Understanding Predictive Markers Drives Ruxolitinib Usage in Myelofibrosis

According to Francesca Palandri, MD, PhD, ruxolitinib will have a less significant effect in patients with myelofibrosis who have a cytopenic phenotype.

For patients with myelofibrosis, ruxolitinib (Jakafi) has been a prominent therapy for over a decade, despite its variability in eliciting responses in all patients. At the Society of Hematologic Oncology 2025 Annual Meeting, Francesca Palandri, MD, PhD, presented on the predictive markers that can help a treating physician understand if a patient should receive ruxolitinib or not.¹

Some of the patient groups that Palandri noted as not being optimal recipients of ruxolitinib were those with a high percentage of blasts, a cytopenic phenotype, a high total symptom score, and a higher burden of disease. In these groups, the agent is associated with lower overall survival (OS) and response rates and a higher rate of early drug discontinuation.

Regarding dosages, she also emphasized that many patients often start ruxolitinib at an underdose. While this may occur due to a risk of early hematological toxicities, starting at a lower dose also decreases the probability of spleen and symptom responses.

As for next steps, Palandri hoped for a model that takes into account clinical and molecular parameters to best guide treatment decisions. She also noted that it will be important to consider the dynamics of the disease over time.

Palandri is an adjunct professor in the Department of Medical and Surgical Sciences at the University of Bologna in Bologna, Italy.

CancerNetwork®: What was the rationale for analyzing predictive biomarkers for ruxolitinib therapy in myelofibrosis?

We have been using ruxolitinib for nearly 15 years now, and this has proven clear superiority vs the [best available therapy]—for example, hydroxyurea and corticosteroids—in the control of splenomegaly symptoms. Still, the response rates vary [significantly], and we have 40% to 70% of the patients who will [progress on] ruxolitinib and discontinue the drug in 3 to 5 years. That’s why it is so important to assess predictors of response to orient our clinical decision strategy.

How might this analysis influence clinical practice?

Predictors of response, both in terms of clinical and molecular evaluation, do affect our clinical practice because we can select the best frontline JAK inhibitors for the treatment. For example, for a patient with a high percentage of blasts, ruxolitinib therapy may not be optimal. Also, for patients who have a cytopenic phenotype, ruxolitinib may not be the go-to option. On the other hand, we must learn how to deal with ruxolitinib dosing and how to be timely in our treatment decision to start ruxolitinib because this may have a prognostic implication. Also, the use of molecular data may orient not only the decision for transplantation but perhaps help to avoid ruxolitinib for patients with RAS/CBL mutations.

What are the most significant takeaways from your research?

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 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 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 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 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 have 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.^2,3 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] 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, 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 an alarm]. [We should] seek additional combinational or alternative therapies regarding ruxolitinib.

What additional research is necessary to identify the potential role of predictive markers in myelofibrosis?

What we need now is the integration of all the factors. We must work on clinical predictors based on the disease phenotype, we must work on the physician’s attitude, and [we must work to] stimulate the correct and timely usage of ruxolitinib. We also have to implement our knowledge of the biological characteristics of a disease. In the future, I hope that we can have an integrated model sharing clinical parameters and molecular parameters in order to guide our treatment decisions. There is one more thing to do, [and it is] to assess the dynamics of a disease over time. I do believe that, for example, the response to ruxolitinib after 6 months prognostic model, which was developed by Francesco Passamonti, MD, and recently integrated by the intermediate RR6 model, may be very important in evaluating the dynamics of a disease over the first 6 months of therapy and to isolate the patients who are predicted to have a poor prognosis. The implementation of molecular findings over time could be a step forward in our understanding of the disease and in improving and optimizing the management of myelofibrosis.

References

1. Palandri F. Predictive markers for ruxolitinib in MF. Presented at the Society of Hematologic Oncology 2025 Annual Meeting; September 3-6, 2025; Houston, TX.
2. 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
3. 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