The purpose of the study is to evaluate the effectiveness, safety, and tolerability of a study drug called fedratinib in participants with myelodysplastic/myeloproliferative neoplasms (MDS/MPNs) and chronic neutrophilic leukemia (CNL).

Inclusion Criteria:

• Patient must understand and voluntarily sign an ICF prior to any study-related assessments/ procedures being conducted

• 18 years of age or older on day of signing informed consent.

• Morphologically confirmed diagnosis of one of the following in accordance with WHO (2016) diagnostic criteria:

  1. Atypical Chronic Myeloid Leukemia (aCML), BCR-ABL1 negative
  2. Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable (MDS/MPN-U)
  3. Myelodysplastic Syndrome/Myeloproliferative Neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T)
  4. Chronic Neutrophilic Leukemia (CNL).

• Palpable splenomegaly ≥ 5 cm below left costal margin (LCM), spleen volume ≥ 450 cc, AND/OR MPN-SAF TSS > 10.

• Has an Eastern Cooperative Oncology Group (ECOG) Performance Score (PS) of 0, 1 or 2

• Able to adhere to the study visit schedule and other protocol requirements.

• Females of childbearing potential (FCBP) must have a negative serum pregnancy test at screening. A FCBP is considered when a sexually mature female: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 12 consecutive months.

• A FCBP must agree to use of two methods of highly effective contraception, be surgically sterile, or abstain from heterosexual activity for the course of the study through 30 days after the last dose of study treatment.

• Male patients must agree to use an adequate method of contraception starting with the first dose of study therapy through 90 days after the last dose of study therapy. Men must agree to not donate sperm during study therapy and for 30 days after the last dose of study therapy

Exclusion Criteria:

• Any of the laboratory abnormalities as listed in the protocol.

• Patient is pregnant or lactating female

• Patient is a woman of childbearing potential as previously defined in inclusion #7, unless using effective contraception while on study treatment

• Patient is a man who is a partner with of a woman of childbearing potential, unless they agree to use effective contraception while on study treatment as previously defined in inclusion #9.

• Patient with prior history of encephalopathy, including Wernicke's Encephalopathy (WE)

• Patient has signs or symptoms of encephalopathy, including Wernicke's Encephalopathy (e.g., severe ataxia, ocular paralysis or cerebellar signs) in which case thiamine deficiency needs to be excluded and a brain MRI might be required to exclude possible Wernicke's encephalopathy

• Patient has thiamine deficiency if not corrected before enrollment on the study

• Patient with concomitant treatment with or use of pharmaceutical or herbal agents known to be moderate or strong inducers of CYP3A4 or dual CYP3A4 and CYP2C19 inhibitors. For a list of moderate or strong inhibitors or inducers of CYP3A4, see table 3-2 and 3-3 at https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers.

• Patient on any chemotherapy, immunomodulatory drug therapy (e.g., lenalidomide, pomalidomide, thalidomide, interferon-alpha), ruxolitinib, anagrelide, corticosteroids >10 mg/day prednisone or equivalent. Patients may remain on hydroxyurea (e.g., hydrea) if it is being employed to control leukocytosis as long as the patient has been on a stable dose for > 14 days prior to initiation of fedratinib.

• Prior treatment with fedratinib

• Patient on treatment with myeloid growth (e.g., G-CSF) factor within 14 days prior to initiation of fedratinib

• Patient on treatment with aspirin with doses > 150 mg daily.

• Patient with diagnosis of chronic liver disease (e.g., chronic alcoholic liver disease, autoimmune hepatitis, sclerosing cholangitis, primary biliary cirrhosis).

• Patients with active (uncontrolled, metastatic) second malignancies are excluded.

• Patient with uncontrolled congestive heart failure (New York Heart Association Classification 3 or 4).

• Patient with known human immunodeficiency virus (HIV), active infectious Hepatitis B (Hep B), and/or active Hepatitis C (Hep C).

  a. Patients with known HIV are eligible if the following criteria are met: i. Patient has CD4+ T-cell count ≥ 350 cells/µL ii. Patient is on established anti-retroviral therapy (ART) (with medications that are not specifically excluded due to potential interactions within this study) for at least four weeks prior to study enrollment and have an HIV viral load less than 400 copies/mL prior to enrollment.

  b. Patients with a history of Hep C infection are eligible if: i. Patient has completed curative antiviral treatment and has hepatitis C viral load below the limit of quantification ii. Pt has Hep C antibody positive but Hep C RNA negative due to prior treatment or natural resolution.

• Patient with serious active infection requiring IV anti-microbials.

• Patient with presence of any significant gastric or other disorder that would inhibit absorption of oral medication.

• Patient is unable to swallow capsules.

• Patient with participation in any study of an investigational agent (drug, biologic, device) within 30 days prior to start of fedratinib.

• Patient has any condition including the presence of laboratory abnormalities, which places the patient at unacceptable risk if he/she were to participate in the study.

• Patient has any condition that confounds the ability to interpret data from the study.

• Any major surgery or radiation therapy within four weeks.