Expert Breaks Down Diagnosis and Treatment of Classical MPNs

Vivian G. Oehler, MD, discusses the diagnosis, risk prognostication and therapeutic strategies for polycythemia vera, essential thrombocytopenia, and myelofibrosis.

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.

Polycythemia Vera

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 mutation.

"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 = .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.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

Essential Thrombocytopenia

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.

"We know from earlier work that has been published since 2013 that JAK2 mutations make up about 60% to 65% of ET and MF, 205 to 25% of these non—JAK-mutated patients with CALR and MPL make up about 5% of cases."

CALR mutations are exon 9 somatic insertions or deletions. This is a protein that is involved in chaperoning and calcium buffering activities. A mutation of CALR in 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% of CALR-mutated patients, said Oehler.

Additional mutations in ET that signal adverse outcomes are SH2B3, IDH2, SF3B1, U2AF1, EZH2, and TP53, said Oehler. These mutations are associated with inferior OS independent of age and karyotype, and impact MF-free survival.

"For CALR, know that there is no difference in OS, myelofibrosis or leukemic transformation compared with JAK2—outcome is not impacted by CALR mutation type. TP53 is associated with inferior leukemia-free survival in multivariate analyses," she summarized.

Thrombosis in JAK2-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 that JAK2V617F drives 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% of CALR- and MPL-mutated patients.6 No events were registered in triple-negative patients, but JAK2 mutations 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 with JAK2V617F and/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.7 CR 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 for CALR, 9.2 years for JAK2, 9.1 years for MPL, and 3.2 years for triple-negative.

Non-driver mutations with high molecular risk in MF are ASXL1, EZH2, IDH1/2, and SRSF2. Oehler said that survival is longest for CALR-positive, ASXL1-negative patients and is shortest in patients with CALR-negative ASXL1-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 a JAK2 mutation-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 2.9,10 Trials 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 a CALR exon 9-mutant peptide vaccine in patients with CALR-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).


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  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.
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  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.