John O. Mascarenhas, MD, associate professor of medicine, hematology, and medical oncology at the Icahn School of Medicine at Mount Sinai; director of the Adult Leukemia Program; and leader of Clinical Investigation within the Myeloproliferative Disorders Program at Mount Sinai, and a member of the Tisch Cancer Institute, discusses limitations with JAK inhibitors in myelofibrosis.

Myelofibrosis is a ​complex hematopoietic malignancy that often results in multiple hematologic events, including anemia, thrombocytopenia, increased blasts, transformation to acute leukemia, and spleen​/symptom burden, says Mascarenhas.

Notably, ​the JAK inhibitors ruxolitinib (Jakafi) and fedratinib (Inrebic) have been fundamental in treating certain aspects of the disease, such as spleen ailments​, Mascarenhas says. However, JAK inhibitors cannot treat anemia or ​alter the natural history of the disease.

As such, ongoing research efforts ​are evaluating a host of therapies that could potentially be used in the salvage setting for patients who progress on or are refractory to JAK inhibitors, Mascarenhas concludes.

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John O. Mascarenhas, MD, discusses limitations with JAK inhibitors in myelofibrosis.

Dr. Mascarenhas on Limitations With JAK Inhibitors in Myelofibrosis 

John O. Mascarenhas, MD, associate professor of medicine, hematology, and medical oncology at the Icahn School of Medicine at Mount Sinai; director of the Adult Leukemia Program; and leader of Clinical Investigation within the Myeloproliferative Disorders Program at Mount Sinai; and a member of the Tisch Cancer Institute, discusses ongoing clinical trials in myelofibrosis. 

Myelofibrosis is a rare, often chronic, and aggressive disease with significant unmet needs. Therefore, Mascarenhas recommends enrolling patients in clinical trials when possible to push agents into the commercial space. 

For example, patients with low platelet counts may be eligible to enroll on the phase 3 PACIFICA study which is evaluating the JAK inhibitor pacritinib in patients with primary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocythemia myelofibrosis, Mascarenhas explains. 

Transfusion-dependent patients may be considered for the phase 3 MOMENTUM trial which is evaluating momelotinib versus danazol in anemic patients with symptomatic myelofibrosis, Mascarenhas says. 

Additionally, the investigational BET inhibitor CPI-0610 is likely to be evaluated in a phase 3 study in combination with ruxolitinib (Jakafi) for patients with JAK-inhibitor naïve myelofibrosis, adds Mascarenhas.

Finally, a phase 3 study evaluating imetelstat may be on the horizon in myelofibrosis, concludes Mascarenhas.

John O. Mascarenhas, MD, discusses ongoing clinical trials in myelofibrosis.  



Dr. Mascarenhas Discusses Ongoing Clinical Trials in Myelofibrosis 

John O. Mascarenhas, MD, associate professor of medicine, hematology, and medical oncology at the Icahn School of Medicine at Mount Sinai; director of the Adult Leukemia Program; and leader of Clinical Investigation within the Myeloproliferative Disorders Program at Mount Sinai; and a member of the Tisch Cancer Institute, discusses approved and emerging treatment options in myelofibrosis. 

The field of myelofibrosis is becoming more competitive as alternative treatments for patients who progress on ruxolitinib (Jakafi) enter the pipeline, explains Mascarenhas. 

One agent, fedratinib (Inrebic), received FDA approval for the treatment of patients with intermediate-2 or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis, says Mascarenhas.

The JAKARTA-2 study, results of which led to the approval of fedratinib, evaluated the agent in the second-line setting. The agent led to significant reduction in splenomegaly in patients who progressed on ruxolitinib, Mascarenhas explains. Although the agent is associated with some gastrointestinal toxicities, it provides another JAK inhibitor option in this space. 

Other novel agents such as CPI-0610 are being evaluated in combination with ruxolitinib in patients who had a suboptimal response to ruxolitinib, says Mascarenhas. Additionally, the BCL-2 inhibitor navitoclax is being explored in the myelofibrosis space.

Ultimately, the goal of clinical trials is to develop novel therapies to better manage spleen symptoms, improve quality of life, and increase overall survival rates, concludes Mascarenhas. 

John O. Mascarenhas, MD, discusses approved and emerging treatment options in myelofibrosis.  



Dr. Mascarenhas on Approved and Emerging Treatment Options in Myelofibrosis 

John Mascarenhas, MD, associate professor of Medicine, Mount Sinai School of Medicine, discusses pacritinib in patients with myelofibrosis.

Pacritinib has been shown to be effective in reducing spleen volume and symptom burden in the frontline setting, and can be delivered safely in patients with low platelet count, says Mascarenhas.

In the second-line setting, several JAK2 inhibitors have been tested but haven’t progressed due to toxicities. Recently, the phase III PERSIST-2 study tested pacritinib versus best available therapy.

Pacritinib was put on full clinical hold by the FDA in February 2016 due to excessive mortality, cardiac toxicity, and bleeding. But, Mascarenhas notes, there was no observable significant difference in mortality rates between pacritinib and the best available therapy, per the survival results of the PERSIST-2 study.

Dr. Mascarenhas Discusses Pacritinib in Myelofibrosis

John Mascarenhas, MD, associate professor of Medicine, Mount Sinai School of Medicine, discusses the results from the interim analysis of the MPD-RC 112 study, which compared frontline pegylated interferon-alpha-2a (Pegasys) with hydroxyurea in the treatment of patients with high-risk polycythemia vera (PV) and essential thrombocythemia (ET).

This randomized phase III study was conducted, explains Mascarenhas, because both physicians and patients are concerned that hydroxyurea is a leukemogenic drug, and many suspect that pegylated interferon-alpha-2a may be a superior agent. Preclinical studies have shown that pegylated interferon-alpha-2a has a direct effect on hematopoietic stem cells. Moreover, he says, early phase II studies have demonstrated an impressive overall response rate for the agent. These findings support the rationale to study the drug in the upfront setting for these patients.

In fact, he says, many institutions already hold the belief that pegylated interferon-alpha-2a is superior to hydroxyurea in the treatment of patients with high risk PV and ET. The MPD-RC 112 study set out to provide evidence-based recommendations that one of these drugs is superior to the other. It is particularly important to compare these 2 agents, says Mascarenhas, because of their different mechanisms of action and toxicity profiles.

John Mascarenhas, MD, associate professor of Medicine, Mount Sinai School of Medicine, discusses the results from the interim analysis of the MPD-RC 112 study, which compared frontline pegylated interferon-alpha-2a with hydroxyurea in the treatment of patients with high risk polycythemia vera and essential thrombocythemia.

John Mascarenhas, MD

Articles

Dr. Mascarenhas on Limitations With JAK Inhibitors in Myelofibrosis

Dr. Mascarenhas Discusses Ongoing Clinical Trials in Myelofibrosis

Dr. Mascarenhas on Approved and Emerging Treatment Options in Myelofibrosis

Dr. Mascarenhas Discusses Pacritinib in Myelofibrosis

Dr. Mascarenhas on the MPD-RC 112 Study in PV and ET