Inclusion Criteria:

• - Confirmed diagnosis of primary myelofibrosis or post-polycythemia vera/essential thrombocythemia myelofibrosis classified as high risk, intermediate-2 risk, or intermediate 1 risk by IPSS.

• - Severe thrombocytopenia defined as platelet count < 50,000/microL (confirmed on at least two measurements over an 8-week period prior to start of study).

• - At least 18 years of age.

• - ECOG performance status ≤ 2.

• - Able to swallow pills.

• - Adequate bone marrow and organ function as defined below: - ANC ≥ 1000/microL.

• - Peripheral blood blasts ≤ 10% - Albumin > 2.7 g/dL.

• - Total bilirubin ≤ 1.5 x IULN; patients with Gilbert's syndrome may enroll if direct bilirubin ≤ 1.5 x IULN.

• - AST(SGOT)/ALT(SGPT) ≤ 1.5 x IULN.

• - Creatinine clearance > 30 mL/min by Cockcroft-Gault.

• - Female subjects must be either post-menopausal for at least 1 year or surgically sterile; or, if of childbearing potential, must not be pregnant or lactating and must agree to use a highly effective method of birth control throughout the duration of the trial and for 30 days following the last dose.

Acceptable methods of birth control are defined as: hormonal contraception (pill, injection or implant) used consistently for at least 30 days prior to screening, an intrauterine device (IUD), or intrauterine hormone-releasing system (IUS), or true abstinence (i.e. abstinence is in line with the preferred and usual lifestyle of the subject.). Male subjects do not need to use contraception for fostamatinib because human studies showed minimal R406 in sperm.

• - Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable).

Exclusion Criteria:

• - History of allogeneic stem cell transplant.

• - Any solid tumor or hematologic malignancy (other than myelofibrosis) requiring active treatment at the time of study entry.

• - Currently receiving any other investigational agents.

• - A history of allergic reactions attributed to compounds of similar chemical or biologic composition to fostamatinib, ruxolitinib, or other agents used in the study.

• - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, or cardiac arrhythmia.

• - Subject has uncontrolled or poorly controlled hypertension, defined as systolic blood pressure ≥130 mmHg or diastolic blood pressure ≥80 mmHg, whether or not the subject is receiving anti-hypertensive treatment.

• - Pregnant and/or breastfeeding.

Women of childbearing potential must have a negative pregnancy test within 14 days of study entry and prior to the first dose of fostamatinib.

• - Known positive status for human immunodeficiency virus (HIV) - Chronic, active, or acute viral hepatitis A, B, or C infection, or hepatitis B or C carrier.

• - Treatment with strong CYP3A inhibitors or inducers within 14 days before the first dose of study drug.

Strong CYP3A inhibitors and CYP3A inducers are not permitted during the study.

• - Ongoing gastrointestinal medical condition such as Crohn's disease, inflammatory bowel disease, or chronic diarrhea that is not well controlled and could interfere with absorption of oral medication or be exacerbated by study medication.

• - Known hepatic cirrhosis or severe pre-existing hepatic impairment.

• - Uncontrolled coagulopathy or bleeding disorder.

• - Female patients who intend to donate eggs and male patients who intend to donate sperm during the course of this study or for 4 months after receiving the last dose of study treatment.

Arms

Experimental: Part A: Fostamatinib

The starting dose of fostamatinib is 100 mg twice daily (BID). After the first cycle, if no major dose related safety issue is observed and the platelet count is less than 50K/microL, then the fostamatinib dose will be increased to 150 mg BID for the next 2 cycles; otherwise the dose may be continued at 100 mg BID.

Experimental: Part B: Fostamatinib + Ruxolitinib

After 3 cycles of fostamatinib monotherapy, all patients with a sustained platelet count ≥ 50K/microL, will continue on the current fostamatinib dose plus ruxolitinib at the recommended dose per standard prescribing guidelines for an additional 9 cycles. Patients who do not reach platelet count of at least 50K/microL but who achieve clinical benefit per the treating provider may continue on single agent fostamatinib for up to 12 total treatment cycles. If these patients achieve a sustained platelet count of ≥ 50K/microL at any point prior to Cycle 10 Day 1, then they may be eligible to enroll in Part B of the study and continue treatment with fostamatinib and ruxolitinib for the remainder of the study.

Interventions

Drug: - Fostamatinib

Fostamatinib will be supplied by Rigel Pharmaceuticals.

Drug: - Ruxolitinib

Ruxolitinib is commercially available.