Vivian G. Oehler, MD
Myeloproliferative neoplasms (MPNs) are a spectrum of hematologic diseases in which factors of diagnosis and treatment vary, according to Vivian G. Oehler, MD.
In a presentation during the 2018 OncLive®
State of the Science Summit™ on Hematologic Malignancies, Oehler, an associate member of the Fred Hutchinson Cancer Research Center, discussed the diagnosis, risk prognostication and therapeutic strategies for polycythemia vera (PV), essential thrombocytopenia (ET), and myelofibrosis (MF).
In 2017, the World Health Organization (WHO) defined PV with updated criteria. Hemoglobin has been lowered to >16.5g/dL in men and >16 g/dL in women, bone marrow with trilineage growth, and the presence of a JAK2
"These lowered hemoglobin thresholds were done in order for us to better identify a group of patients with masked PV,” Oehler said. “Additionally, [WHO] is recommending a bone marrow biopsy in order to distinguish PV from JAK2
-mutated ET that might have polycythemia vera, given the changes to criteria 1.”
In an analysis of masked PV and outcomes of about 400 patients, 257 patients were diagnosed conventionally using WHO 2008 guidelines. There was also a group of 140 patients who were JAK2V617F
mutation–positive. This population had a bone marrow morphology consistent with PV, but lower hemoglobin.1
Outcomes in terms of leukemia-free survival and MF-free survival were poor for this group of masked PV patients. There also was no difference in thrombosis-free survival. Investigators noted a worse overall survival (OS) in patients with masked PV compared with overt PV following WHO (P
= .011) as well as the British Committee for Standards in Haematology criteria (P
"The take-home point here is that this will help us identify a subgroup of patients who may actually do worse," said Oehler.
Currently, patients are risk-stratified based on age and thrombosis. However, a 2016 study aimed to categorize the outcomes of mutations associated with PV.2
Investigators found that ASXL1, SRSF2
, and IDH2
were associated with poorer OS in patients with PV. Other mutations evaluated were TET2, SH2B3, SF3B1, SETBP1, DNMT3A, CSF3R, CEBPA, SUZ12, ZRSR2, KIT, RUNX1, FLT3, CBL
, and TP53
Since 2014, ruxolitinib (Jakafi) has been approved for patients who are intolerant or resistant to hydroxyurea. This approval was based on data from the phase III RESPONSE trial, which demonstrated that 60% of patients treated with ruxolitinib achieved hematocrit control without phlebotomy compared with 19.6% receiving best available therapy.3
Additionally, complete hematologic remission (CHR) was seen in 24% of patients who received ruxolitinib versus 9% who received best available therapy.
Another highly discussed topic in the MPN space is interferon redux. There is an increasing interest in re-examining interferon for the treatment of PV and ET, Oehler said. Two previous phase II clinical studies of pegylated interferon alpha-28 (peg-IFN-α2a) showed that clinical hematological response rates spanned from 79% to 100%.4
Complete response (CR) was observed in 54% to 95% of patients. Additionally, bone marrow histopathology could also revert to normal after IFN-α therapy in some patients.
Oehler said the mechanism is not fully understood and is an item of interest for the MPN Research foundation that they are currently funding.
PROUD-PV is a randomized controlled phase III trial that compared ropeginterferon alfa-2b with hydroxyurea in patients with PV. The primary endpoint of this study was noninferiority at 12 months in terms of CHR rate. Results showed that ropeginterferon alfa-2b was noninferior to hydroxyurea, with the CHR at 12 months being 43.1% versus 45.6%, respectively.5
Data from MPD-RC 112 (NCT01259856) is anticipated to be released soon, hinted Oehler. This recently completed phase III trial evaluated frontline peg-IFN-α2a with hydroxyurea in patients with high-risk PV and ET.
The major criteria for ET is a platelet count of great than or equal to 450 x 109
/L; proliferation mainly of the megakaryocyte lineage with increased numbers of enlarged, mature megakaryocytic with hyperlobulated nuclei, no significant increase or left shift in neutrophil granulopoiesis or erythropoiesis and very rare minor increase in reticulin fibers; not meeting WHO criteria for chronic myeloid leukemia, PV, pre-fibrotic primary MF (prePMF), myelodysplastic syndrome, or other myeloid neoplasms; and presence of a JAK2, CALR
, or MPL
mutation. Minor criteria are the presence of a clinical marker or absence of evidence for relative thrombocytosis.