Pacritinib, a Kinase Inhibitor of CSF1R, IRAK1, JAK2, and FLT3, in Adults and Pediatric Participants 12 Years of Age or Older With Myelodysplastic Syndromes or Myelodysplastic/Myeloproliferative Neoplasms

* INCLUSION CRITERIA:
* Participants must have histologically or cytologically confirmed MDS or MDS/MPN, including therapy-related MDS or MDS/MPN, and MDS or MDS/MPN with germline predisposition, by the Department of Laboratory Medicine Hematology Laboratory, CC or by the Laboratory of Pathology, NCI as defined according to the 2016 WHO criteria, 2022 WHO criteria, or 2022 International Consensus Classification
* Age 12-17 years for phase I and age \>= 18 years for phase II
* Participants \>= 18 years of age with HR-MDS must have resistance to hypomethylating agents as defined as failure to show improvement after at least 4 cycles of treatment (primary resistance) or relapse in participants with initial response to long-term treatment (secondary resistance) OR have intolerance to hypomethylating agents OR have a contraindication to hypomethylating agents
* Participants \>= 18 years of age with LR-MDS must be refractory to or ineligible to receive standard of care therapies, i.e. erythropoietin-stimulating agents, lenalidomide, luspatercept, and present with one of the following characteristics:

  * Severe neutropenia defined by absolute neutrophils count \<=0.5(SqrRoot) 10\^9/L without the use of granulocyte colony-stimulating factors
  * Symptomatic anemia defined by hemoglobin 16-week average \<10 g/dL and symptoms that may include fatigue, weakness, reduced exercise tolerance, dyspnea on exertion, palpitations, (orthostatic) hypotension, near syncope and restless legs
  * Thrombocytopenia defined as platelets \<20(SqrRoot) 10\^9/L or platelets \<50(SqrRoot) 10\^9/L and a history of clinically relevant non-major or major bleeding according to the ISTH classification
* Participants 12-17 years of age with MDS must be relapsed/refractory OR ineligible to receive immunosuppressive therapy and hematopoietic stem cell transplantation

  --Ineligibility to receive hematopoietic stem cell transplantation will include participants who are not anticipated to be candidates to receive transplantation within the next 3 months due to medical comorbidities, lack of appropriate donor, or logistical barriers to transplant
* Participants with MDS/MPN must be relapsed/refractory (failed a minimum of 1 standard of care therapy) OR ineligible to receive standard of care OR without known life-prolonging therapy options OR have a diagnosis for which no known standard of care exists
* Participants 12-17 years of age must weigh \>= 35 kg
* If any of the prior therapies noted below were given to the participant, they must have been completed within the following timeframes:

  * 7 days from last dose of short-acting myeloid growth factors (i.e., filgrastim) and \>= 14 days for long-acting (i.e., pegfilgrastim)
  * 14 days from last dose of short-acting thrombopoietic growth factors (i.e.,eltrombopag) and \>= 28 days for long-acting (i.e., romiplostim)
  * 14 days or 5 pharmacokinetic half-lives from biological therapy agent
  * 21 days from myelosuppressive chemotherapy
  * 28 days from last dose of immunosuppressive therapy (e.g., ATG, cyclosporine, steroids greater than physiologic replacement)
  * 28 days from last dose of lenalidomide
  * 28 days from last dose of venetoclax
  * 28 days from any other investigational agent
  * 42 days from last dose of erythropoiesis stimulating agents
  * 56 days from last dose of luspatercept
  * 100 days from stem cell transplant with no evidence of active graft vs. host disease in participants who relapsed following transplant
  * 150 days from total body irradiation
* Performance status:

  * For participants \>= 16 years of age, ECOG performance status \< 2 (Karnofsky \>= 60%)
  * For participants \< 16 years of age, Lansky \>= 60%
* Participants must have adequate organ function as defined below:

  * Total bilirubin: \<= 1.5 X institutional upper limit of normal OR \<= 3 x institutional upper limit of normal in participants with Gilbert s syndrome
  * AST(SGOT)/ALT(SGPT): \<= 2.5 X institutional upper limit of normal
  * Creatinine clearance: \>= 50 mL/min/1.73 m\^2 for participants with creatinine levels above institutional normal
  * PT and PTT: \<= 1.5 X institutional upper limit of normal, except in the setting of PTT elevation due to lupus anticoagulant, in which case these participants would be exempt from meeting this inclusion criterion
* Individuals of child-bearing potential (IOCBP) and individuals able to father a child with a partner able to become pregnant must agree to use one (1) highly effective form of contraception (e.g., intrauterine device \[IUD\], surgical) or two (2) effective forms of contraception (e.g., barrier method) while on study drug and for 30 days after the last dose of study drug
* Nursing participants must discontinue breastfeeding and/or not begin breastfeeding until 2 weeks after the last dose of study drug
* Ability of participant or parent/guardian (for participants 12-17 only) to understand and the willingness to sign a written informed consent document

EXCLUSION CRITERIA:

* Participants with platelet transfusion-refractory thrombocytopenia, with inability to keep platelet threshold above 10 K/mcL with transfusions
* Participants with evidence of ongoing hemorrhage, active signs/symptoms of bleeding, or history of severe (grade \>= 3) unprovoked bleeding complications in the one year prior to enrollment, or any unprovoked grade 2 bleeding complications in the 3 months prior

to enrollment

* Use of anti-platelet or anticoagulant medication other than low-dose aspirin (100 mg daily or less) in the 14 days prior to enrollment, or any ongoing requirement for these medications
* Participants who are unwilling to accept blood transfusions
* Participants with ANC \< 500 cells/mcL AND hospitalization for a fungal infection in the 12 months prior to enrollment
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to pacritinib
* Concomitant administration with sensitive substrates/narrow therapeutic index drugs of CYP3A4, CYP1A2, P-gp BCRP, and OCT1 should be avoided. Concurrent use of strong inhibitors and inducers of CYP3A4 are not allowed. Prior use is allowed as long as medication is stopped two weeks prior to study drug initiation. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference. As part of the enrollment/informed consent procedures, the participant will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the participant is considering a new over-the-counter medicine or herbal product.
* Concomitant administration of medications with significant potential to cause QTc prolongation.
* Participants with the following cardiac conditions at screening:

  * Symptomatic congestive heart failure
  * Unstable angina pectoris
  * Uncontrolled cardiac dysrhythmias
  * QTc(F) prolongation \>450 ms, or other factors that increase the risk for QT prolongation (i.e., heart failure, or a history of long QT interval syndrome)
* Grade \>= 3 cardiac complication in the 6 months prior to enrollment
* Left ventricular ejection fraction \<= 50% by transthoracic echocardiogram (TTE) at screening
* Participants with any active, uncontrolled viral, bacterial, or fungal infection, including active HIV-1, Hepatitis B (HBV) and/or Hepatitis C (HCV) infection (positive HBV or HCV viral load in the setting of positive HBV core antibody or surface antibody or HCV antibody); history of HIV, HBV, or HCV is allowed if there is no uncontrolled viral infection
* Pregnancy
* Presence of another known cause of cytopenia or dysplastic marrow that is untreated and may limit interpretation of results
* Uncontrolled intercurrent illness or any significant disease, evaluated by history, physical exam and chemistries or social situations that may limit interpretation of results, limit compliance with study requirements, or that could increase risk to the participant