Updates in the Diagnosis and Treatment of MPNs


Vivian G. Oehler, MD, discusses the diagnosis, risk prognostication, and therapeutic strategies for myeloproliferative neoplasms.

Vivian G. Oehler, MD

Vivian G. Oehler, MD

The diagnosis and treatment of myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocytopenia (ET), and myelofibrosis (MF) may vary, according to Vivian G. Oehler, MD.

Oehler, an associate member of the Fred Hutchinson Cancer Research Center, recently discussed the diagnosis, risk prognostication and therapeutic strategies for this spectrum of hematologic diseases.

Polycythemia Vera

The criteria by which PV is defined was updated by the World Health Organization (WHO) in 2017. The criteria now include hemoglobin lowered to >16.5g/dL in men and >16 g/dL in women, bone marrow with trilineage growth, and the presence of aJAK2mutation.

"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 fromJAK2-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 wereJAK2V617Fmutation—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= .0019).

"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.2Investigators found thatASXL1, SRSF2, andIDH2were associated with poorer OS in patients with PV. Other mutations evaluated wereTET2, SH2B3, SF3B1, SETBP1, DNMT3A, CSF3R, CEBPA, SUZ12, ZRSR2, KIT, RUNX1, FLT3, CBL, andTP53.

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.3Additionally, 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%.4Complete 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.

Essential Thrombocytopenia

The major criteria for ET is a platelet count of greater 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 aJAK2, CALR, orMPLmutation. Minor criteria are the presence of a clinical marker or absence of evidence for relative thrombocytosis.

"We know from earlier work that has been published since 2013 thatJAK2mutations make up about 60% to 65% of ET and MF, 205 to 25% of these non—JAK-mutated patients withCALRandMPLmake up about 5% of cases."

CALRmutations are exon 9 somatic insertions or deletions. This is a protein that is involved in chaperoning and calcium buffering activities. A mutation ofCALRin ET or MF can lead to loss of KDEL sequence and altered C-terminus, explained Oehler. Type I, which is a 52-base pair deletion, is the most frequent. Type II, which is a 5-base pair TTGTC insertion, is rare, as it is found in about 25% ofCALR-mutated patients, said Oehler.

Additional mutations in ET that signal adverse outcomes areSH2B3, IDH2, SF3B1, U2AF1, EZH2, andTP53, said Oehler. These mutations are associated with inferior OS independent of age and karyotype, and impact MF-free survival.

"ForCALR, know that there is no difference in OS, myelofibrosis or leukemic transformation compared withJAK2—outcome is not impacted byCALRmutation type.TP53is associated with inferior leukemia-free survival in multivariate analyses," she summarized.

Thrombosis inJAK2-mutated ET occurs due to platelet activation, formation of platelet-neutrophil aggregates, and increased red blood cell mass. Although data like these do not exist in ET, Oehler says that one could make the case thatJAK2V617Fdrives thrombosis in MF.

This was shown in a study of 281 patients with follow-up of 3.17 years. This study showed that fatal and nonfatal cardiovascular vents occurred in less than 1% ofCALR- andMPL-mutated patients.6No events were registered in triple-negative patients, butJAK2mutations had the highest rate of thrombosis compared with all other groups at 2.52% per patient per year.

The overall therapeutic approach to ET is to consider the observation alone in patients with no risk factors and no symptoms. Furthermore, Oehler suggested low-dose aspirin withJAK2V617Fand/or cardiovascular risk factors.

"Some older patients with intermediate risk may not need a cytoreductive treatment if asymptomatic," said Oehler. "And treatment for high-risk patients has not changed much here."

MAJIC is a randomized phase II trial of ruxolitinib versus best available therapy in patients with ET and PV who are resistant or intolerant to hydroxycarbamide. Findings from this study showed that there was no evidence of improvement in CR within 1 year.7CR was reported in 27 patients (46.6%) treated with ruxolitinib compared to 23 patients (44.2%) with best available therapy (P=.04).

Additionally, rates of thrombosis, hemorrhage, and transformation were not significantly different at 2 years, Oehler said. The results of this study were in contrast to the findings from the RESPONSE and RESPONSE-2 trials.

Studies that are still underway in high-risk ET include RESET-272 (NCT03123588) and Ruxo-BEAT (NCT02577926).


In 2017, WHO defined prePMF and overt primary MF (PMF).

"The difference here for prePMF is without reticulin fibrosis greater than 1, and grade 2 and 3 will bring you the definition of MF, especially if you also have leuko- or erythroblastosis," explained Oehler. "We know that these are younger patients, they have fewer and infrequent cytopenias, lower LDH [lactate dehydrogenase], less splenomegaly, infrequent unfavorable karyotype, and have less frequent high-risk mutations."

OS and leukemia-free survival outcomes differ between the 2 conditions. For overt PMF, OS is about 7 years compared with 14.2 years with prePMF, Oehler said. Prognostication in PMF is done by DIPSS. Beyond what is prognosticated by DIPSS, OS for driver mutations are 17.7 years forCALR, 9.2 years forJAK2, 9.1 years for MPL, and 3.2 years for triple-negative.

Non-driver mutations with high molecular risk in MF areASXL1, EZH2, IDH1/2, andSRSF2. Oehler said that survival is longest forCALR-positive,ASXL1-negative patients and is shortest in patients withCALR-negativeASXL1-positive MF. MIPSS70 is used to prognosticate for these factors.

In 2011, ruxolitinib was approved by the FDA for the treatment of patients with intermediate or high-risk myelofibrosis, including primary MF, post-PV MF and post-ET MF.

Oehler concluded, however, by posing the question of why JAK2 inhibitors are not disease-modifying. She said that it might be because the response is better in those with higher mutation variant allele frequency, the presence of other mutations, inadequate exposure, or escape pathways.

"Know that optimal inhibition of JAK is probably not possible due to other off-target effects, and that more potent type 2 inhibitors have been developed, but they are likely too toxic for clinical use. You could argue that aJAK2mutation-specific drug design is possible and that has already been demonstrated, but has not been taken much further," Oehler explained.

The bottom line for other JAK2 inhibitors:

•Fedratinib: JAKARTA showed a primary endpoint of point ≥35% reduction in spleen volume achieved in the fedratinib 400 mg and 500 mg groups. Development was discontinued, but is resuming.8

•Pacritinib: Promising results for PERSIST 1 and 2, with twice daily dosing being more effective in PERSIST 2.9,10Trials have resumed after an FDA hold due to higher death rates from intracranial hemorrhage, heart failure, and cardiac arrest.

•Momelotinib: Clinical development has stopped due to higher rates of infections and treatment-emergent peripheral neuropathy.11

Other JAK2 inhibitors discontinued due to toxicity are AZD1280 due to neurological adverse events, and lestaurtinib for gastrointestinal toxicities.

New treatment directions for JAK2 inhibitors alone or in combination included azacitidine, hedgehog inhibitors, HDAC inhibitors, HSP-90 inhibitors, and PI3K inhibitors.

Two ongoing trials that Oehler highlighted were a study of aCALRexon 9-mutant peptide vaccine in patients withCALR-mutant MPNs (NCT03566446), and an open-label, randomized, phase II dose-finding study of pacritinib in patients with primary MF, post-PV MF, or post-ET MF previously treated with ruxolitinib (NCT03165734).


  1. Barbui T, Thiele J, Carobbio A, et al. Masked polycythemia vera diagnosed according to WHO and BCSH classification.Am J Hematol. 2014 Feb;89(2):199-202. doi: 10.1002/ajh.23617.
  2. Tefferi A, Lasho TL, Guglielmelli P, et al. Targeted deep sequencing in polycythemia vera and essential thrombocythemia.Blood Advances. 2016;(1)21-30; doi: https://doi.org/10.1182/bloodadvances.2016000216.
  3. Vannucchi AM, Kiladjian JJ, Griesshammer M, et al. Ruxolitinib versus standard therapy for the treatment of polycythemia vera.N Engl J Med. 2015;372:426-435. doi: 10.1056/NEJMoa1409002.
  4. Pai SG, Kaplan JB, Giles FJ. Long-acting interferon for myeloproliferative neoplasms - an update.Expert Review of Hematology. 2016;9(10):915-917. doi: 10.1080/17474086.2016.1231571.
  5. Gisslinger H, Klade C, Georgiev P, et al. Final results from proud-pv a randomized controlled phase 3 trial comparing ropeginterferon alfa-2b to hydroxyurea in polycythemia vera patients.Blood. 2016;128(22):475.
  6. Finazzi MC, Carobbio A, Cervantes F, et al. CALR mutation, MPL mutation and triple negativity identify patients with the lowest vascular risk in primary myelofibrosis.Leukemia. 2015 May;29(5):1209-10. doi: 10.1038/leu.2014.343.
  7. Harrison CN, Mead AJ, Panchal A, et al. Ruxolitinib vs best available therapy for ET intolerant or resistant to hydroxycarbamide.Blood. 2017 Oct 26;130(17):1889-1897. doi: 10.1182/blood-2017-05-785790.
  8. Harrison CN, Schaap N, Vannucchi AM, et al. Janus kinase-2 inhibitor fedratinib in patients with myelofibrosis previously treated with ruxolitinib (JAKARTA-2): a single-arm, open-label, non-randomised, phase 2, multicentre study.Lancet Haematol. 2017;4(7):e317-e324. doi: 10.1016/S2352-3026(17)30088-1.
  9. Mesa RA, Vannucchi AM, Mead A, et al. Pacritinib versus best available therapy for the treatment of myelofibrosis irrespective of baseline cytopenias (PERSIST-1): an international, randomised, phase 3 trial.Lancet Haematol. 2017;4(5):e225-e236. doi: 10.1016/S2352-3026(17)30027-3.
  10. Mascarenhas J, Hoffman R, Talpaz M, et al. Pacritinib vs best available therapy, including ruxolitinib, in patients with myelofibrosis: a randomized clinical trial.JAMA Onc. 2018;4(5):652-659. doi:10.1001/jamaoncol.2017.5818
  11. Harrison CN, Vannucchi AM, Platzbecker U, et al. Momelotinib versus best available therapy in patients with myelofibrosis previously treated with ruxolitinib (SIMPLIFY 2): a randomised, open-label, phase 3 trial.Lancet Haem. 2018;5(2):e373-e381. doi: 10.1016/S2352-3026(17)30237-5.
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