marrow fibrosis and variant allele frequency, in patients with a suboptimal response to ruxolitinib. This study is registered with ClinicalTrials.gov (NCT03222609) and is ongoing. Between Nov 14, 2017, and April 10, 2019, 34 patients in cohort 1a received at least one dose of navitoclax plus ruxolitinib. 23 (68%) patients were male, with 32 (94%) being White. At data cutoff (May 6, 2021), the median follow-up for survivors was 26·2 months (IQR 21·9-32·3). 33 patients were evaluable for biomarker analyses; 19 (58%) had high molecular risk mutations. Five (31%) of 16 patients had SVR35 at week 24 in the high molecular risk group, as did four (31%) of 13 in the non-high molecular risk group. Four (36%) of 11 patients in the high molecular risk group had TSS50 at week 24 compared with two (25%) of eight in the non-high molecular risk group; seven (39%) of 18 in the high molecular risk group had an improvement in fibrosis by at least one grade compared with five (36%) of 14 in the non-high molecular risk group; and four (28%) of 14 had reductions in variant allele frequency of 20% or greater in the high molecular risk group compared with two (17%) of 12 in the non-high molecular risk group. Patients with improvements in fibrosis of one grade or more and a reduction of 20% of more in variant allele frequency had improved overall survival (median overall survival not reached) compared with those who did not achieve fibrosis improvement or a reduction in variant allele frequency (median overall survival 28·5 months [95% CI 19·6-not estimable] for both), suggesting potential disease modification. Additionally, changes in concentrations of β-2-microglobulin (week 12: r=0·57; week 24: r=0·57), TIMP metallopeptidase inhibitor 1 (week 12: r=0·47; week 24: r=0·54), TNF receptor type II (r=0·55; week 24: r=0·40), and vascular cell adhesion molecule-1 (r=0·58; week 24: r=0·50) were positively associated with changes in spleen volume. These biomarker analyses reveal clinically meaningful splenic responses independent of high molecular risk mutation status in patients treated with navitoclax plus ruxolitinib who were not benefiting from ruxolitinib monotherapy. Furthermore, the overall survival benefit observed in those with an improvement in fibrosis or a reduction in variant allele frequency is suggestive of disease modification, implying the therapeutic potential of adding navitoclax to ruxolitinib for patients with myelofibrosis who had disease progression or suboptimal response to ruxolitinib monotherapy. AbbVie.

Pelabresib (CPI-0610) Monotherapy in Patients with Myelofibrosis - Update of Clinical and Translational Data from the Ongoing Manifest Trial

Pelabresib (CPI-0610) Monotherapy in Patients with Myelofibrosis - Update of Clinical and Translational Data from the Ongoing Manifest Trial