Omar Alkharabsheh, MD, discusses the growing treatment options for patients with myeloproliferative neoplasms, including polycythemia vera, essential thrombocythemia and myelofibrosis, and how available agents have not induced a biological change or shown improvement in disease outcomes.
Omar Alkharabsheh, MD
Despite growing options for the treatment of patients with myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocythemia (ET) and myelofibrosis, available agents have yet to induce a biological change or improve disease outcomes, according to Omar Alkharabsheh, MD. However, combining novel agents with JAK2 inhibitors, such as ruxolitinib (Jakafi) or fedratinib (Inrebic), may induce the clinical response that is needed to improve outcomes in this patient population.
“The only potential cure for patients with myelofibrosis or advanced MPNs is allogeneic stem cell transplant (allo-SCT); however, these are diseases [that usually impact] elderly patients who are not always candidates for allo-SCT,” said Alkharabsheh. “We manage symptoms with treatment and use cytoreductive therapy to decrease the risk of clotting, but we are not changing the disease biology or the course of disease. Allo-SCT is a potentially curative option, but has a higher risk of complications. Transplant requires a lot of logistics in terms of donor identification and access to transplant centers.”
In an interview with OncLive, Alkharabsheh, an assistant professor of Interdisciplinary Clinical Oncology at the USA College of Medicine, and a medical oncologist and hematologist at the Mitchell Cancer Institute at USA Health, discussed the current treatment landscape of MPNs, remaining challenges that need to be addressed, and promising investigational agents in the pipeline.
OncLive: What treatment options are currently available to patients with MPNs, including ET, PV, and myelofibrosis?
Alkharabsheh: The current goals of treatment in MPNs, especially ET and PV, are to decrease the risk of clotting; control cardiovascular risk factors, such as hypertension, diabetes, and lipedema; initiate antiplatelet therapy when it is indicated; assess for the need of cytoreductive therapy; and monitor for progression to myelofibrosis. Patients also need to be assessed for myelofibrosis symptoms if they progress from ET or PV to myelofibrosis.
The standard of care for cytoreduction is still hydroxyurea. I feel that JAK2 inhibitors have not been shown to change the biology of the disease through, for example, complete remissions or molecular responses. However, from the COMFORT-I and COMFORT-II trials, ruxolitinib was shown to improve symptoms and spleen size, which are the 2 most important factors I consider when initiating a JAK2 inhibitor. Otherwise, we are still not able to change the biology of the disease.
In the second-line setting, for ET, I would consider pegylated interferon after hydroxyurea. [This approach has shown] cytoreductive activity, and molecular remissions have also been demonstrated by this agent. Anagrelide (Agrylin) has been used for ET, but it is associated with a higher [rate of] progression to myelofibrosis.
For patients with PV after hydroxyurea failure, we have the option of [using either] pegylated interferon or ruxolitinib. I would consider ruxolitinib if the patient is very symptomatic or their spleen is enlarged and causing them discomfort. Otherwise, pegylated interferon has demonstrated good activity to induce cytoreduction.
Last year, a new JAK inhibitor called fedratinib was approved based on [data from] the JAKARTA trial, for use in patients with intermediate-2 and high-risk myelofibrosis or post-ET or PV myelofibrosis. The primary outcome in that trial was similar to [that of the trial examining] ruxolitinib. Investigators examined patient symptom and spleen size reductions from baseline.
The inhibition of the JAK/STAT pathway with ruxolitinib or fedratinib does not change the disease biology, but they are very exciting drugs [that can be used to] control symptoms and decrease spleen size.
What are some of the most intriguing data that have emerged in the MPNs space recently?
Ropeginterferon alfa-2b (P1101), another interferon [agent, is] now in development and being explored in clinical trials in Europe; this agent was compared with hydroxyurea in a phase 3 trial. Results showed durable responses and noninferior hematologic response [with ropeginterferon alfa-2b]; however, the [agent] was not able to induce a good spleen size reduction.
Patients who [progress on] JAK2 inhibitors need to be treated in clinical trials, as we still don’t have an [acceptable] option for them. Most of those clinical trials require good platelet counts; however, after JAK2 inhibitors, or upon disease progression, patients will have thrombocytopenia that limits their options in terms of accrual to clinical trials.
We also have another JAK2 inhibitor called momelotinib. The agent is still in clinical trials, but uniquely, the drug demonstrated improvement in anemia and reduced transfusion dependency [in patients with myelofibrosis].
What is some of the work that is being done in myelofibrosis?
Many clinical trials, still in the early phase, are looking [to improve] the treatment of patients with myelofibrosis. A BCL-2 inhibitor called navitoclax is being combined with JAK inhibitors in [this disease]. We know that ruxolitinib will induce some suppression of the JAK/STAT pathway, which will lead to improvement in symptoms and splenomegaly. However, again, we are not changing the biology of the disease. Hopefully, with this clinical trial, we will see that by adding a BCL-2 inhibitor [to ruxolitinib], we can change the disease biology by decreasing the risk of progression to acute myeloid leukemia (AML) and improving overall survival. This [approach] will need [to be investigated further in] a more advanced phase 2 or 3 clinical trial.
Another investigational agent is tagraxofusp (SL-401; Elzonris), which is an immuno-toxin that is being examined in early-phase clinical trials for the treatment of patients with relapsed/refractory myelofibrosis after JAK2 inhibition. This may be a promising agent that could induce a decreased risk of progression to AML and improve outcomes.