We hypothesize that pacritinib leads to modification of the myelofibrosis (MF) disease phenotype, especially related to BM fibrosis and cytopenias; due potentially to its dual effect as an inhibitor of the JAK and NFκB pathways, through its targets JAK2 and IRAK1 respectively, leading to a decrease of inflammatory cytokines and/or effects on stem/progenitor populations restoring hematopoiesis New evidence suggests that blocking simultaneously the JAK/STAT and NF-κB pathways might have a beneficial effect on aspects that only inhibition of the JAK pathway cannot achieve: partial recovery of BM histology and

PACRIMYEL is a multicenter, open-label, single arm, phase II, exploratory study including patients with MF and platelet count between 50 - 120 x 109/L. Clinic visits will occur on weeks 4, 8, 12, 24, 36 and 52 during the first year and every 12 weeks during the second year of the treatment, and pacritinib will be dispensed at every visit to the clinic.

Bone fibrosis will be assessed by biopsy and MRI imaging [mDixon Quant "(Philips), IDEAL IQ (General Electric) or qDixon (Siemens)] on weeks 24 and 52 after the first dose of study treatment. Splenomegaly and SVR (Splenic Volume Reduction) will be assessed by physical exam and MRI imaging on weeks 24 and 52 after the first dose of study treatment if splenomegaly at diagnosis. Same MRI to evaluate BM imaging will be used to measure spleen volume. Additionally, spleen size will be assessed by physical exam during the routine clinic visits. All patients should complete all efficacy assessments through Week 52, including patients who stop study treatment or have protocol-defined progressive disease prior to Week 24 and 52, unless the patient withdraws consent or dies. For patients who discontinue treatment before disease assessments on week 24 and week 52 for other reasons different than protocol-based progression of the disease (i.e. toxicity), and with no recent disease / fibrosis assessment (last BM biopsy > 12 weeks), disease and fibrosis assessments will be performed by the end of treatment visit. The trial includes the assessment of safety (AEs, comorbidities) throughout the study period at every visit.

Patient-reported symptoms through MPN-SAF TSS 2.0 will be collected screening, baseline (C1D1), and on Week 12, Week 24, Week 36, Week 52 and in 12-weeks intervals during the second year. Blood samples for translational research will be collected at screening and at week 24 for determination of cytokines.

Inclusion Criteria:

1. Signed written and voluntary informed consent.

2. Age ≥18 years

3. Patients with a confirmed diagnosis of myelofibrosis, either primary myelofibrosis (PMF) or post polycythemia vera (PPV-MF) or post essential thrombocythemia (PET-MF).

4. Patients with thrombocytopenia, delimited by platelets counts between 50 - 120 x 109/L.

5. Patients who require JAK-2 inhibitor therapy in the opinion of the investigator and are eligible to start treatment with pacritinib either in the first line (JAK2 inhibitor-naive) or in second line setting (after no response or loss of response or intolerance to one prior JAK2 inhibitor ).

   Note: patients should have recovered to grade ≤ 1 from any toxicity from previous treatment.

6. Have a Eastern Cooperative Oncology Group Performance Status (ECOG-PS) of 0 - 2.

7. Have a dynamic international prognostic scoring system (DIPSS) Intermediate-1, Intermediate-2, or High risk.

8. Peripheral blasts count < 5% and absolute neutrophil count (ANC) of ≥500/μL.

9. Adequate liver and renal function, defined by:

   1. liver transaminases, including alanine aminotransferase (ALT or GOT) and aspartate aminotransferase (AST or GOT) ≤ 3 x upper limit normal (ULN). AST/ALT ≤5 × ULN if transaminase elevation is related to MF.
   2. Total bilirubin and/or direct bilirubin ≤ 4 x ULN.
   3. Estimated glomerular filtration rate (eGFR) > 30 mL/min.

10. Adequate coagulation defined by prothrombin time/international normalized ratio and partial thromboplastin time ≤ 1.5 × ULN.

11. If fertile, willing to use effective birth control methods during the study and up to 30 days after the last dose of pacritinib.

12. Willing to undergo and able to tolerate frequent MRI during the study and BM biopsy

13. Able to understand and willing to complete symptom assessments.

Exclusion Criteria:

1. Life expectancy <6 months.
2. Splenic irradiation within the last 6 months.
3. Previously treated with pacritinib.
4. Concurrent enrollment in another interventional trial.
5. Treatment with an experimental therapy within 28 days prior to the first dose of study treatment.
6. Systemic treatment with a strong CYP3A4 inhibitor or inducer and the treatment cannot be either discontinued or switched to a different medication within 5 half-lifes prior to study entry.
7. Severe (Child-Pugh C) liver impairment.
8. Significant recent bleeding history defined as NCI CTCAE grade ≥2 within 3 months prior to first dose of study treatment, or with active bleeding, unless precipitated by an inciting event (e.g., surgery, trauma, or injury).
9. Conditions or medications that increase the risk of bleeding, except for aspirin (dosages of ≤100 mg per day). Patients treated with "direct-acting oral anticoagulants (DOACs), could be considered for inclusion (may be consulted with the Sponsor, GEMFIN).
10. Any history of CTCAE grade ≥2 dysrhythmias or non-dysrhythmia cardiac conditions within 6 months prior to the first dose of study treatment. Patients with non-dysrhythmia or non-QTc grade 2 cardiovascular conditions , may be considered for inclusion, if stable , asymptomatic and unlikely to affect patient safety.
11. QT corrected by the Fridericia method (QTcF) prolongation >480 ms or other factors that increase the risk for QTcF interval prolongation (e.g., heart failure, hypokalemia or history of long QT interval syndrome).
12. New York Heart Association Class II, III, or IV congestive heart failure.
13. Active or uncontrolled inflammatory or chronic functional bowel disorder such as Crohn's disease, inflammatory bowel disease, chronic diarrhea or constipation
14. Other malignancy within 3 years prior to treatment Day 1, other than curatively treated basal cell or squamous cell skin or corneal cancer; curatively treated carcinoma in situ of the cervix. The exception is if patients have been disease-free for at least 5 years, and are deemed by the investigator to be at low risk for recurrence of that malignancy.
15. Known seropositivity for human immunodeficiency virus. Known active hepatitis B, or C virus infection.
16. Women who are pregnant or lactating
17. Uncontrolled intercurrent illness, including, but not limited to, ongoing active infection, psychiatric illness, or social situation that, in the judgment of the treating physician, would limit compliance with study requirements.
18. Any active GI or metabolic condition that could interfere with absorption of oral medication.