“Historically, there has always been prejudice against phlebotomy therapy for PV in favor of chemotherapy,” said Dr Spivak. “Yet PV is impervious to chemotherapy because PV stem and progenitor cells are normal, and the bias against phlebotomy therapy is [because of] the false perception that leukocytosis and thrombocytosis in PV are causes of thrombosis, [though] this has been disproved repeatedly.”
Confirming a diagnosis of PV can be challenging, as it mimics other diseases. When it presents with erythrocytosis, leukocytosis, and thrombocytosis with or without splenomegaly, a diagnosis can be made even in the absence of a clonal marker. However, PV can also present as isolated erythrocytosis, leukocytosis, thrombocytosis, or splenomegaly, with myelofibrosis, or any combination of these conditions. The 2016 World Health Organization (WHO) PV diagnostic criteria stipulate specific hemoglobin, hematocrit, and red cell mass (RCM) values in addition to marrow histologic criteria and a low serum erythropoietin, but Dr Spivak noted that RCM assays are not widely available. There can also be discrepancies between hemoglobin and hematocrit values, and the designated thresholds may not take into account patients with masked erythrocytosis due to plasma volume expansion.
When a patient is being evaluated, initial laboratory tests should include a complete blood count, blood smear, and JAK2V617F assay. Dr Spivak noted that he does not obtain a marrow specimen for diagnostic purposes or to screen for myelofibrosis in the absence of splenomegaly, a leukoerythroblastic reaction, unexplained anemia, or thrombocytopenia. However, he always orders a quantitative JAK2V617F variant allele frequency (VAF) because MPN driver mutations are not mutually exclusive, and the VAF allows assessment of the disease burden and clonal dominance. Other tests include a ristocetin cofactor assay to identify acquired von Willebrand disease, a uric acid level to identify leukocytosis, and serum tryptase levels to identify the Darier sign.
Dr Spivak emphasized the importance of ordering a quantitative JAK2 V617F assay rather than a qualitative one. The qualitative assay is favored by pathology labs and the US Food and Drug Administration (FDA), “but only the [quantitative assay] can establish the presence of an MPN because normal people can have a positive qualitative assay, due to the sensitivity of the qualitative test,” he said. “The problem is that patients [with an MPN] can have more than 1 type of mutation, and quantitation is the only way to know which mutation is important clinically. Also, it is possible to distinguish essential thrombocytosis from PV in some patients with a quantitative assay.”
The goals of PV treatment are to alleviate symptoms and prolong survival by reducing the risk for thrombosis, preventing bleeding events, and minimizing the risk of transformation to post-PV myelofibrosis and acute myeloid leukemia. Ideally, treatment needs to be tailored to suit the clinical needs of the patient, taking into consideration the status of the formed elements of the blood, bone marrow, and organomegaly.
Current therapy for PV includes phlebotomy; cytoreductive therapy, with hydroxyurea being the most commonly used agent; and 2 nonmyelotoxic, target-specific agents, pegylated interferon and ruxolitinib. In particular, ruxolitinib, a JAK1/2 inhibitor, has opened a new era for MPN therapeutic management, as it has demonstrated efficacy in post-PV myelofibrosis and in chronic phase PV, providing durable symptom relief, blood count control, and reduction in splenomegaly; it has also been found superior to hydroxyurea. However, information is limited regarding how it compares with phlebotomy in chronic-phase PV.
Dr Spivak noted that there has always been prejudice against phlebotomy therapy, with many clinicians advocating chemotherapy. “[However,] chemotherapy shortens survival in PV compared to phlebotomy and causes acute leukemia and hydroxyurea is no different than other forms of chemotherapy,” he said. “The use of hydroxyurea is, unfortunately, promoted by the FDA.”
Thrombosis is the most immediate threat to health in patients with PV, and phlebotomy is the cornerstone of therapy. For newly diagnosed patients, this can be accomplished by daily or every-other-day procedures or all at once by erythrocytapheresis. The ultimate aim is to induce a state of chronic iron deficiency, which reduces phlebotomy frequency.
Because of FDA policy, clinical trials in PV continue to be compromised by having hydroxyurea therapy as the control arm when phlebotomy alone should be the control arm, Dr Spivak argued, noting that this has been particularly true in interferon trials. “Interferon attacks the malignant stem cell and hydroxyurea does not.”
The current therapeutic challenge, he concluded, is how to best integrate ruxolitinib and pegIFN into treatment in order to control PV symptoms as well as prevent the development of JAK2V617F-positive hematopoietic stem cell clonal dominance and extramedullary hematopoiesis in those patients “most at risk in accordance with the dictates of precision medicine.”
1. Spivak JL. How I treat polycythemia vera [published online July 25, 2019]. Blood. doi:10.1182/blood.2018834044