The purpose of this research study is to see how effective hematopoietic stem cell transplantation (HCT) is compared to best available non-transplant therapies (BAT) in patients with high risk myelofibrosis. This will be done by asking participants to choose the treatment that they prefer to receive (HCT or BAT) and then comparing the outcomes of the participants in both treatment groups.

There is currently little information regarding which treatments are best for patients with myelofibrosis. On one hand, hematopoietic stem cell transplantation (HCT) is potentially curative treatment but is associated with significant risk of complications related to graft failure (the new donor cells does not grow properly after the transplant), side effects such as graft versus host disease (the patient's cells attack the new donor cells), and risk of infections. Non-transplant therapies such as ruxolitinib provide effective symptom control for few months to few years, but are not curative in nature. As such, this study will compare the effectiveness of HCT versus best available non-transplant therapies (BAT) in patients with high risk myelofibrosis.

This is an observational study, meaning that participants will be followed to assess the effects of their treatment, but no intervention (treatments) will be given as a part of this study.

Inclusion Criteria:

Recruitment Part:

• Documented diagnosis of pre-fibrotic primary myelofibrosis (pre-fibrotic PMF), overt PMF, post-polycythemia MF (PPV-MF) or post-essential thrombocythemia MF (PET-MF) confirmed by bone marrow biopsy
• Have been tested or have results available for phenotypic driver mutations (JAK2/CALR/MPL) and high molecular risk (HMR) mutations using a broad myeloid malignancies targeted gene panel.
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Able to provide informed consent
• Adequate organ function
• Donor search initiated or patient is agreeable to donor search
• Meet the definition/criteria for high-risk myelofibrosis

Study Arm Allocation:

• Grade of fibrosis on bone marrow biopsy available according to World Health Organization (WHO) criteria
• Results available for phenotypic driver mutations (JAK2/CALR/MPL) and targeted sequencing results using a broad myeloid malignancy panel with a minimal requirement to include results on High molecular risk (HMR) mutations such as ASXL1/EZH2/IDH1/IDH2/SRSF2/U2AF1/TP53
• ECOG performance status 0-2
• Adequate organ function
• Information on donor search and donor type available

Exclusion Criteria:

Recruitment Part:

• Blasts in peripheral blood or bone marrow ≥10%
• For patients already on ruxolitinib at study entry, and meet the criteria of ruxolitinib failure
• Previous history of transformation to blast phase or acute myeloid leukemia
• Received allogeneic stem cell transplant for myeloproliferative neoplasm
• Presence of an active uncontrolled infection
• Myocardial infarction in the preceding 3 months
• Active hepatitis A, B or C
• Known human immunodeficiency virus (HIV) positive
• History of active malignancy in the previous 2 years, except basal cell carcinoma or squamous cell carcinoma of skin or stage 0 cervical cancer
• Any psychiatric illness or social circumstances or significant co-morbid conditions that will prevent patient from proceeding to allogeneic hematopoietic cell transplantation.
• Pregnant or breastfeeding women

Study Arm Allocation:

• Blasts in peripheral blood or bone marrow ≥10%
• Meet the criteria of ruxolitinib failure
• Presence of an active uncontrolled infection
• Myocardial infarction in the preceding 3 months
• Active hepatitis A, B or C
• Known HIV positive
• History of active malignancy in the previous 2 years, except basal cell carcinoma or squamous cell carcinoma of skin or stage 0 cervical cancer
• Pregnant or breastfeeding women
• Any psychiatric illness or social circumstances or significant co-morbid conditions that will prevent patient from proceeding to allogeneic hematopoietic cell transplantation.
• Time between registration and allocation of study arm >24 weeks

Patients with high-risk myelofibrosis including pre-fibrotic primary myelofibrosis (pre-fibrotic primary myelofibrosis), overt primary myelofibrosis, post-polycythemia myelofibrosis or post-essential thrombocythemia myelofibrosis.