Inclusion Criteria:
* 1\. Male or female subject aged ≥ 18 years old with erythrocytosis (Hb\>18g/dL in male and Hb\>16g/dL in a female\>18 years old and Hb\>0.5g/dL the upper limit of normal range for their age) with a known EPAS1, EGLN1, or VHL mutation 2. Neutrophils\>1.5 k/uL, Hb\>10g/dL, platelet count \>100x106 without transfusions 3. CrCl\>30using Cockcroft Gault; total bilirubin \<1.5x ULN (\<3xULN in patients with Gilbert's disease), and alkaline phosphatase\<2.5x ULN 4. Females or male patients with a female partner of childbearing potential must agree to effective methods of contraception 5. Possible iron deficiency needs to be evaluated and if present, corrected. Then, baseline Hb level obtained at least after 4 weeks of correction of iron deficiency 6. Able to swallow oral medications 7. Have an Eastern Cooperative Oncology Group (ECOG) performance score of 0 to 1 (refer to appendix). Evaluation of ECOG is to be performed within 10 days prior to the first dose of study intervention.
Exclusion Criteria:
1. Any of the following:
1. A pulse oximeter reading \<92% at rest, or
2. Requires intermittent supplemental oxygen, or
3. Requires chronic supplemental oxygen
2. Clinically significant cardiac disease, including unstable angina, acute myocardial infarction ≤3 months from Day 1 of study drug administration, or New York Heart Association Class III or IV congestive heart failure. Medically controlled arrhythmia stable on medication is permitted
3. Moderate to severe hepatic impairment (Child-Pugh B or C)
4. Received colony-stimulating factors (e.g., G-CSF, GM-CSF or recombinant EPO) ≤28 days prior to the first dose of study intervention
5. Known psychiatric or substance abuse disorder that would interfere with cooperation with the requirements of the study
6. Unable to swallow orally administered medication or has a gastrointestinal disorder affecting absorption (e.g., gastrectomy, partial bowel obstruction, malabsorption)
7. Known hypersensitivity or allergy to the active pharmaceutical ingredient or any component of the study intervention (belzutifan) formulations
8. Received prior treatment with belzutifan or another HIF-2α inhibitor
9. Received any type of small molecule kinase inhibitor (including investigational kinase inhibitor) ≤5 half lives before \[randomization/allocation\]
10. Major surgery ≤3 weeks prior to first dose of study intervention Note: Adequate wound healing after major surgery must be assessed clinically, independent of time elapsed for eligibility
11. Is currently receiving either strong (phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) or moderate (e.g., bosentan, efavirenz, modafinil) inducers of CYP3A4 that cannot be discontinued for the duration of the study Note: A current list of strong/moderate inducers of CYP3A4 can be found at the following website: https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers
12. Is currently participating in a study of an investigational agent or is currently using an investigational device Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent\\
13. Active infection requiring systemic therapy
14. Active TB
15. Diagnosis of immunodeficiency
16. History or current evidence of any condition, therapy, or laboratory abnormality or other circumstance that might confound the results of the study, interfere with the participant's ability to cooperate with the requirements of the study, such that it is not in the best interest of the participant to participate, in the opinion of the treating investigator
17. Has received therapeutic phlebotomy within 3 months of starting therapy
18. Uncorrected iron deficiency
19. Diagnosed with another form of erythrocytosis such as polycythemia vera, EPO or EPOR mutations, high oxygen affinity Hb mutations, current smoking, testosterone use, untreated/unsupported heart or lung disease, Eisenmenger complex
20. Pregnant
