Back Back
MF/PV Studies at Hematology 2016
My Thoughts on Key Myelofibrosis and Polycythemia Vera Management Studies From the Hematology 2016 Meeting

Released: December 30, 2016

Expiration: December 29, 2017

Activity Information

Activity

Progress
1
Course Completed
Continue

The 2016 Hematology meeting was among the busiest since the meeting’s inception. As a hematologist who focuses on myeloproliferative neoplasms, including myelofibrosis (MF) and polycythemia vera (PV), I found the following studies to be of the greatest potential clinical relevance.

Interferon-Based Therapy
At the 2016 Hematology meeting, eagerly awaited results from 2 randomized phase III studies (MPD-RC 112 and PROUD-PV) comparing peginterferon (pegIFN) with hydroxyurea (HU) for the treatment of PV and/or essential thrombocythemia (ET) were presented. To date, the use of pegIFN as a first-line cytoreductive therapy for patients with PV has been supported by phase II studies in which pegIFN demonstrated impressive hematologic and molecular response rates. However, tolerability concerns and a lack of randomized data have tempered enthusiasm for the use of this agent.

For study MPD-RC 112, 12-month interim results were presented for the first 75 treatment-naive, high-risk patients with PV/ET. The primary endpoint of complete hematologic response rate was statistically similar for patients in the pegIFN α-2a and HU treatment groups (33% vs 28%; P = .60). Similar reductions in symptom burden were seen for the 2 groups, and grade ≥ 3 adverse events were more commonly observed for pegIFN-treated patients vs those treated with HU (47% vs 14%; P = .002).

The PROUD-PV study randomized 254 patients with PV to treatment with ropeginterferon α-2b—a longer-acting pegIFN administered at 2-week intervals—or HU. Noninferiority between the 2 agents was reported for complete hematologic response rate (ropeginterferon vs HU: 43% vs 45%), and the investigators reported that the safety profile favored ropeginterferon.

For many who have followed the IFN in PV/ET story, these results would appear disappointing. However, the investigators cautioned that a longer follow-up time is necessary before drawing final conclusions about a frontline role for pegIFN therapy in PV and ET. At present, these data do not yet firmly establish pegIFN as a superior frontline treatment for all patients with PV. Rather, based on consensus opinion, pegIFN would still be reserved for use in patients who are pregnant, younger than 40 years of age, or who require cytoreduction but decide against use of HU.

In a phase II study correlating the mutational status of 30 patients with early MF with their response to recombinant IFN-α, 73% of patients were clinically improved or stable, with 2 and 9 patients achieving CR and PR, respectively. Whereas driver mutations (JAK2/CALR/MPL) had no impact on outcome, patients with high molecular risk (HMR) markers, including ASXL1, IDH1/2, EZH2, and SRSF2, had less favorable responses. A correlation between HMR status and adverse prognosis in MF has been established. However, HMR status does not routinely influence nontransplantation treatment decisions in clinical practice. At present, pegIFN is infrequently used in MF, although guidelines do state that this agent may be a treatment choice for patients with low-risk, symptomatic MF.

JAK Inhibitor–Based Therapy
Ruxolitinib is a JAK inhibitor that is currently approved for treating patients with MF and PV. An interesting open-label phase II trial in which 44 patients with MF were treated with ruxolitinib and 5-azacitidine showed an objective response in 69% (27/39) of patients (2 PRs; all others had varied permutations of clinical improvement in spleen, anemia, and symptom responses). The authors noted that the spleen response was superior to that seen previously with ruxolitinib alone. Guidelines support the use of ruxolitinib with a hypomethylating agent (HMA) if a patient is receiving ruxolitinib at the time that disease acceleration prompts initiation of the HMA. Specifically, ruxolitinib can be continued if cytokine-associated/spleen-related symptoms are controlled by this agent. The caution with this combination in clinical practice is the overlapping toxicity of myelosuppression.

Encouraging results were also reported for phase I trials in which ruxolitinib was combined with either decitabine or the PI3Kδ inhibitor TGR-1202.

Data on several investigational JAK inhibitors were also presented. The phase III PERSIST-2 study compared once- or twice-daily pacritinib (a multikinase inhibitor) with best available therapy (ruxolitinib in 44% of patients) for patients with MF with platelets ≤ 100,000/μL. Spleen volume reduction by MRI was more likely to be observed in pacritinib-treated patients vs those receiving best available therapy (18% vs 2.8%; P = .001), although there was no difference in symptom improvement between the 2 groups. BID dosing of pacritinib appeared more effective than QD dosing. This drug remains on clinical hold due to concerns regarding survival, CV events, and bleeding.

Six-year follow-up data for a phase I/II study of momelotinib (a JAK1/2 inhibitor) for the treatment of MF (N = 100) showed an anemia response in 44% of patients (51% of transfusion-dependent patients became independent) and a spleen reduction in 43% of patients. Following a median of 1.7 years of treatment, 34% developed grade 3/4 thrombocytopenia, and 47% developed irreversible neuropathy. Phase III momelotinib results have not yet been presented. However, a press release in November 2016 reported that noninferiority to ruxolitinib was achieved in splenic reduction but not symptom improvement (SIMPLIFY-1). Noninferiority criteria for splenic reduction were not met when momelotinib was compared with best available therapy in SIMPLIFY-2.

Lastly, phase I/II data for the JAK2 inhibitor NS-018 revealed that 56% (20/36) of patients with MF experienced a > 50% reduction in spleen size, including 47% (9/19) who were previously treated with JAK inhibitors. Anemia and thrombocytopenia were noted in 21% and 17% of patients, respectively. Nausea was the most common nonhematologic adverse event.

Other Therapies
Sotatercept is a ligand trap that binds TGF-β, relieving blockade on terminal erythroid differentiation. In a phase II study, 5/14 evaluable patients with MF (all women) responded to sotatercept, including transfusion-dependent and independent patients. The only adverse event attributed to the drug was hypertension.

One of the most intriguing presentations at the 2016 Hematology meeting focused on a small study of Blu-285 (a selective KIT D816V inhibitor) for patients with advanced mastocytosis. Albeit in only 6 patients, Blu-285 was associated with relief of allergic symptoms, improved urticaria pigmentosa, weight gain, and albumin increase, along with decreased splenomegaly, mast cell burden, tryptase, and KIT D816V DNA levels.

My Takeaways
Despite the many interesting reports discussed above, I would not yet consider any to have immediate impact on routine clinical practice. Although we have made progress in addressing symptoms and improving quality of life for our patients with MPN, we are still in need of disease-modifying therapies. The great challenge lies in identifying monotherapies or combinations that display anticlonal activity and have unequivocal impact on marrow histology.

A New Tool to Help Guide Treatment Decisions for Patients with MF or PV
With numerous therapeutic options to consider for patients with MF or PV, selecting a treatment strategy can be challenging. To assist with treatment selection, my colleagues John Mascarenhas, MD; Michael W. N. Deininger, MD, PhD; Ruben Mesa, MD; Srdan Verstovsek, MD, PhD; and I are creating an Interactive Treatment Decision Tool designed to allow you to rapidly determine individualized treatment options. Based on the specific characteristics of your patients with MF or PV, it will provide recommendations from each of the experienced faculty listed above specifically for your case. Check the CCO Web site in early 2017 to begin using this tool!

What Hematology 2016 data did you find most interesting and potentially relevant for your practice? For what patients with MF/PV do you think the greatest treatment needs remain? Please share your questions or thoughts in the comment box below.

Continue

Poll

1.
Which of the following would you be most likely to use as first-line treatment of PV in a 45-year-old man with a history of thrombosis?
Submit