Criteria

Inclusion Criteria: Main Study Inclusion Criteria Subject is at least 18 years of age at the time of signing the informed consent form (ICF) Subject has an Eastern Cooperative Oncology Group (ECOG) Performance Score (PS) of 0, 1 or 2 Subject has diagnosis of primary myelofibrosis (PMF) according to the 2016 World Health Organization (WHO) criteria, or diagnosis of post-ET or post-PV myelofibrosis according to the IWG-MRT 2007 criteria, confirmed by the most recent local pathology report Subject has a DIPSS Risk score of Intermediate or High Subject has a measurable splenomegaly during the screening period as demonstrated by spleen volume of ≥ 450 cm3 by MRI or CT-scan assessment or by palpable spleen measuring ≥ 5 cm below the left costal margin. Subject has been previously exposed to ruxolitinib, while diagnosed with MF (PMF, post-ET MF or post-PV MF), and must meet at least one of the following criteria (a or b) Treatment with ruxolitinib for ≥ 3 months Treatment with ruxolitinib for ≥ 28 days complicated by any of the following: Development of a red blood cell transfusion requirement (at least 2 units/month for 2 months) or Grade ≥ 3 AEs of thrombocytopenia, anemia, hematoma, and/or hemorrhage while on treatment with ruxolitinib Subject must have treatment-related toxicities from prior therapy resolved to Grade 1 or pretreatment baseline before start of last therapy prior to fedratinib treatment. Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted Subject is willing and able to adhere to the study visit schedule and other protocol requirements Participants must agree to use effective contraception Sub-Study Inclusion Criteria Subject must understand and voluntarily sign an optional sub-study ICF prior to any sub study-related assessments/procedures being conducted Subject must have been taking fedratinib for at least 32 weeks (~ 8 cycles) Subject must be on a stable dose of fedratinib for at least 16 weeks (~ 4 cycles) [no dose level changes] in the time immediately up to the projected date of enrollment (SC1D1) Subject has anemia defined as either: Group A - Transfusion dependent (TD) anemia RBC-transfusion frequency: 4 to 12 RBC units/84 days immediately up to the SC1D1 date (Sub-study Cycle 1 Day 1), with no interval of > 6 weeks (42 days) without an RBC transfusion. Subjects must have a Hgb value of < 11.5 g/dL on SC1D1 prior to luspatercept administration. Group B - Non-transfusion dependent (NTD) anemia RBC-transfusion frequency: < 4 RBC units/84 days immediately up to the SC1D1 date. OR At least 3 Hgb levels of ≤ 9.5 g/dL recorded on ≥ 3 different days, including the day of dosing, in the 84-day period immediately up to Sub-study C1D1 date. There must be ≥ 14 days in between each Hgb measurement. No subjects with an interval ≥ 42 days between hemoglobin measurements will be enrolled. Baseline is defined as the 84-day rolling period (3 cycles at 28 days each) prior to Sub-study Cycle 1 Day 1. Any transfusions given either at a Hgb ≤ 7 or for a Hgb ≤ 9.5 g/dL with symptoms will be counted towards baseline transfusion needs. Transfusions given only for bleeding or infections will not be counted towards eligibility baseline transfusion requirements. Subject has an Eastern Cooperative Oncology Group (ECOG) performance score of ≤ 2. Exclusion Criteria: Main Study Exclusion Criteria Any of the following laboratory abnormalities: Platelets < 50,000/μL Absolute neutrophil count (ANC) < 1.0 x 109/L White blood count (WBC) > 100 x 10^9/L Myeloblasts > 5 % in peripheral blood Estimated glomerular filtration rate < 30 mL/min/1.73 m^2 (as per the Modification of Diet in Renal Disease [MDRD] formula) Serum amylase or lipase > 1.5 x ULN (upper limit of normal) Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 x ULN Total bilirubin > 1.5 x ULN, subject's total bilirubin between 1.5 - 3.0 x ULN are eligible if the direct bilirubin fraction is < 25% of the total bilirubin Subject is pregnant or lactating female Subject with previous splenectomy Subject with previous or planned hematopoietic cell transplant Subject with prior history of encephalopathy, including Wernicke's Subject with signs or symptoms of encephalopathy including Wernicke's (eg, severe ataxia, ocular paralysis or cerebellar signs) Subject with thiamine deficiency, defined as thiamine levels in whole blood below normal range according to institutional standard and not corrected prior to enrollment on the study Subject with concomitant treatment with or use of pharmaceutical, herbal agents or food known to be strong or moderate inducers of Cytochrome P450 3A4 (CYP3A4), or dual CYP2C19 and CYP3A4 inhibitors Subject on any chemotherapy, immunomodulatory drug therapy (eg, thalidomide, interferon-alpha), anagrelide, immunosuppressive therapy, systemic corticosteroids > 10 mg/day prednisone or equivalent. Subjects who have had prior exposure to hydroxyurea (eg, Hydrea) in the past may be enrolled into the study as long as it has not been administered within 14 days prior to the start of fedratinib treatment Subject has received ruxolitinib within 14 days prior to the start of fedratinib Subject on treatment with myeloid growth factor (eg, granulocyte-colony stimulating factor [G-CSF]) within 14 days prior to the start of fedratinib treatment Subject with previous exposure to Janus kinase (JAK) inhibitor(s) for more than 1 cycle other than ruxolitinib treatment Subject on treatment with aspirin with doses > 150 mg daily Subject with major surgery within 28 days before starting fedratinib treatment Subject with diagnosis of chronic liver disease (eg, chronic alcoholic liver disease, autoimmune hepatitis, sclerosing cholangitis, primary biliary cirrhosis, hemochromatosis, non-alcoholic steatohepatitis) Subject with prior malignancy other than the disease under study unless the subject has not required treatment for the malignancy for at least 3 years prior to enrollment. However, subject with the following history/concurrent conditions provided successfully treated may enroll: non-invasive skin cancer, in situ cervical cancer, carcinoma in situ of the breast, incidental histologic finding of prostate cancer (T1a or T1b using the tumor, nodes, metastasis [TNM] clinical staging system), or is free of disease and on hormonal treatment only Subject with uncontrolled congestive heart failure (New York Heart Association Classification 3 or 4) Subject with known human immunodeficiency virus (HIV), known active infectious Hepatitis B (HepB), and/or known active infectious Hepatitis C (HepC) Subject with serious active infection Subject with presence of any significant gastric or other disorder that would inhibit absorption of oral medication Subject is unable to swallow capsule Subject has any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study Subject has any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study Subject has any condition that confounds the ability to interpret data from the study Subject with participation in any study of an investigational agent (drug, biologic, device) within 30 days prior to start of fedratinib treatment Subject with life expectancy of less than 6 months. Sub- Study Exclusion Criteria Subject with anemia from causes other than MPN-associated MF or JAK2 inhibitor therapy (eg, iron deficiency, vitamin B12 and/or folate deficiencies, autoimmune or hemolytic anemia, infection, or any type of known clinically significant bleeding or sequestration). Subject with any of the following laboratory abnormalities at SC1D1: Neutrophils < 1 x 10^9/L White blood count (WBC) > 100 x 10^9/L Platelets < 50 x 10^9/L or > 1000 x 10^9/L Peripheral blood myeloblasts > 5%. Estimated glomerular filtration rate < 40 mL/min/1.73 m^2 (via the 4-variable modification of diet in renal disease [MDRD] formula) Aspartate aminotransferase (AST) or alanine transaminase (ALT) > 3.0 x upper limit of normal (ULN) Direct bilirubin ≥ 2 x ULN (higher levels are acceptable if these can be attributed to active red blood cell precursor destruction within the bone marrow (ie, ineffective erythropoiesis)) Subject with diastolic blood pressure ≥ 90 mmHg or systolic blood pressure ≥ 140 mmHg before SC1D1 despite appropriate treatment. Subject with prior malignancy other than the disease under study unless the subject has not required treatment for the malignancy for at least 3 years prior to enrollment. However, subject with the following history/concurrent conditions is allowed: Basal or squamous cell carcinoma of the skin Carcinoma in situ of the cervix Carcinoma in situ of the breast Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, nodes, metastasis [TNM] clinical staging system) Subject with stroke, deep venous thrombosis, pulmonary or arterial embolism within 6 months immediately up to SC1D1. Subject with major surgery within 2 months up to the enrollment date. Subject must have completely recovered from any previous surgery immediately up to the enrollment date. Subject with inadequately controlled heart disease and/or have a known left ventricular ejection fraction < 35%. Subject with uncontrolled systemic fungal, bacterial, or viral infection (defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment). Subject with prior therapy of luspatercept or sotatercept. Subject with history of severe allergic or anaphylactic reactions or hypersensitivity to recombinant proteins or excipients in the investigational products (see luspatercept IB). Subject with a major bleeding event (defined as symptomatic bleeding in a critical area or organ and/or bleeding causing a decrease in Hgb of ≥ 2 g/dL or leading to transfusion of ≥ 2 units of packed red cells) in the last 6 months prior to enrollment. Subject use of erythropoietin-stimulating agents (ESA) ≤ 56 days prior to SC1D1.