JAK Inhibition Continues to Push Progress in Myelofibrosis

Ruben Mesa, MD

With fedratinib (Inrebic) joining ruxolitinib (Jakafi) in the myelofibrosis armamentarium following its FDA approval in August 2019, physicians now have an additional treatment option and a second-line therapy should patients have a suboptimal response to frontline ruxolitinib, explained Ruben Mesa, MD.

The approval of fedratinib was based on the phase III JAKARTA study, which found that patients with primary or secondary myelofibrosis achieved a significant reduction in splenomegaly and symptom burden with the JAK inhibitor.¹

An analysis of the JAKARTA and JAKARTA-2 trials, the latter of which evaluated fedratinib as a second-line therapy following ruxolitinib, was presented during the 2019 SOHO Annual Meeting. Results showed that patients with low platelet counts achieved splenic response and a reduction in symptom burden regardless of whether they received fedratinib upfront or as a salvage therapy following ruxolitinib.²

"Now that we have a second agent available that can be given at full dose to patients above 50,000 platelets, a clear benefit is [we have] second-line therapy,” said Mesa, the director of the Mays Cancer Center at UT Health San Antonio MD Anderson Cancer Center. “Additionally, as we've seen an increased number of [treatment] options develop in multiple hematologic malignancies, the ability to have additional agents approved for patients with myeloproliferative neoplasms is really a positive occurrence for all involved."

In an interview with OncLive during the 2019 SOHO Annual Meeting, Mesa discussed the JAKARTA and JAKARTA-2 studies and the implications their data have on the field of myelofibrosis.

OncLive: Could you provide an overview of the JAKARTA and JAKARTA-2 studies?

Mesa: We did an analysis specifically looking at patents enrolled in 2 studies that had baseline thrombocytopenia, between 50,000 to 100,000 platelets: the JAKARTA study, which was a randomized study of placebo versus fedratinib, as well as the JAKARTA-2 study, which was a second-line study [in patients who have progressed on] ruxolitinib.

We found that there was similar efficacy [with fedratinib] as related to assessment of splenomegaly improvement and improvement in symptoms [burden], whether they have thrombocytopenia or not at the 400-mg dose level, which is the FDA-approved dose. This is impactful because the number of options for patients with thrombocytopenia and myelofibrosis are relatively limited. Additionally, we found a similar safety signal as it relates to risk of bleeding or other difficulties. All of that is very encouraging and timely as physicians can now prescribe [fedratinib] for their patients, if appropriate.

In your practice, has the recent approval of fedratinib impacted your decision to use ruxolitinib in patients with myelofibrosis?

Ruxolitinib has been our approved frontline therapy of choice for several years. With the approval of fedratinib, the most immediate impact is for individuals who have not had an optimal response to ruxolitinib, or have lost their response and now might benefit from a change to a different agent.

As things evolve in terms of frontline therapy, there is no head-to-head data between fedratinib and ruxolitinib. They both had very positive phase III studies; there are slightly different toxicity profiles that have to be considered. Going forward, there are additional subsets [of patients who] perhaps benefit from fedratinib as it relates to those with significant splenomegaly, more advanced fibrosis, or things of that nature. Over time, we will find the niches for each agent as frontline therapy. [We will probably obtain it] more clearly as greater experience is gathered with the actual prescribing of fedratinib, and its likely immediate utilization in the second-line setting.

What differences are there in adverse events (AEs) between ruxolitinib and fedratinib?

Both drugs can cause cytopenia, anemia, and thrombocytopenia; perhaps there are differences between them that we will find out over time. With ruxolitinib, we've learned some things about the duration of the time we've been using the drug, such as increased rates of non-melanoma skin cancers, certain infections, and herpes zoster infection.

Given the arch of the development for fedratinib, we don't know whether these [agents] are similar, but it may have something to do with the duration of time we've used the agent. Fedratinib has a couple additional toxicities we need to be mindful of; it causes some gastrointestinal disturbances. In the studies, pretreating patients with some anti-nausea and anti-diarrheal medications seem to aggregate that to a significant degree and did not end up being a major issue [in trials], but it is something to be aware of.

Most importantly, there is a Black Box warning around a rare but important potential AE of fedratinib. Eight of the 900 patients treated with fedratinib in prior large clinical trials had some sort of encephalopathy, whether that was Wernicke or something else is the subject of much debate.

Regardless, the FDA has put a Black Box warning to try to mitigate that. Seven of those 8 individuals received a higher dose than the current FDA-approved dose at 500 mg daily of fedratinib; the prescribed level now is 400 mg. That might take care of things.

The Black Box warning also advises physicians to measure thiamine levels in patients pretherapy. If patients are deficient, they must have replacement of vitamin before they begin. Hopefully—between an abundance of caution, lower dose, checking thiamine, and giving thyme—we won't see [encephalopathy] manifest as an actual AE patients experience.

What advice do you have for community oncologists who are using these 2 JAK inhibitors?

Having a second option is a big plus in many ways. It opens the door to additional therapies over time. They are different compounds, though they are in the same class. In other related myeloid disorders, such as chronic myeloid leukemia, myelodysplastic syndromes, and acute myeloid leukemia, we benefited from having more than one option.

The way [having a second therapy] impacts patients most clearly is in patients with myelofibrosis who are already on therapy. Before, patients who had a suboptimal response did not had a lot of options if they weren't willing to travel for clinical trials. The availability of an agent that has clear data in the second-line setting and is prescriptible is a major advance. For newly diagnosed patients going forward, we will continue to be looking at all of these data, as well as gather additional subset analysis from molecular studies and profiling to see where the natural niche for each agent is.

What are your thoughts on the special considerations in the National Comprehensive Cancer Network (NCCN) guidelines for the use of JAK inhibitors?

I was involved in the initial development of the NCCN guidelines. The special considerations are there to hopefully help guide physicians in their utilization of the agents. [The guidelines] will probably be amended now with the approval of an additional agent, as well as additional considerations. They are meant to provide some guidance, and some things have not been mentioned yet. For example, how does one transition off of a JAK inhibitor, if that is necessary? Over time, it's been found that abruptly stopping a JAK inhibitor is probably suboptimal. It is better to ween [the patient] off because they can have a rebound effect in terms of their spleen or symptoms.

Another issue that will clearly arise, of which there is no literature, is how one transitions from ruxolitinib to fedratinib if an individual has a suboptimal response. In the absence of prospective data, which does not exist, as long as there is not a gap between the two, the patient would be safe switching from one medication to the other.

How have these data already impacted myelofibrosis treatment?

The most immediate implications are that an individual with baseline thrombocytopenia is traditionally given ruxolitinib at a reduced dose based on the degree of thrombocytopenia and some concerns regarding safety. A full dose of fedratinib in that group of patients suggests that is certainly an option for consideration in the second-line setting. However, based on the data, it would be a reasonable consideration in the frontline setting if someone has baseline thrombocytopenia in that 50,000 to 100,000 [platelet] range.

References

1. U.S. FDA Approves INREBIC^® (Fedratinib) as First New Treatment in Nearly a Decade for Patients With Myelofibrosis. Celgene Corporation. Published August 16, 2019. https://bit.ly/2ZbYLjH. Accessed August 16, 2019.
2. Harrison C, Schaap N, Vannucchi A, et al. Fedratinib induces spleen responses and reduces symptom burden as first-line or salvage therapy in patients with myeloproliferative neoplasm-associated intermediate- or high-risk myelofibrosis (MF) and low platelet counts. Clin Lymph Myel and Leuk. 2019;19:S355. doi: 10.1016/j.clml.2019.07.374.