Combinations of JAK inhibitors and novel agents, such as epigenetic regulators, could help prolong survival in patients with myeloproliferative neoplasms.
Combinations of JAK inhibitors and novel agents, such as epigenetic regulators, could help prolong survival in patients with myeloproliferative neoplasms (MPNs), providing patients with more than a reduction in spleen size and symptomatic relief, explained Shella Saint Fleur-Lominy, MD, PhD, who added that for patients who have already progressed on ruxolitinib (Jakafi), fedratinib (Inrebic), momelotinib, and pacritinib could be potential second-line options.
“A lot of these agents will probably be used in combination with ruxolitinib for the most optimal response. It’s very promising to see all those different agents emerge that have an effect on disease outcome and modulation of the bone marrow,” said Saint Fleur-Lominy. “For every symptomatic patient who gets diagnosed with myelofibrosis, polycythemia vera [PV], or essential thrombocythemia [ET], we need to determine if they’re a candidate for a clinical trial, because that’s how we advance the treatment landscape.”
In an interview with Oncology Nursing News' sister publication, OncLive® during a 2020 Institutional Perspectives in Cancer webinar on hematologic malignancies, Saint Fleur-Lominy, an assistant professor, Department of Medicine, at NYU Langone Health’s Perlmutter Cancer Center, discussed the current landscape of MPNs and the importance of addressing disease burden and progression.
OncLive: What are some pathways apart from JAK that are involved in disease modulation that could become potential targets in MPNs?
Saint Fleur-Lominy: Downstream of JAK, there are STAT dependent and independent pathways that are involved in disease modulation. A number of newer agents target those signals downstream of JAK. For example, there’s the oral kinase inhibitor alisertib, which is downstream of cNeT, which is downstream of JAK. It’s one of the molecules that is upregulated in this disease. The phase 1 study was very small, but when they analyzed bone marrow samples pre- and posttreatment, they saw that there was improvement in the degree of fibrosis, and preclinical data showed the same thing.
Other agents include epigenetic regulators. We have an ALS21 inhibitor. We have BT inhibitors. One was studied in combination with ruxolitinib in [JAK-inhibitor naïve patients] and patients who didn’t have a good response to ruxolitinib. One of the themes among these different agents is that that they modulate the disease. One of the key findings, particularly for the LSD1 inhibitor was that the bone marrow fibrosis and variant allele frequency was reduced significantly. Those diseases don’t just have the JAK mutation, they have a lot of other genes that could be mutated and that have [an effect on] survival, disease progression, and response to treatment. Having drugs that target those repeated clones is very significant. There’s also a telomerase inhibitor, and there is a phase 3 trial that is being planned.
What are some common complications of patients with MPNs that are being evaluated in studies?
Patients can have thrombotic events like clots, and we see that across the different subtypes of PV, ET, and myelofibrosis. Patients who have a low level of fibrosis can have those complications. It doesn’t matter how much fibrosis you have in the bone marrow. The risk is usually lower in younger people, but as you age, you see [patients at greater] risk.
There is also a risk of bleeding events as well, especially in ET when people have a very high platelet count. There is also a risk of leukemic transformation because MPN is a disease that has mutations in hematopoietic stem cells, and those stem cells can transform [and] acquire new high-risk mutations and other chromosomal abnormalities and transform into acute leukemia.
In terms of symptom burden, a very large study looked at the symptomatic manifestation of MPNs [and found that] the burden is really high. Approximately 80% of patients have a really high symptomatic burden, [ranging] from fatigue to other symptoms like reduced appetite, early satiety because of big spleen, or the big spleen causing abdominal discomfort. As high as 60% of patients have abdominal discomfort, or early satiety. Up to 80% of patients reported fatigue.
Other symptoms like itching and night sweats [were also common]. Itching you see more with PV. Weight loss, fever, and bone pain [are additional symptoms that patients may experience]. The severity varies, so some patients have mild symptoms, and some patients have more severe symptoms. The main thing is that patients with MPNs have a very high symptomatic burden. That’s one of the reasons [a lot of studies] evaluating drugs in this disease usually use spleen reduction size and symptomatic relief as end points.
What mutations are of the most interest in patients with PV, ET, and myelofibrosis?
One of the most common mutations is JAK2. These are diseases of abnormal JAK signaling. About 95% of patients with PV have the classic JAK2 V617F mutation, and the rest usually have [a JAK exon 12 or exon 14 mutation]. The JAK V617F mutation is found in up to 60% of patients with ET or myelofibrosis. MPL and CALR mutations are found in up to 30% [of patients].
How do the data with ruxolitinib and fedratinib stack up against each other?
Ruxolitinib was the first JAK inhibitor that was approved for the treatment of higher-risk myelofibrosis, and then later on was approved for the treatment of patients with PV who are intolerant to hydroxyurea or have not responded to hydroxyurea and are symptomatic.
[The end point that was evaluated in the pivotal trial] in myelofibrosis was reduction of spleen volume and symptomatic relief. The COMFORT-I and COMFORT-II trials were both randomized controlled trials. The COMFORT-I trial had a placebo [control] and the COMFORT-II trial had best available therapy [as the control]. Both of these studies also had significant crossover. Once the investigators realized that ruxolitinib [led to a significant improvement in] patient outcomes and symptom relief, and that there was a signal for overall survival [OS], [patients were] allowed crossover [to receive ruxolitinib]. In COMFORT-II, there wasn’t really a significant [improvement in] OS, but the crossover [probably] affected that.
In terms of PV, patients were higher risk and were not responding to hydroxyurea or were intolerant to hydroxyurea. These patients were phlebotomy dependent. A significant number of patients achieved phlebotomy independence and had a reduction in spleen volume and symptoms.
Fedratinib [Inrebic] is a selective JAK2 inhibitor compared with ruxolitinib, which is a JAK1/2 inhibitor. The thought is that [fedratinib] will be better tolerated than [ruxolitinib. When the investigators did the randomized placebo-controlled trial for fedratinib, they evaluated 2 different doses of fedratinib. At the higher dose, they saw a rare but serious complication of Wernicke encephalopathy. Because of that, we’re using the lower dose of 400 [mg].
In terms of the decrease in spleen size and symptoms, there didn’t seem to be a difference between the 400 [-mg] and the 500 [-mg] dose. Therefore, it makes sense that the 400 [-mg dose] is the one that we’re using. [Although fedratinib] results in less thrombocytopenia, ruxolitinib is the go-to drug for patients who can tolerate it. You can still use fedratinib post-ruxolitinib, but I don’t know about the reverse [sequence].
Do the data with momelotinib provide any insight into whether it should be used in the JAK inhibitor—naïve or post-ruxolitinib setting?
We saw updated data [for momelotinib from the SIMPLIFY-1 and -2 studies] at the 2020 ASH Annual Meeting and Exposition. [Momelotinib] inhibits JAK1/2 and Activin receptor 1. One of the studies was a noninferiority study that randomized JAK-inhibitor naïve patients to ruxolitinib or momelotinib. The outcome was about the same. The other study was designed to be a superiority trial that was against best available therapy in patients who were post-ruxolitinib. The primary end point was clinical response rate, and it met the end point. [We also saw an improvement in] the total symptom scores and transfusion independence. The sustained responses and the survival benefit [for momelotinib] makes it a very promising [agent], especially for patients post-ruxolitinib compared with best available therapy.
A lot of those patients are older, and they may not be candidates for transplant. Therefore, having something that can prolong survival and make them feel better, post-ruxolitinib, is really important. When you withdraw ruxolitinib, patients can have symptoms rebound, which also seems to have an effect on survival, so if you have another JAK inhibitor that can keep them going, that’s very helpful. I’m hopeful for momelotinib and pacritinib.