David S. Snyder, MD
Ruxolitinib (Jakafi), the sole FDA-approved agent for the treatment of patients with myelofibrosis, though effective in reducing splenomegaly and mitigating constitutional symptoms, does not significantly or reliably reduce the molecular burden or prevent progression to acute leukemia, noted David S. Snyder, MD.
Ongoing research is aiming to address the gap in efficacy as improved understanding of molecular markers comes to the forefront. “It looks like the more secondary mutations you have, the more aggressive the disease tends to be,” explained Snyder. “Those are things we're learning in terms of prognosis [and will hopefully] lead to specific targeted therapies of value.”
In an interview during the 2018 OncLive®
State of the Science SummitTM
on Multiple Myeloma and Myeloproliferative Neoplasms, Snyder, associate chair and professor, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, detailed these mutations and discussed investigational treatments within the field of myeloproliferative neoplasms (MPNs).
OncLive: Please provide an overview of your presentation.
: The field of MPNs is hitting its stride with new molecular markers that are being defined. We know about the important driver mutations including, JAK2
, and NPL
. Now, we are learning more about the prognostic importance of secondary mutations. The hope is that some of these findings will lead to targeted therapies. That’s what led to ruxolitinib, the only FDA-approved drug [that was developed for myelofibrosis]. There are other JAK2 inhibitors in clinical trials, one of which is pacritinib.
There are non-JAK2 inhibitors that are being studied, as well; imetelstat is an example of that. It's a telomerase inhibitor, which is a totally different kind of molecule. There are still a lot of unmet needs in this area. Ruxolitinib is the leader right now; it has very good properties that enable shrinking spleens and curbing constitutional symptoms, but there is a lot that it doesn't do. It doesn't significantly or reliably reduce the molecular burden. It doesn't seem to prevent progression to acute leukemia, and it's not a cure.
[Cure is] something we would all [like] to be able to reach for. In the meantime, there's allogeneic stem cell transplantation, which is the only curative option for [patients with] myelofibrosis. We presented some of our work from City of Hope at the 2017 Annual ASH Meeting. [Stem cell transplant] is not a perfect answer either. There are a lot of toxicities associated with it, including morbidity and mortality; however, for the right patient, it's the only curative option.
For polycythemia vera (PV), I spoke about the current state-of-the-art regimen, hydroxyurea, which remains to be the frontline drug of choice when cytoreduction is needed. Before that, low-dose aspirin and phlebotomy has been and still is the mainstay treatment. For those who need something further, hydroxyurea is [indicated in the] first-line [setting]. There are other options. Ruxolitinib is now FDA approved as a second-line therapy for patients with PV who are resistant or intolerant to hydroxyurea. Interferon is [also] making a resurgence. There are these newer formulations of interferon—pegylated interferon—that are longer lasting and may be less toxic than the standard interferon.
How have you seen ruxolitinib impact the landscape since its approval?
It's very good at what it does: shrinking spleen size and controlling constitutional symptoms, which are very important sources of clinical problems for our patients. It is part of the reason why patients lose weight, have decreased muscle mass, and poor performance status. If physicians can significantly reduce the spleen size and improve their patient's ability to eat, that can help performance status.
Reducing some of the constitutional symptoms also improves a patient’s quality of life. The use of ruxolitinib does, however, lower platelet count. Physicians must be careful about that and adjust the dose appropriately. It may worsen anemia, at least initially, which is a problem that most patients are dealing with already. For most patients, if their hemoglobin drops, it will recover to baseline after a few months. That effect does not seem to impair or impact the ultimate benefits of the drug.