Division of Cancer Medicine
Department of Leukemia
The University of Texas MD Anderson Cancer Center
Srdan Verstovsek, MD, PhD, has disclosed that he has received consulting fees from Celgene, Constellation, Incyte, Novartis, Pragmatist, and Sierra and funds for research support from Blueprint Medicines, Celgene, CTI BioPharma, Genentech, Gilead Sciences, Incyte, Novartis, NS Pharma, Promedior, and Roche.
New and forthcoming clinical data will continue to shape best practices in managing patients with the myeloproliferative neoplasms (MPNs) essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF) in 2019. In this commentary, I highlight recent key developments and ongoing clinical studies that have the potential to affect clinical practice in the near future.
Ruxolitinib, a JAK 1/2 inhibitor, is approved by the FDA for treating patients with intermediate-risk or high-risk MF or those with PV who have demonstrated an inadequate response or intolerance to hydroxyurea (HU). An open-label phase II study suggested that ruxolitinib may also be beneficial (in terms of reduction in platelet and white blood cell counts and symptoms) for patients with ET who are resistant to or intolerant of HU, a standard first-line cytoreductive for this condition.
Recently, the MAJIC-ET study—a phase II trial in which 110 patients with high-risk ET and resistance or intolerance to HU were randomized to ruxolitinib or best available therapy (BAT)—found that ruxolitinib was noninferior to BAT in terms of CR, but symptom burden was improved. Several ongoing studies continue to examine the use of ruxolitinib in patients with high-risk ET and resistance or intolerance to HU, including RESET-272, a phase II trial comparing ruxolitinib with anagrelide and primarily assessing platelet and white blood cell control.
There have been several important developments in the use of ruxolitinib and interferon to manage patients with PV. Five-year follow-up data from the randomized phase III RESPONSE study—which initially showed that ruxolitinib significantly improved hematocrit control and reduced spleen volume and symptoms vs BAT at Week 32 for PV patients with HU resistance/intolerance—were presented at ASH 2018 and showed that the median duration of response was not reached with ruxolitinib, most responders to this agent were still responding, and no new toxicities were observed. These data support the long-term use of second-line ruxolitinib for patients with PV.
Turning to interferon, an analysis of the large randomized US phase III MPN-RC 112 trial presented at ASH 2018 reported that there was no difference in 24-month CR rates with frontline oral HU twice daily vs peginterferon alfa-2a SC weekly. This finding supports current guidelines recommending either HU—preferred by most US clinicians—or interferon as frontline therapy for PV.
In Europe, a similar phase III trial (PROUD-PV/CONTINUATION-PV) compared frontline oral HU twice daily with ropeginterferon alfa-2b SC every 2 weeks. At ASH 2018, the investigators reported that ropeginterferon significantly improved the 36-month hematologic CR rate vs HU (70.5% vs 51.4%, respectively; P = .0122). In December 2018, the European Medicines Agency recommended that ropeginterferon alfa-2b be approved in this setting. Ropeginterferon alfa-2b will be evaluated this year in clinical studies of US patients with PV and ET.
There were several publications in 2018 on enhanced prognostic scoring systems to better select patients with MF for bone marrow transplantation, which is usually reserved for patients with a life expectancy of less than 5 years. Enhanced systems integrate molecular findings and chromosomal abnormalities into traditional prognostic scoring systems based on blood cell count, symptoms, and age. These new systems include the Mutation‐Enhanced International Prognostic Score System (MIPSS70), the Genetically Inspired Prognostic Scoring System (GIPSS), and an MPN multistage model.
There has also been a need to develop systems that offer better prognostication of transplant success. A major presentation at ASH 2018 focused on a new European prognostic scoring system for transplant outcome, the Myelofibrosis Transplant Scoring System (MTSS). The MTSS categorizes patients into 4 survival risk groups based on their number of points, with 1 point each assigned for leukocytosis, thrombocytopenia, a Karnofsky performance score < 90, age older than 57 years, a cytomegalovirus-seronegative donor paired with a seropositive recipient, and ASXL1 mutation; 2 points are assigned for JAK2-mutated/triple-negative status and mismatched unrelated donors. In an international European cohort, the 5-year survival rates were 88% for the low-risk group (0-2 points), 71% for intermediate risk (3-4 points), 50% for high risk (5-6 points), and 20% for very high risk (7-9 points).
Another area of active research involves evaluating combinations with ruxolitinib for patients who have had suboptimal spleen and symptom responses or have significant anemia despite treatment with this agent. Combinations currently under investigation (presented at ASH 2018) include ruxolitinib plus azacytidine, decitabine, interferon, lenalidomide, thalidomide, the PI3K inhibitor INCB050465, and the antifibrotic agent PRM151.
Another major development in MF was the revival of the JAK inhibitors fedratinib and momelotinib as possible therapy in the second-line setting after ruxolitinib failure, a setting in which there are currently few options for patients. Fedratinib had been previously studied in the JAKARTA-1 and -2 trials. JAKARTA-1 was a phase III study that randomized patients with MF to frontline fedratinib or placebo and showed significant improvements in symptom burden and spleen response with fedratinib. JAKARTA-2—an open-label phase II study in which patients with MF who were resistant to or intolerant of ruxolitinib were treated with fedratinib—again showed spleen responses for treated patients. Although the development of fedratinib was put on hold by the FDA due to potential cases of Wernicke encephalopathy, the clinical hold was removed in 2017 and 2 additional trials are under way with fedratinib in the setting of ruxolitinib failure.
In 2 previous phase III trials, momelotinib was found to be active in the first-line or second-line setting, with benefits seen in terms of spleen response and anemia improvement. Momelotinib will continue to undergo evaluation in 2019 in a phase III trial in the second-line setting for symptomatic MF patients who are anemic, highlighting how momelotinib may offer different benefits than spleen and symptom improvements usually associated with JAK inhibitors.
Finally, pacritinib is an agent that had previously shown efficacy in a randomized phase III trial in the first-line setting for patients with high-risk MF (vs non-JAK inhibitor treatments). A second randomized phase III trial demonstrated that pacritinib was associated with improved symptoms and spleen response vs BAT, which included ruxolitinib for patients with MF and platelets < 100 x 109/L. Although the development of pacritinib was put on hold by the FDA due to reports of patient deaths related to intracranial hemorrhage, cardiac failure, and cardiac arrest, the clinical hold was removed in 2017 and a dose-finding phase II study is under way, with a phase III trial planned to evaluate pacritinib in patients who have a platelet count < 50 x 109/L—a population in need of treatment options, given that they are not traditionally treated with JAK inhibitors.
Additional agents in development include the erythroid maturation agent luspatercept, which is being assessed as a treatment for anemia. At ASH 2018, we saw positive data from the randomized, double-blind phase III MEDALIST trial on luspatercept for anemia in a subgroup of patients with myelodysplastic syndromes, and it is expected that this agent will be approved in this setting. A phase II trial is recruiting to evaluate luspatercept in the setting of anemia in MF.
How has your management of ET, PV, or MF changed in the past year? What do you see as the most exciting avenues of research and greatest ongoing needs in managing patients with MPNs? Please share your thoughts in the comments box.
For more coverage of key studies in other hematologic diseases presented at ASH 2018, please click here.