Presentation by Jason Chandler, MD, West Cancer Center
At the 2023 West Oncology Virtual Conference for Advanced Practicioners and Nurses presented by Total Health, Dr Jason Chandler from West Cancer Center presented an overview of current diagnosis and treatment strategies for the myeloproliferative neoplasms (MPN), with a focus on the conditions of polycythemia vera (PV), essential thrombocytopenia (ET), and primary myelofibrosis (PMF). For each of these MPN conditions, Dr Chandler reviewed the key elements in diagnosis, assessing the patient’s overall risk for disease progression or death (risk stratification), and current treatment paradigms.
Polycythemia vera (PV): Diagnosis, Risk Stratification, and Treatment
Polycythemia vera (PV) is a condition characterized by overproduction of red blood cells, and may be suspected if hemoglobin (Hb) levels are > 16.5 in men or > 16.0 g/dL in women. Although other conditions may account for these Hb elevations, PV can be easily diagnosed with a blood test looking for a mutation in the JAK2 gene in the blood cell progenitor (stem cells), which is present in 99% of PV patients. Symptoms may include headaches, dizziness, itchiness in the shower, ruddy complexion, early satiety (feeling full), and weight loss.
For PV, risk can be determined using an online calculator by inputting various factors, including a history of thrombosis, age, and the presence of any deleterious mutations (BOX 1). The survival for individuals within the three risk groups (low, intermediate, or high) differs markedly, and as such, this can be used to determine how aggressively (or non-aggressively) the patient should be managed. Dr Chandler noted that other calculators which incorporate additional patient-specific factors are also available for a more accurate assessment [Patient-specific risk calculator: https://www.sanger.ac.uk/science/tools/progmod/progmod/].
Box 1. Risk Calculator for PV
Prognostic Variables (Points)
Risk Group (Points)
History of thrombosis (+1)
Leukocyte count > 15 x 109/L (+1)
Age > 67 (+2)
Adverse mutations [SRSF2] (+3)
Not reached (>25 yr)
Management of PV in the low risk category starts with aspirin to control vasomotor symptoms and phlebotomy (blood draw) as a means to keep the hematocrit below 45%, and prevent events such as stroke and blood clots. Dr Chandler noted that most low risk patients can be managed conservatively, without chemotherapy to reduce blood cell counts (cytoreductive therapy), but for those who fail treatment or for higher risk patients, cytoreductive therapy is needed. Cytoreductive therapy options include hydroxyurea (HU), pegylated-interferon-alfa-2a, or ropegylated interferon-alfa-2b, with the two types of interferon differing in their adverse event and tolerability profiles. In clinical studies, long term event free survival (EFS) was better for high risk patients treated with ropegylated interferon as compared with HU. Dr Chandler also noted that the levels of JAK2 mutant cells in the blood (a measure of the stem cell levels) was also significantly reduced to <1%, in 20.7% of the interferon treated patients as compared to 1.4% of the HU-treated patients (P=0.0001), and this suggests that interferon treatment could possibly alter the natural history of PV for these patients, although this remains to be proven. Similar findings have been observed in low risk patients, when comparing the addition of interferon to phlebotomy, as compared with phlebotomy alone.
Essential thrombocytopenia (ET): Diagnosis, Risk Stratification, and Treatment
Essential thrombocytopenia (ET) is a condition characterized by overproduction of platelets and may be suspected if a patient’s platelet count is elevated (> 450 x 10(9)/mL). Diagnosis is once again made by mutational screening with a blood test, and Dr Chandler noted that, while there are about 20% of ET patients who have no mutation (“triple negative”), most patients will have a mutation in the gene for JAK2 (~57%), CALR (~20%), or MPL (~3%). Symptoms may include vasomotor (blood vessel related) effects such as lightheadedness, and burning in the hands and feet.
Risk stratification in ET has evolved over the last decade, and Dr Chandler reviewed the Revised IPSET Thrombosis Prognostic Scoring System (BOX 2), which is based on three risk factors, to determine the need for aspirin, with or without cytoreductive therapy (Cytored). He noted that, in the absence of high risk, the benefit of HU with aspirin versus aspirin alone is limited in the 40 to 59 year old age group. While the preferred agent is HU for cytoreductive therapy, he noted that pegylated interferon is another option, although it is not approved for use in ET.
Box 2. Revised IPSET Thrombosis Prognostic Scoring System for ET
Age > 60 yrs
JAK2 V617F mutation
Very Low (no risk factors)
Low (JAK2 V617F only)
Intermediate (Age > 60 yrs only)
High (prior thrombosis, OR Age > 60 yrs AND JAK2 V617F)
NO Aspirin (?)
Aspirin NO Cytored (?)
Aspirin and Cytored
Primary myelofibrosis (PMF): Diagnosis, Risk Stratification and, Treatment
PMF differs from PV and ET, both of which result from blood cell overgrowth; in PMF, the bone marrow has become “scarred” from chronic blood cell hyperproliferation (“too much pressing on the gas pedal”) which ultimately results in the symptom of blood cell counts dropping, or anemias. PMF may also be characterized by symptoms such as enlarged spleen (splenomegaly), and leakage of immature blood cell ‘blasts’ into the blood (leukoerythroblastosis). Diagnosis of PMF is made through a bone marrow biopsy and screening for mutations, and genetic analysis of the blood cells (cytogenetics). Mutations common to PMF include JAK2(60%), CALR (22%), TN (10%), and MPL (8%).
Risk stratification in PMF is based on the MIPSS-70 Score (BOX 3), which incorporates multiple clinical factors, as well as the presence (or not) of several high-molecular risk (HMR) mutations. Dr Chandler noted that, for the highest risk patients, the prognosis is extremely poor, with the majority of patients not surviving past 5 years. Treatment is determined according to risk group, the presence of disease symptoms, and the eligibility of the patient for an allogeneic stem cell transplant (ASCT). With regard to transplant, Dr Chandler noted that ASCT is not the easiest option for the majority of PMF patients, but should nonetheless be considered, if possible, since outcomes are so uniformly poor among the highest risk patients. For patients who are transplant ineligible, drug therapy with the JAK2 inhibitors ruxolitinib or fedratinib is indicated, although because these drugs can further reduce platelet counts, if patient’s platelet counts are low, another agent, pacritinib should be used (BOX 3). JAK2 inhibitors have been shown to significantly improve splenomegaly and other symptoms over placebo or best available treatment. Dr Chandler noted that anemias (in the absence of other symptoms) are associated with poor prognosis in PMF, and are difficult to manage but some treatments are available such as erythropoietin, steroids, and immunomodulatory agents like thalidomide can be used.
Box 3. MIPSS-70 Risk Stratification for PMF in Patients < 70 years
Prognostic Variables (Points)
Risk Group (Points)
Hb < 10 mg/dL (+1)
Leukocytes count > 25 x 109/L (+2)
Platelets < 100 x 109/L (+2)
Circulating blasts > 2% (+1)
Bone marrow fibrosis grade > 2 (+1)
Constitutional symptoms (+1)
CALR type-1 unmutated genotype (+1)
High Molec Risk (HMR) mutations* (+1)
> 2 HMR mutations (+2)
Asymptomatic: Observation or clinical trial
Symptomatic: Clinical trial, observation, or ruxolitinib or pegylated interferon alfa-2a or HU
Transplant-ineligible: Ruxolitinib or fedratinib (either for patients with platelets >50K) or pacritinib (for patients with platelets <50K), or clinical trial
Transplant-ineligible/anemia: Anemia therapy or clinical trial
*HMR mutations: At least one mutated gene among ASXL1, EZH2, SRSF2, IDH1/2 MIPSS-70 calculator: http://www.mipss70score.it
Speaker Disclosure Information: Dr Chandler listed no disclosures for this presentation.