Showing papers by "Claire N. Harrison published in 2022"

The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms

Abstract: Abstract The upcoming 5th edition of the World Health Organization (WHO) Classification of Haematolymphoid Tumours is part of an effort to hierarchically catalogue human cancers arising in various organ systems within a single relational database. This paper summarizes the new WHO classification scheme for myeloid and histiocytic/dendritic neoplasms and provides an overview of the principles and rationale underpinning changes from the prior edition. The definition and diagnosis of disease types continues to be based on multiple clinicopathologic parameters, but with refinement of diagnostic criteria and emphasis on therapeutically and/or prognostically actionable biomarkers. While a genetic basis for defining diseases is sought where possible, the classification strives to keep practical worldwide applicability in perspective. The result is an enhanced, contemporary, evidence-based classification of myeloid and histiocytic/dendritic neoplasms, rooted in molecular biology and an organizational structure that permits future scalability as new discoveries continue to inexorably inform future editions.

Addition of Navitoclax to Ongoing Ruxolitinib Therapy for Patients With Myelofibrosis With Progression or Suboptimal Response: Phase II Safety and Efficacy

Abstract: PURPOSE Targeting the BCL-XL pathway has demonstrated the ability to overcome Janus kinase inhibitor resistance in preclinical models. This phase II trial investigated the efficacy and safety of adding BCL-XL/BCL-2 inhibitor navitoclax to ruxolitinib therapy in patients with myelofibrosis with progression or suboptimal response to ruxolitinib monotherapy (ClinicalTrials.gov identifier: NCT03222609). METHODS Thirty-four adult patients with intermediate-/high-risk myelofibrosis who had progression or suboptimal response on stable ruxolitinib dose (≥ 10 mg twice daily) were administered navitoclax at 50 mg once daily starting dose, followed by escalation to a maximum of 300 mg once daily in once in weekly increments (if platelets were ≥ 75 × 109/L). The primary end point was ≥ 35% spleen volume reduction (SVR35) from baseline at week 24. Secondary end points included ≥ 50% reduction in total symptom score (TSS50) from baseline at week 24, hemoglobin improvement, change in bone marrow fibrosis (BMF) grade, and safety. RESULTS High molecular risk mutations were identified in 58% of patients, and 52% harbored ≥ 3 mutations. SVR35 was achieved by 26.5% of patients at week 24, and by 41%, at any time on study, with an estimated median duration of SVR35 of 13.8 months. TSS50 was achieved by 30% (6 of 20) of patients at week 24, and BMF improved by 1-2 grades in 33% (11 of 33) of evaluable patients. Anemia response was achieved by 64% (7 of 11), including one patient with baseline transfusion dependence. Median overall survival was not reached with a median follow-up of 21.6 months. The most common adverse event was reversible thrombocytopenia without clinically significant bleeding (88%). CONCLUSION The addition of navitoclax to ruxolitinib in patients with persistent or progressive myelofibrosis resulted in durable SVR35, improved TSS, hemoglobin response, and BMF. Further investigation is underway to qualify the potential for disease modification. Novel Combo: Navitoclax plus Rux for patients w/MF and poor Rux response ïƒ improved SVR, TSS, and BMF | #MPNSM

Managing hematological cancer patients during the COVID-19 pandemic: an ESMO-EHA Interdisciplinary Expert Consensus

Abstract: The COVID-19 pandemic has created enormous challenges for the clinical management of patients with hematological malignancies (HMs), raising questions about the optimal care of this patient group.This consensus manuscript aims at discussing clinical evidence and providing expert advice on statements related to the management of HMs in the COVID-19 pandemic. For this purpose, an international consortium was established including a steering committee, which prepared six working packages addressing significant clinical questions from the COVID-19 diagnosis, treatment, and mitigation strategies to specific HMs management in the pandemic. During a virtual consensus meeting, including global experts and lead by the European Society for Medical Oncology and the European Hematology Association, statements were discussed and voted upon. When a consensus could not be reached, the panel revised statements to develop consensual clinical guidance.The expert panel agreed on 33 statements, reflecting a consensus, which will guide clinical decision making for patients with hematological neoplasms during the COVID-19 pandemic.

Overall survival in the SIMPLIFY-1 and SIMPLIFY-2 phase 3 trials of momelotinib in patients with myelofibrosis

Abstract: Abstract Janus kinase inhibitors (JAKi) approved for myelofibrosis provide spleen and symptom improvements but do not address anemia, a negative prognostic factor. Momelotinib, an inhibitor of ACVR1/ALK2, JAK1 and JAK2, demonstrated activity against anemia, symptoms, and splenomegaly in the phase 3 SIMPLIFY trials. Here, we report mature overall survival (OS) and leukemia-free survival (LFS) from both studies, and retrospective analyses of baseline characteristics and efficacy endpoints for OS associations. Survival distributions were similar between JAKi-naïve patients randomized to momelotinib, or ruxolitinib then momelotinib, in SIMPLIFY-1 (OS HR = 1.02 [0.73, 1.43]; LFS HR = 1.08 [0.78, 1.50]). Two-year OS and LFS were 81.6% and 80.7% with momelotinib and 80.6% and 79.3% with ruxolitinib then momelotinib. In ruxolitinib-exposed patients in SIMPLIFY-2, two-year OS and LFS were 65.8% and 64.2% with momelotinib and 61.2% and 59.7% with best available therapy then momelotinib (OS HR = 0.98 [0.59, 1.62]; LFS HR = 0.97 [0.59, 1.60]). Baseline transfusion independence (TI) was associated with improved survival in both studies (SIMPLIFY-1 HR = 0.474, p = 0.0001; SIMPLIFY-2 HR = 0.226, p = 0.0005). Week 24 TI response in JAKi-naïve, momelotinib-randomized patients was associated with improved OS in univariate (HR = 0.323; p < 0.0001) and multivariate (HR = 0.311; p < 0.0001) analyses. These findings underscore the importance of achieving or maintaining TI in myelofibrosis, supporting the clinical relevance of momelotinib’s pro-erythropoietic mechanism of action, and potentially informing treatment decision-making.

Safety and efficacy of fedratinib, a selective oral inhibitor of Janus kinase‐2 (JAK2), in patients with myelofibrosis and low pretreatment platelet counts

Abstract: Fedratinib, an oral Janus kinase‐2 (JAK2) inhibitor, is approved for patients with myelofibrosis (MF) and platelet counts ≥50 × 109/l, based on outcomes from the phase 3, placebo‐controlled JAKARTA trial in JAK‐inhibitor‐naïve MF, and the phase 2, single‐arm JAKARTA2 trial in patients previously treated with ruxolitinib. We evaluated the efficacy and safety of fedratinib 400 mg/day in patients with baseline platelet counts 50 to <100 × 109/l (“Low‐Platelets” cohorts), including 14/96 patients (15%) in JAKARTA and 33/97 (34%) in JAKARTA2. At 24 weeks, spleen response rates were not significantly different between the Low‐Platelets cohort and patients with baseline platelet counts ≥100 × 109/l (“High‐Platelets” cohort), in JAKARTA (36% vs. 49%, respectively; p = 0.37) or JAKARTA2 (36% vs. 28%; p = 0.41). Symptom response rates were also not statistically different between the Low‐ and High‐Platelets cohorts. Fedratinib was generally well‐tolerated in both platelet‐count cohorts. New or worsening thrombocytopaenia was more frequent in the Low‐Platelets (44%) versus the High‐Platelets (9%) cohort, but no serious thrombocytopaenia events occurred. Thrombocytopaenia was typically managed with dose modifications; only 3/48 Low‐Platelets patients discontinued fedratinib due to thrombocytopaenia. These data indicate that fedratinib 400 mg/day is safe and effective in patients with MF and low pretreatment platelet counts, and no initial fedratinib dose adjustment is required for these patients.

Deciphering TP53 mutant Cancer Evolution with Single-Cell Multi-Omics

Abstract: TP53 is the most commonly mutated gene in human cancer, typically occurring in association with complex cytogenetics and dismal outcomes. Understanding the genetic and non-genetic determinants of TP53-mutation driven clonal evolution and subsequent transformation is a crucial step towards the design of rational therapeutic strategies. Here, we carry out allelic resolution single-cell multi-omic analysis of haematopoietic stem/progenitor cells (HSPC) from patients with a myeloproliferative neoplasm who transform to TP53-mutant secondary acute myeloid leukaemia (AML), a tractable model of TP53-mutant cancer evolution. All patients showed dominant TP53 ‘multi-hit’ HSPC clones at transformation, with a leukaemia stem cell transcriptional signature strongly predictive of adverse outcome in independent cohorts, across both TP53-mutant and wild-type AML. Through analysis of serial samples and antecedent TP53-heterozygous clones, we demonstrate a hitherto unrecognised effect of chronic inflammation, which supressed TP53 wild-type HSPC whilst enhancing the fitness advantage of TP53 mutant cells. Our findings will facilitate the development of risk-stratification, early detection and treatment strategies for TP53-mutant leukaemia, and are of broader relevance to other cancer types.

Imetelstat in intermediate-2 or high-risk myelofibrosis refractory to JAK inhibitor: IMpactMF phase III study design.

Abstract: Imetelstat, a first-in-class telomerase inhibitor, demonstrated meaningful clinical benefit including a robust symptom response rate and potential overall survival benefit in IMbark, a phase II study in intermediate-2 or high-risk MF patients who have relapsed after or are refractory to JAK inhibitors. We describe the rationale and design for the phase III trial, IMpactMF (NCT04576156), an open-label evaluation of imetelstat versus best available therapy, excluding JAK inhibitors, in MF patients refractory to JAK inhibitor. Imetelstat 9.4 mg/kg is administered as an intravenous infusion every 21 days. Primary objective is to assess overall survival. Secondary objectives include symptom and spleen responses, progression-free survival, clinical response assessment, bone marrow fibrosis reduction, safety and pharmacokinetics. Biomarker, cytogenetics and mutation analyses will be performed.

MPN-375 BET Inhibitor Pelabresib (CPI-0610) Combined With Ruxolitinib in Patients With Myelofibrosis - JAK Inhibitor-Naïe or With Suboptimal Response to Ruxolitinib - Preliminary Data From the MANIFEST Study.

Abstract: CONTEXT Myelofibrosis is characterized by splenomegaly, symptoms, cytopenias, and bone marrow (BM) fibrosis. Pelabresib is an investigational, oral, small-molecule BET inhibitor designed to selectively inhibit the BD1 and BD2 bromodomains of BET proteins. OBJECTIVE Evaluation of pelabresib combined with ruxolitinib in patients with myelofibrosis. DESIGN In Arm 3 of the Phase 2 MANIFEST study (NCT02158858), JAKi-naïve myelofibrosis patients are treated with pelabresib combined with ruxolitinib. In Arm 2, myelofibrosis patients with suboptimal response to ruxolitinib are treated with pelabresib as 'add-on' to ruxolitinib (Arm 2A: transfusion-dependent [TD]; Arm 2B: non-TD). The primary endpoints are ≥35% spleen volume reduction (SVR35) at Week 24 for Arms 3 and 2B and TD to transfusion independence (TI) in Arm 2A. The key secondary endpoint is ≥50% total symptom score reduction (TSS50) at Week 24; in Arm 2A, SVR35 is an additional key secondary endpoint. BM biopsies to assess BM fibrosis and safety data are also evaluated. RESULTS As of September 2021, at Week 24 in Arm 3 (N=84), 68% (57/84) of patients achieved SVR35 (median change: -50%), and 56% (46/82) of patients achieved TSS50 (median change: -59%). At Week 24 in Arm 2 (N=86), 20% (16/81; 17% in Arm 2A and 26% in Arm 2B) of patients achieved SVR35 (median change: -18%), and 37% (30/81) of patients achieved TSS50 (median change: -47%). In Arm 2A, the TD to TI rate was 16% (6/38). At Week 24, BM fibrosis improvement ≥ 1 grade was achieved in 28% (16/57) and 26% (12/47) of patients in Arms 3 and 2, respectively. Hematologic treatment-emergent adverse events (TEAEs) included thrombocytopenia, in 52% (≥Grade 3: 12%) and 52% (≥Grade 3: 33%) of patients, and anemia, in 42% (≥Grade 3: 35%) and 27% (≥Grade 3: 19%) of patients in Arms 3 and 2, respectively. Low-grade gastrointestinal TEAEs and respiratory infections were observed but rarely resulted in discontinuation. CONCLUSIONS In ruxolitinib treatment-naïve and previously treated patients with myelofibrosis, pelabresib combined with ruxolitinib resulted in splenic and symptom responses and BM fibrosis improvement and was generally well tolerated. The Phase 3 MANIFEST-2 study is evaluating pelabresib combined with ruxolitinib in JAKi treatment-naïve patients with myelofibrosis (NCT04603495).

Phase III MANIFEST-2: pelabresib + ruxolitinib vs placebo + ruxolitinib in JAK inhibitor treatment-naive myelofibrosis.

Abstract: Myelofibrosis (MF) is a clonal myeloproliferative neoplasm, typically associated with disease-related symptoms, splenomegaly, cytopenias and bone marrow fibrosis. Patients experience a significant symptom burden and a reduced life expectancy. Patients with MF receive ruxolitinib as the current standard of care, but the depth and durability of responses and the percentage of patients achieving clinical outcome measures are limited; thus, a significant unmet medical need exists. Pelabresib is an investigational small-molecule bromodomain and extraterminal domain inhibitor currently in clinical development for MF. The aim of this article is to describe the design of the ongoing, global, phase III, double-blind, placebo-controlled MANIFEST-2 study evaluating the efficacy and safety of pelabresib and ruxolitinib versus placebo and ruxolitinib in patients with JAKi treatment-naive MF. Clinical Trial Registration: NCT04603495 (ClinicalTrials.gov).

MPN-145 Retrospective Analysis of Anemia Benefit of Pacritinib From the PERSIST-2 Trial.

Abstract: Pacritinib (PAC) is a novel JAK2/IRAK1 inhibitor approved for patients with myelofibrosis (MF) and platelets <50×109/L. Previous publications have characterized PAC's unique advantage of reduced myelosuppression. We conducted a retrospective analysis of the phase 3 PERSIST-2 trial to assess PAC's impact on anemia and performed in vitro analysis to explore PAC inhibition of ACVR1 (ALK2).This analysis included PERSIST-2 patients with platelet count ≤100×109/L randomized to PAC 200mg BID, PAC 400mg QD, or best available therapy BAT. Transfusion independence (TI) was defined as no RBC transfusions and no hemoglobin level <8g/dL. PAC's activity against ACVR1 was assessed using the HotSpot assay from Reaction Biology Corporation. The activity of the JAK1/JAK2/ACVR1 inhibitor momelotinib was also assessed. IC50 was calculated using 3-fold serial dilutions starting at 10µM.The analysis included 106 patients on PAC 200mg BID, 104 on 400mg QD and 98 on BAT. Patients at baseline, were severely cytopenic, with a median platelet count of 55×109/L. Among patients with baseline hemoglobin <10g/dL, the percentage who achieved ≥1g/dL improvement at any time through week 24 was higher on PAC than BAT (PAC 200mg BID: 15% (5/33); PAC 400mg QD: 23% (7/30); BAT: 7% (2/28). The percentage who achieved an increase of ≥2g/dL trended similarly: PAC 200mg BID: 9% (3/33), PAC 400mg QD: 7% (2/30), BAT: 4% (1/28)). Among patients receiving transfusions or with Hb <8 at baseline, the percentage who achieved TI at any point (evaluated at 12-week intervals) through week 24 was greater on PAC 200mg BID (7/26, 27%) and PAC 400mg QD (6/24, 25%) than BAT (1/19, 5%). On duplicate assays, pacritinib was shown to inhibit ACVR1 with an IC50 of 23 and 11nM. Momelotinib's IC50 was 70 and 35nM in the same assay.Improvement in hemoglobin levels and transfusion requirements was greater on PAC than BAT, in PERSIST-2. This anemia benefit could be due to PAC's ability to inhibit the iron regulator ACVR1, which has been linked to hepcidin reduction and anemia benefit. These data suggest an important role for PAC in anemic patients with myelofibrosis. This study was supported by CTI BioPharma.

Anemia in myelofibrosis: current and emerging treatment options.

Abstract: Myelofibrosis (MF) is a clonal hematologic malignancy with progressive bone marrow fibrosis. Clinical manifestations of MF include splenomegaly, constitutional symptoms, and anemia, whose pathogenesis is multifactorial and largely due to ineffective erythropoiesis and is clinically associated with poor quality of life and reduced overall survival. The only curative treatment for MF is allogenic stem cell transplantation; however, few patients are eligible. Disease management strategies for MF-related anemia have limited effectiveness, and Janus kinase (JAK) inhibitors may induce or worsen related anemia. Thus, there is a significant unmet need for the treatment of patients with MF-related anemia. This review summarizes current and emerging treatments for anemia in MF, including luspatercept and KER-050 (transforming growth factor-β ligand traps), momelotinib and pacritinib (JAK inhibitors), pelabresib (a bromodomain extra-terminal domain inhibitor), PRM-151 (an antifibrotic agent), imetelstat (a telomerase inhibitor), and navitoclax (a BCL-2/BCL-xL inhibitor). Therapeutic combinations with ruxolitinib may offer another treatment approach.

Chronic myeloid leukaemia patients at diagnosis and resistant to tyrosine kinase inhibitor therapy display exhausted T‐cell phenotype

Abstract: The search for novel targets in chronic myeloid leukaemia (CML) is ongoing, to improve treatment efficacy in refractory disease and increase eligibility for tyrosine kinase inhibitor (TKI) discontinuation. Increased frequency of Tregs and effector Tregs was evident at diagnosis, together with increased expression of T‐cell exhaustion markers, including in regulatory T cells at diagnosis and in patients with refractory disease. Plasma analysis revealed significantly increased levels of cytokines including tumour necrosis factor (TNF)‐a and interleukin (IL)‐6 at diagnosis, in keeping with a pro‐inflammatory state prior to treatment. We hence demonstrate T‐cell exhaustion and a pro‐inflammatory state at diagnosis in CML, likely secondary to leukaemia‐associated antigenic overload associated with increased disease burden.

Biological drivers of clinical phenotype in myelofibrosis

Abstract: Abstract Myelofibrosis (MF) is a myeloproliferative disorder that exhibits considerable biological and clinical heterogeneity. At the two ends of the disease spectrum are the myelodepletive or cytopenic phenotype and the myeloproliferative phenotype. The cytopenic phenotype has a high prevalence in primary MF (PMF) and is characterized by low blood counts. The myeloproliferative phenotype is typically associated with secondary MF (SMF), mild anemia, minimal need for transfusion support, and normal to mild thrombocytopenia. Differences in somatic driver mutations and allelic burden, as well as the acquisition of non-driver mutations further influences these phenotypic differences, prognosis, and response to therapies such as JAK2 inhibitors. The outcome of patients with the cytopenic phenotype are comparatively worse and frequently pose a challenge to treat given the inherent exacerbation of cytopenias. Recent data indicate that an innate immune deregulated state that hinges on the myddosome-IRAK-NFκB axis favors the cytopenic myelofibrosis phenotype and offers opportunity for novel treatment approaches. We will review the biological and clinical features of the MF disease spectrum and associated treatment considerations.

Continuous Indexing of Fibrosis (CIF): improving the assessment and classification of MPN patients

Abstract: The grading of fibrosis in myeloproliferative neoplasms (MPN) is an important component of disease classification, prognostication and monitoring. However, current fibrosis grading systems are only semi-quantitative and fail to fully capture sample heterogeneity. To improve the quantitation of reticulin fibrosis, we developed a machine learning approach using bone marrow trephine (BMT) samples (n = 107) from patients diagnosed with MPN or a reactive marrow. The resulting Continuous Indexing of Fibrosis (CIF) enhances the detection and monitoring of fibrosis within BMTs, and aids MPN subtyping. When combined with megakaryocyte feature analysis, CIF discriminates between the frequently challenging differential diagnosis of essential thrombocythemia (ET) and pre-fibrotic myelofibrosis with high predictive accuracy [area under the curve = 0.94]. CIF also shows promise in the identification of MPN patients at risk of disease progression; analysis of samples from 35 patients diagnosed with ET and enrolled in the Primary Thrombocythemia-1 trial identified features predictive of post-ET myelofibrosis (area under the curve = 0.77). In addition to these clinical applications, automated analysis of fibrosis has clear potential to further refine disease classification boundaries and inform future studies of the micro-environmental factors driving disease initiation and progression in MPN and other stem cell disorders.

Efficacy and safety of ruxolitinib in patients with myelofibrosis and low platelet count (50 × 109/L to <100 × 109/L) at baseline: the final analysis of EXPAND

Abstract: Background: Thrombocytopenia is a common feature of myelofibrosis (MF), a myeloproliferative neoplasm driven by dysregulated JAK/STAT signaling; however, pivotal trials assessing the efficacy of ruxolitinib (a JAK1/2 inhibitor) excluded MF patients with low platelet counts (<100 × 109/L). Objectives: Determination of the maximum safe starting dose (MSSD) of ruxolitinib was the primary endpoint, with long-term safety and efficacy as secondary and exploratory endpoints, respectively. Design: EXPAND (NCT01317875) was a phase 1b, open-label, ruxolitinib dose-finding study in patients with MF and low platelet counts (50 to <100 × 109/L). Methods: Patients were stratified according to baseline platelet count into stratum 1 (S1, 75 to <100 × 109/L) or stratum 2 (S2, 50 to <75 × 109/L). Previous analyses established the MSSD at 10 mg twice daily (bid); long-term results are reported here. Results: Of 69 enrolled patients, 38 received ruxolitinib at the MSSD (S1, n = 20; S2, n = 18) and are the focus of this analysis. The incidence of adverse events was consistent with the known safety profile of ruxolitinib, with thrombocytopenia (S1, 50%; S2, 78%) and anemia (S1, 55%; S2, 44%) the most frequently reported adverse events and no new or unexpected safety signals. Substantial clinical benefits were observed for patients in both strata: 50% (10/20) and 67% (12/18) of patients in S1 and S2, respectively, achieved a spleen response (defined as ⩾50% reduction in spleen length from baseline) at any time during the study. Conclusion: The final safety and efficacy results from EXPAND support the use of a 10 mg bid starting dose of ruxolitinib in patients with MF and platelet counts 50 to <100 × 109/L. Registration: ClinicalTrials.gov NCT01317875.

P1042: safety and tolerability results from the phase 3b freedom trial of fedratinib (fedr), an oral, selective jak2 inhibitor, in patients with myelofibrosis (mf) previously treated with ruxolitinib (rux)

Abstract: Background: FEDR is an oral, selective Janus kinase 2 (JAK2) inhibitor approved for treatment (Tx) of patients (pts) with MF, including those previously treated with RUX. In the single-arm, phase 2 JAKARTA2 trial in pts with MF resistant/intolerant to prior RUX, the most common adverse events (AEs) during FEDR Tx were gastrointestinal (GI) events. JAKARTA2 ended in 2013, when a temporary clinical hold was placed on FEDR due to suspected cases of Wernicke’s encephalopathy (WE). The safety and efficacy of FEDR in pts with MF previously treated with RUX are being further evaluated in the ongoing, single-arm, phase 3b FREEDOM trial (NCT03755518), which includes prospective strategies for preventing or mitigating GI AEs, thiamine decreases, and potential WE. Aims: To assess the safety of FEDR and the effectiveness of AE mitigation strategies in the FREEDOM trial. Methods: Eligible pts had intermediate- or high-risk MF, platelets ≥50×109/L, and spleen volume ≥450cm3 by MRI/CT or palpable spleen ≥5 cm below the left costal margin. Pts must have received prior RUX for ≥3 mo, or for ≥28 d with development of red blood cell transfusion requirement (≥2 units/mo for 2 mo) or grade ≥3 thrombocytopenia, anemia, hematoma, or hemorrhage. All pts received FEDR 400 mg/d in continuous 28-d cycles. AE mitigation strategies include prophylactic and symptomatic use of anti-nausea/vomiting and anti-diarrheal Tx, thiamine supplementation, FEDR dosing modifications, and administration of FEDR with food. Results: In all, 34 pts were enrolled and 16 pts continued to receive FEDR at data cutoff (April 9, 2021). Reasons for FEDR discontinuation (D/C) in >1 pt were lack of efficacy (n=5), AEs (n=4), disease progression (n=2), pt decision (n=2), and to undergo transplant (n=2). Median FEDR Tx duration at cutoff was 28.3 (range, 1.6–101.3) wk; 14 (41%) pts had completed >12 cycles. At baseline (BL), median (range) age was 68.5 (49–82) y, time from MF diagnosis was 3.4 (0.1–17.4) y, and spleen size was 15 (3–31) cm. Most pts (62%) had primary MF, and all pts had received ≥3 mo of prior RUX; the most common reason for RUX D/C was loss of response/Tx failure (41%). During FEDR Tx, 22 (65%) pts received ondansetron and 11 (32%) pts received loperamide. GI AEs in >10% of pts were constipation (47%), diarrhea (35%), nausea (26%), abdominal pain (24%), and vomiting (18%). Nausea, vomiting, and diarrhea decreased as Tx continued. Most GI AEs were grade (G) 1/2 (including nausea, vomiting, and diarrhea) and there were no Tx-related G3/4 GI AEs. No pt required FEDR reduction, interruption, or D/C due to a Tx-related GI AE. Tx-related G3/4 AEs were reported in 11 (32%) pts, including anemia in 7 (21%) pts, and neutropenia, thrombocytopenia, and hyperkalemia in 2 (6%) pts each. At BL, 1 pt had thiamine below the 70 nmol/L lower limit of normal (LLN), which normalized before the pt received FEDR. During FEDR Tx, thiamine levels dropped below the LLN for 4 pts between cycles 2 and 3 (and for 1 pt at end of Tx); for these pts, levels returned to normal with thiamine supplementation and no FEDR interruption or reduction was required (Figure). Five other pts received prophylactic thiamine supplementation. There were no cases of WE. Image:Summary/Conclusion: FEDR was generally well tolerated in pts with MF previously treated with RUX. The frequency and severity of GI AEs were substantially lower in FREEDOM than in previous FEDR clinical trials, likely due to early implementation of GI prophylaxis. Thiamine decreases were uncommon and easily managed with routine monitoring and oral supplementation as needed.