Aaron Gerds, MD
For select patients with myelofibrosis and polycythemia vera (PV), the JAK1/2 inhibitor ruxolitinib (Jakafi) has been an effective option to reduce symptom burden. However, according to Aaron Gerds, MD, additional therapeutic strategies are needed within the myeloproliferative neoplasm (MPN) landscape—potentially with novel mechanisms of action.
“The fact of the matter is, there is only one FDA-approved medication for MPNs to date and we really need more to help take care of our patients,” explained Gerds, an assistant professor in the Department of Hematology and Oncology, Cleveland Clinic.
In PV, ruxolitinib was approved by the FDA in 2014 as a treatment for patients who are resistant or intolerant to hydroxyurea. The drug was initially approved in 2011 for patients with intermediate and high-risk myelofibrosis. Clinical trials of combinations with ruxolitinib have previously been associated with higher levels of toxicity; however, ongoing trials with the PI3K-delta inhibitor umbralisib (TGR-1202; NCT02493530) have peaked interest, said Gerds.
But beyond ruxolitinib, the JAK2 inhibitors pacritinib and fedratinib continue to move through the pipeline after the FDA lifted their clinical holds, as well as studies of antifibrotic agents and telomerase inhibitors. In an interview during the 2018 OncLive®
State of the Summit™ on Hematologic Malignancies, Gerds discussed the activity and drawbacks with these systemic agents in MPNs.
OncLive: How has the addition of ruxolitinib shaped the MPN landscape?
It can improve patients’ symptoms and perhaps lead to better survival in these folks. The latter [part of that statement] is still somewhat debated, but clearly we can improve patients’ symptoms [with ruxolitinib] in these diseases. The pivotal trials were done in myelofibrosis, which ultimately led to the FDA approval of this medication. Again, it showed that with this medication, we are able to shrink peoples’ spleens and improve their symptoms quite reliably.
In PV, it has also been shown to help control red blood cell counts in addition to improving symptoms and spleen size. It does have a second-line indication in PV. There have been a couple of phase II studies in essential thrombocytopenia (ET), but it doesn’t carry a label at this point and its role within the treatment matrix of ET is still a little unclear.
What are some therapies that have shown some promise but, given safety issues and clinical holds, their roles are unclear?
With the discovery of JAK-STAT
activating mutations in these diseases, there was a wave of development of JAK inhibitors. It was a very logical thing. Each JAK inhibitor had unique properties; there were some that were JAK1 inhibitors versus JAK2 inhibitors. There were others that were more of a JAK2 inhibitor. There were others that were specific to the V6174 mutation within JAK2
Many of these drugs also had off-target effects on other tyrosine kinases, which may impact disease burden and response rates. A number of these drugs were coming through, and they have all fallen victim to these 2 things: either serious adverse events (AEs), which put holds on the development of these medications, or response rates that weren’t appreciably different than what we would expect with ruxolitinib. Therefore, it certainly has been interesting to watch the development of these drugs and their progress over time. The drugs notably put on hold by the regulatory bodies for concerns over toxicity were fedratinib and pacritinib. However, these holds are now lifted, the drugs are under further development, and seem to be moving forward.
Momelotinib is a very interesting medication, because it can inhibit JAK1/2 and lead to spleen responses as well as symptom burden responses. However, we also see a fair number of patients’ anemia improve, which is a very intriguing concept because many of these patients are burdened with anemia, and even transfusion-dependent anemia.