Analyzing Predictive Biomarkers for Ruxolitinib Treatment in Myelofibrosis

At the Society of Hematologic Oncology 2025 Annual Meeting, CancerNetwork® spoke with Francesca Palandri, MD, PhD, an adjunct professor in the Department of Medical and Surgical Sciences at the University of Bologna in Bologna, Italy, about predictive markers for ruxolitinib (Jakafi) in myelofibrosis.

Of the many points discussed, she emphasized the clinical variables that are correlated with fewer responses and decreased overall survival. They include peripheral blast counts exceeding 5%, higher burden of disease, and the cytopenic phenotype.

Additionally, around 40% of patients who are administered ruxolitinib receive it at an underdose, likely to mitigate early hematological toxicities, but by doing so, the probability of spleen and symptom responses is much lower.

Transcript:

Over the last 15 years, we have gained a lot of knowledge about the clinical predictors of response to ruxolitinib. For example, there are some clinical variables, [such as] peripheral blast counts exceeding 5%, cytopenic phenotype, higher burden of a disease…of large splenomegaly, high total symptom score, or cytopenic phenotypes, in terms of transfusion-dependent anemia and platelet counts below 200 [µL]. It may be associated with a lower response rate, but it also decreases the overall survival [OS] and has a higher probability of early drug discontinuation.

This is a crucial point, but we also have some knowledge on how the doctors can make some decisions that are prognostically relevant. For example, we recently observed that, in a real-life context, over 40% of patients started ruxolitinib with a dose, which is an underdose compared with their baseline platelet counts. This decision to start with lower doses is possibly related to the concerns over an early hematological toxicity. However, for the patient to start ruxolitinib [as an] underdose, the probability of spleen and symptom responses is much lower. The rate of discontinuation of the drug is higher, and overall, the [OS] is decreased. That’s why it is very important to have an educational point recommending the use of the higher tolerated dose. We also got another insight that is doctor-related, which concerns the timing delay from the diagnosis of myelofibrosis to the start of ruxolitinib. For example, both in the real-world [ROMEI] study from Italy and in the prospective sub-cohort analysis of the [COMFORT-I (NCT00952289) and COMFORT-II (NCT00934544)] studies, we observed that if we delay the start of a treatment by more than 1 year, then the probability of response and the [OS] of a patient is decreased.1,2 That’s why a timely initiation of treatment could be a real prognostic marker in our hands.

But there are not only clinical factors. We are gaining more evidence about the impact of molecular evaluation and the importance of molecular [assessment], also in driving the therapeutic decisions. For example, we know from the [COMFORT-I and COMFORT-II studies] that if a patient has more than 1 high molecular risk mutation, then the probability of response, and the [OS] may be decreased. More recently, we are gaining evidence that an alteration in the [CBL]/RAS pathway may directly correlate with a lower probability of response. So far, I do not think that molecular evaluation may significantly decide whether to start ruxolitinib, but having a RAS/CBL mutation, for example, should [raise our alarm bells]. [We should] seek additional combinational or alternative therapies regarding ruxolitinib alone.

References

1. Breccia M, Palandri F, Martelli M, et al. Dosing and clinical outcomes of ruxolitinib in patients with myelofibrosis in a real-world setting: Interim results of the Italian observational study (ROMEI). Cancer. 2025;131(9):1642-1651. doi:10.1002/cncr.35801
2. Verstovsek S, Kiladjian JJ, Vannucchi AM, et al. Early intervention in myelofibrosis and impact on outcomes: A pooled analysis of the COMFORT-I and COMFORT-II studies. Cancer. 2023;129(11):1681-1690. doi:10.1002/cncr.34707