Observational MOST Trial Reveals Progression Trends in Low-Risk Myelofibrosis

Findings from the prospective, observational MOST trial (NCT02953704) showed that 58.5% of patients with low- or intermediate-1–risk myelofibrosis enrolled in cohort A (n = 205) met at least 1 criterion for disease progression after a median follow-up of less than 53 months, which was a higher rate than investigators expected, according to Aaron Gerds, MD.

Cohort A included patients with low-risk or intermediate-1–risk disease, where patients were considered to have intermediate-1–risk myelofibrosis based on age only. Cohort B (n = 27) featured patients with intermediate-1–risk disease with other Dynamic International Prognostic Scoring System (DIPSS) risk factors beyond age.

Findings presented at the 2024 EHA Congress showed that of the 120 patients in cohort A who experienced disease progression, 64 (53.3%) met 1 criterion for progression, 27 (22.5%) met 2 criteria, and 29 (24.2%) met at least 3 disease progression criteria. The most common progression criteria met in cohort A included a hemoglobin level of less than 10 g/dL (47.5%) and a platelet count of less than 100 x 109/L (31.7%). For Cohort B, 25 patients (92.6%) met 1 progression criterion, 1 patient (3.7%) met 2 progression criteria, and 1 patient (3.7%) met 3 progression criteria.

“So many patients are progressing early on. This really is a call out to us taking care of these patients to do better [beyond] just careful observation and to develop new therapies that can modify that trajectory,” Gerds said.

In an interview with OncLive®, Gerds, an assistant professor of medicine, Hematology, and Medical Oncology, at Cleveland Clinic Taussig Cancer Institute in Ohio, elaborated on the significance of observing disease progression trends amongst patients with low-risk myelofibrosis, expanded on the findings from the observational MOST trial, and discusses the implications of the results.

OncLive: What challenges are associated with conducting clinical trials for patients with low-risk myelofibrosis, and how did MOST aim to address these challenges?

Gerds: The MOST study was a comprehensive, prospective, observational study in patients with not only low-risk myelofibrosis, but also those with essential thrombocythemia, looking at that spectrum of disease. If we look practically at MPNs [as a whole], essential thrombocythemia blends into myelofibrosis. The whole concept of essential thrombocythemia vs prefibrotic myelofibrosis vs overt myelofibrosis is an artificial construct in our minds to better organize information and different types of patients. Myelofibrosis and essential thrombocythemia are part of the spectrum of disease; therefore, it made sense to observationally look at patients with both low-risk myelofibrosis and essential thrombocythemia.

The whole concept [of the MOST trial] was to look at how often patients progress. How often do patients with essential thrombocythemia progress to myelofibrosis? What should we expect? Are there some telltale signs [of progression]? Similarly, with low-risk myelofibrosis, how often do patients progress into more high-risk disease? How quickly does that happen? The definitions of these [clinical distinctions] are changing over time.We can look back to 2016 when the concept of prefibrotic myelofibrosis was introduced with the updated WHO diagnostic classification system at the time. With that new information in mind, how do these [classifications] look going forward?

What was the design and methodology of the MOST study?

This was a prospective observational study that included patients with essential thrombocythemia and this group of patients with low-risk myelofibrosis who were included in the [EHA] abstract. This included [patients with] primary myelofibrosis, post– polycythemia vera, and post–essential thrombocythemia myelofibrosis who lacked any type of the risk factors we would normally identify through the DIPSS score, other than age being greater than 65. Patients who were not anemic, patients who didn't have a lot of circulating blasts, and patients who didn't have a lot of symptoms were included here. They had to have low DIPSS scores. Most of these patients, by the nature of their low-risk disease, had relatively good counts. Their hemoglobin [levels] were high, their platelet [counts] were good, and their spleens typically weren't very large. This was a group of patients with classic, low-risk myelofibrosis.

The analysis looked at the clinical, pathologic, and lab features to see signs that we could look for to predict progression to high-risk myelofibrosis, blast-phase disease, leukemic transformation, or potentially the development of transfusion [dependency] in the future. When we look at this group of patients, the nice thing about this prospective, observational study is getting that data prospectively [over the course of a long period of time]. The median follow-up was just under 53 months for this cohort.

The study was broken down into 2 different cohorts. Cohort A included patients who didn't have any risk factors. Cohort B [included] patients who ultimately had at least 1 or 2 DIPPS, risk factors. Although typically we were looking for patients who had low-risk myelofibrosis, a few patients with ‘high low-risk’ [disease] trickled in. Cohort B was a very small group of patients, [with] only 27 in total. Cohort A, which [included patients with] typical low-risk myelofibrosis, [consisted of] 205 patients.

What were the key findings regarding progression presented at the 2024 EHA Congress?

The surprising thing, with a median follow-up of under 53 months, 58.5% of the patients in cohort A—those with truly low-risk disease as defined by DIPPS—had some sort of progression. [This] was certainly surprising to me; I thought that [rate of patients who experienced progression] was really high. We talk about the median survival of patients with low-risk—as defined by DIPSS—myelofibrosis being so long. You think about this being measured in years as opposed to months. However, despite that, we saw a high number of patients progressing.

What was the most common form of progression observed?

The form of progression that was most common for these patients was the development of anemia, which is not too surprising. If we look at all patients with myelofibrosis, roughly 30% to 40% of patients will have anemia at the time of diagnosis, and upwards of 40% to 60% of patients over the first year after diagnosis will develop anemia. That was the most common [progression] criteria, indicating disease progression was the development of anemia over time. That is a really important point to make.

The fact that the median follow-up was [less than] 53 months and we're still seeing this degree of progression [means progression is] happening quickly. Many of these patients were progressing within the first year or so of enrolling on the trial. [Progression events] happened at a rate that is much higher than what I normally expect, and in a timeframe that was [faster] than I expected.

What are the implications of these findings?

When you see a patient with a new diagnosis of myelofibrosis, if even if they are low risk by the DIPPS score—I would even argue this would translate to other prognostic models as well—you don't want to say, 'Okay, you have low-risk, myelofibrosis, you're relatively asymptomatic; we'll check your blood counts and see in a year.’ [These patients] need to be followed closely because progression does happen early on. Quite a few of the progressions within the first year [included] the development of anemia that might need intervention. It's important to closely observe these patients, and in the same vein, start to develop therapies that can alter that course.

Are there any next steps for this research?

The logical next step with the MOST study is the fact that we collected a large number of blood and tissue samples for future analyses. [Eventually], we can take those samples and start to look at the differences between patients who progressed and [those who] didn't. [We can] look at the molecular markers, maybe other markers of inflammation, cytokine levels, and adhesion molecule factors [to see if] there are tests that we could potentially run in a patient with low-risk myelofibrosis that would predict for earlier progression rather than later [progression].

This will help in a couple of ways. One, [markers will help us] monitor patients very closely, and two, [markers could potentially help us] identify patients within the low-risk group who are high risk for progression. This could modify our view of one individual's risk to intervene and [conduct] trials to modify disease in those patients who would benefit the most. Can we identify other markers of progression other than the simple clinical variables that we have available today to better identify patients who would traditionally be low risk, but actually are high risk for progression?

Reference

1. Grunwald M, Gerds A, Agrawal, A et al. High rate of disease progression in patients with low-risk myelofibrosis (mf) enrolled in the prospective MOST study. Presented at: 2024 EHA Congress; June 5-14, 2024; Madrid, Spain. Abstract P1053.