Novel Treatment Strategies for Myeloproliferative Neoplasms: What’s New From ASCO and EHA 2019

Brady L. Stein, MD, MHS

Associate Professor of Medicine
Department of Hematology/Oncology
Northwestern University Feinberg School of Medicine
Chicago, Illinois


Brady L. Stein, MD, MHS, has disclosed that he has received consulting fees from Apexx Oncology and Celgene.


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Released: July 8, 2019

The JAK inhibitor ruxolitinib is now the primary option for disease control in patients with intermediate-risk or high-risk myelofibrosis (MF) or patients with polycythemia vera (PV) who have demonstrated an inadequate response or intolerance to hydroxyurea. However, there remain several critical therapeutic unmet needs for these patients, including options for patients who have experienced ruxolitinib failure.

Several studies presented at the 2019 ASCO annual meeting and EHA Congress highlighted emerging therapeutic agents and strategies for patients with myeloproliferative neoplasms (MPNs). In this commentary, I briefly review data and share my thoughts on a few studies that I found particularly interesting.

ASCO 2019: New Strategies for Ruxolitinib-Experienced Patients
A key presentation at ASCO 2019 reported supportive data for the investigational JAK2 inhibitor fedratinib in the setting of ruxolitinib failure. In a reanalysis of the single-arm phase II JAKARTA-2 trial—which assessed fedratinib in patients with MF who were previously treated with ruxolitinib—the authors employed a more stringent definition of ruxolitinib failure than that used in the original analysis and found that 30% of patients with ruxolitinib failure who were treated with fedratinib demonstrated a spleen volume reduction ≥ 35%, whereas 27% showed symptom improvements. Fedratinib is now under investigation in the ongoing single-arm phase IIIb FREEDOM trial, which was introduced at the ASCO meeting and will also enroll patients with MF who were previously treated with ruxolitinib.

Data were also presented from the nonrandomized phase II MANIFEST trial, which assessed the selective BET inhibitor CPI-0610 as treatment for patients with MF. BET regulates key signaling pathways (eg, NF-κB and TGF-β) that drive marrow fibrosis. Patients who were previously treated with ruxolitinib but were refractory or intolerant to this agent were treated with CPI-0610 monotherapy, whereas patients who were JAK inhibitor naive and anemic or who were receiving ruxolitinib but had demonstrated suboptimal responses with this agent were treated with ruxolitinib plus CPI-0610. Preliminary results from the ruxolitinib-experienced cohorts showed that 2 out of 3 transfusion-dependent patients achieved transfusion independence, with hemoglobin improvement observed in the monotherapy cohort and, after some delay, in the combination cohort. Spleen volume reduction was observed in 14 out of 16 evaluable patients (median best spleen volume change: -19.2%). Common treatment-emergent adverse events included nausea, vomiting, diarrhea, and thrombocytopenia; no grade ≥ 3 adverse events were observed in > 5% of patients in either the monotherapy or combination cohorts.

Finally, data were presented from an ongoing phase I/II trial of the CD123-directed cytotoxin tagraxofusp for patients with MF who had experienced relapsed/refractory disease or intolerance to a JAK inhibitor. Splenomegaly reduction was observed in 9 out of 17 evaluable patients, with a particularly high response rate in those with monocytosis. The most common treatment-related adverse events were alanine aminotransferase increase, headache, hypoalbuminemia, anemia, and thrombocytopenia.

EHA 2019: First-line PV Treatment and Novel Agents and Strategies for MF
The EHA Congress included several interesting reports that examined treatment strategies across MPNs. These included a molecular response analysis of the randomized phase II MAJIC PV trial, which compared ruxolitinib vs best available therapy in patients with PV who were resistant or intolerant to hydroxyurea, a standard first-line therapy. The most intriguing finding from this analysis was a significant correlation between molecular response at 1 year and the rate of thrombotic events: No patients with molecular CR/PR experienced a thrombotic event, whereas 19.1% without a molecular response did (P = .01). This finding would be the first to link anti-clonal activity and reduction in thrombosis risk with JAK inhibition.

Also of interest were data from the randomized phase III DALIAH trial, in which patients who were newly diagnosed with an MPN were randomized to recombinant interferon α-2a, interferon α-2b (all patients), or hydroxyurea (only patients older than 60 years). The authors reported a significantly higher 36-month ORR in patients aged older than 60 years who were treated with hydroxyurea vs recombinant interferon-α (71% vs 43%, respectively; P = .02). There have been decades of intrigue with interferon therapy, and this is another study that did not demonstrate superiority of interferon therapy vs hydroxyurea.

Preliminary data were also reported from a phase II trial assessing cytopenia improvement with the addition of thalidomide to ruxolitinib in patients with MF. In 12 evaluable patients, the ORR per IWG-MRT/ELN 2013 criteria was 58.3%, with a major platelet response (≥ 75% increase in platelet count) observed in 6 patients with thrombocytopenia at baseline.

Finally, data were presented regarding IMG-7289, an inhibitor of LSD1, a histone demethylase that can be overexpressed in MPNs. In a phase I/IIa trial evaluating IMG-7289 for patients with high-risk or intermediate 2–risk MF who were resistant to or intolerant of approved therapy, 66% of the 9 evaluable patients achieved spleen volume reduction and 56% had symptom improvement; 2 patients had improvement in marrow fibrosis. The study noted adverse events in 87% of patients, although only 1 event was deemed treatment related.

Your Thoughts
What do you see as the most exciting avenues of research and greatest ongoing needs in managing patients with MPNs? Please answer the polling question and share your thoughts in the comments box.

For more coverage of key studies in other hematologic diseases presented at ASCO 2019, please click here.

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