MPN Research Efforts Expand Beyond JAK1/2 Inhibition, Transplant

Shella Saint Fleur-Lominy, MD, PhD

Transplant and JAK1/2 inhibitors have served as some of the staple treatments for patients with myeloproliferative neoplasms (MPNs), but research efforts are now expanding and exploring new therapeutic options for these patients, such as alisertib and telomerase inhibitors, explained Shella Saint Fleur-Lominy, MD, PhD.

“This is a challenging disease, but it seems that the tide is turning,” said Saint Fleur-Lominy. “We have multiple targets now with preliminary data, either in the preclinical stage or as a phase I trial, that look promising. In the next few years, we are going to have a lot of options. The question will be how to sequence or combine them to get the best benefit for the patient.”

JAK1/2 inhibitors, such as ruxolitinib (Jakafi) and fedratinib (Inrebic), have shown reductions in symptom burden in patients with MPNs after transplant fails or in those who are ineligible for the procedure. However, researchers are investigating other options to treat patients who cannot undergo transplant due to age or comorbidities. Now, these agents are starting to be explored in combination to further improve outcomes.

In an interview during the 2020 OncLive^® State of the Science Summit™ on Hematologic Malignancies, Saint Fleur-Lominy, an assistant professor at NYU Langone Health’s Perlmutter Cancer Center, discussed some of the current and investigational treatment options for patients with MPNs.

OncLive: What is the clinical utility of JAK inhibitors in MPN treatment?

Saint Fleur-Lominy: Ruxolitinib is used in patients with high- or intermediate-risk myelofibrosis who are not candidates for transplant. Patients with any type of MPN can have a lot of symptoms that are associated with splenomegaly, which causes discomfort, or abnormal signaling of cytokine and includes night sweats, fever, and low appetite. There is very high symptom burden.

Ruxolitinib helps reduce the spleen size, leading to patients feeling more comfortable. It also is associated with a significant decrease in the symptom burden in those patients. Similarly, in polycythemia vera, we also saw a reduction in spleen size, less need for phlebotomy, and improvement in symptom burden [with the use of ruxolitinib].

How does fedratinib (Inrebic), the newest approved JAK1/2 inhibitor, compare with ruxolitinib?

The outcomes are very similar [between fedratinib and ruxolitinib] regarding the percentage of patients who had a reduction in spleen size. They use very similar primary and secondary endpoints in those clinical trials [looking at fedratinib and ruxolitinib].

There are some differences. Fedratinib is more selective for JAK2 and targets other tyrosine kinase, such as FLT3. After the [initial] publication of the clinical trial for fedratinib, there was a halt on the development of the drug because of unexpected adverse events (AEs) that they saw during the clinical trial, including encephalopathy. Despite the halt, fedratinib was approved in August 2019.

Some patients cannot tolerate ruxolitinib because they experience profound cytopenia. Even though you can have cytopenia with fedratinib, the thrombocytopenia was a little bit less [common]. Additionally, the encephalography makes [fedratinib] very difficult to use. It requires very close monitoring, including measuring thiamine levels.

How do you currently determine whether to give patients ruxolitinib or fedratinib?

The track record is with ruxolitinib right now, because we have more experience with giving it since it has been approved for a while. We have been using it in so many patients and we are very comfortable at changing the dosage if a patient experiences cytopenia. You can decrease the dose and patients can still derive some benefit from [ruxolitinib]. Given that track record, most people prefer to use ruxolitinib; however, if you look at the National Comprehensive Cancer Network guidelines, fedratinib is considered one of the options for patients with high-risk myelofibrosis.

How would you categorize the role of transplant in MPN treatment?

Transplant is the only curative treatment for patients with MPNs. Targeting JAK2 is only to manage symptoms and help make patients more comfortable. There is evidence that ruxolitinib also improves survival, but it does not have a good disease-modifying effect. Transplant is the curative treatment that we have for patients who have intermediate- to high-risk disease, depending on their age and comorbidities.

What is the current sequencing strategy with transplant, JAK inhibitors, and other options for patients with MPNs?

Depending on the risk level, if they are a transplant candidate, it's better to take them to transplant unless the other option is observation. There are patients who can be observed because they're asymptomatic. When they start developing symptoms, you don't want to delay transplant. Transplant will be the first option, and then you can give patients a JAK inhibitor if they experience relapse or progression.

Are there any emerging agents within MPNs?

Yes, there are a lot. We now understand a lot of the abnormal signals that happen in the hematopoietic stem cells that have the mutation. For example, there is this molecule alisertib, which is an Aurora kinase A inhibitor. When you inhibit Aurora kinase, then you can reverse some of the myelofibrosis that you see in the bone marrow. There was a phase I trial where investigators tested alisertib in a number of patients. Out of those patients, they saw a decrease in the spleen size and improvement in symptoms similar to what we see with the JAK2 inhibitors. Out of 7 patients, 5 of them had a decrease in the amount of fibrosis that they had in the bone marrow. That was very encouraging, and it showed that there is some pathway that can be targeted and may modify the disease course.

A phase II study is looking at the telomerase inhibitor telomeric oligonucleotide. Results showed some decrease in spleen size and symptoms. At the higher dose, there were a lot of benefits, and even the survival outcomes look much better than you would expect in that patient population.

There are also other pathways being targeted. There are some more JAK1/2 inhibitors that are more selective as we saw with fedratinib, but others are being tested. There are a lot of different pathways [dependent or independent of STAT downstream] that are being targeted and showing promising results. Some of these are being tested as single agents and others are being tested in combination with ruxolitinib.

What are some challenges within the MPN space?

One of the main challenges in MPNs is that older patients have comorbidities and the treatments are associated with toxicity. Managing these patients is very challenging. If we can find better targeted agents that patients can tolerate with fewer AEs, or if you can get inhibitors that are more selective and don’t affect other important pathways, treatment can be more tolerable. That will be very good because the number of patients who are candidates for curative allogeneic stem cell transplant is not high. Being able to manage them with drugs that are tolerable is very important.