Ruxolitinib Extends MF Survival, Improves Quality of Life

Srdan Verstovsek, MD, PhD

It has been nearly a decade since the FDA approved ruxolitinib (Jakafi) for the treatment of adult patients with intermediate-or high-risk myelofibrosis (MF) based on data from the phase 3 COMFORT trials. Data from the last decade has found that ruxolitinib greatly improves survival and quality-of-life for those with MF.

Investigators used data from the Medicare Fee-for-Service claims database (Parts A/B/D) from January 2010 to December 2017 to determine the effect of ruxolitinib on MF. Patients included in the analysis were 65 years old or older, with 1 or more inpatient claims, 2 or more outpatient claims, and a documented MF diagnosis. Patients with evidence of an MF diagnosis less than 12 months before the index date were excluded. Patients with evidence of myelodysplastic syndrome, hematologic malignancies, or solid tumors less than a year before were not eligible to participate.

Participants were then split into 3 groups. Group 1 included patients who were diagnosed with MF pre ruxolitinib approval. Group 2 was made up of patients who were diagnosed with MF post ruxolitinib approval but were unexposed to the patient. Group 3 were patients who were diagnosed with MF after approval and were exposed to ruxolitinib.

The median age of the eligible patients was 78 years old, 39.8% were male, and 84.1% were white. Group 1 included 278 patients with a median follow-up of 12.5 months, group 2 included 1127 patients with a median follow-up of 10.2 months, and group 3 included 272 patients with a median follow-up of 14.0 months.

Group 1 had a valid death date rate of 42.8% while group 2 and group 3 had a valid death date rate of 33.9% and 19.9% respectively. The 1-year survival rate of group 1 was 55.6%. Group 2 had a 1-year survival rate of 69.5% and group 3 had a 1-year survival rate of 75.2%. Additionally, those who were diagnosed after the approval of ruxolitinib had a lower risk of mortality compared to those who were diagnosed before.

In an interview with Targeted Oncology, Srdan Verstovsek, MD, PhD, a professor, Department of Leukemia, Division of Cancer Medicine, director, Hanns A. Pielenz Clinical Research Center for Myeloproliferative Neoplasms, and chief, Section for Myeloproliferative Neoplasms, Department of Leukemia at the University of Texas MD Anderson Cancer Center, discussed the impact of ruxolitinib on MF and other issues facing the patient population. 

TARGETED ONCOLOGY: What survival outcomes were historically seen with ruxolitinib in the general population of patients with MF?

VERSTOVSEK: MF is one of the worst myeloproliferative neoplasms. These are chronic conditions of the bone marrow where cells grow without control. But in myelofibrosis, the fibrosis happens and limits the growth of the cells. Therefore most of the patients eventually have anemia and thrombocytopenia as problems to deal with. As a reaction to failing bone marrow function, they have a very big spleen. Having a big spleen and liver means having a bad quality of life. All these problems, leading to untimely death, usually 5 to 7 years on average.

What we know from studies with the ruxolitinib is that it can actually prolong life for about 3 years on average compared to patients who are not exposed to the agent at all. That information came from analysis of the studies that led to its approval, so called COMFORT studies. COMFORT-1 (NCT00952289) and COMFORT-2 (NCT00934544). The claim for a survival benefit was actually recognized by the FDA, and the label for its use in the United States was modified in 2014 to account for it. Now, this was not very well supported by any other analysis until now. We have an analysis done in a specific database presented during the 2020 ASH Meeting. The analysis is of data from the Medicare fee for service claims database in the United States from January 2010 to December 2017. Patients hadintermediate- or higher-risk MF, were older than 65 years of age, and had at least 2 claims for a documented MFdiagnosis were analyzed for their outcome.

Among the eligible patients with MF based on these characteristics, which was about 1600, we analyzed those that had a decent follow up, and exposure or non exposure to ruxolitinib. In this setting, patients that were exposed to ruxolitinib after approval of ruxolitinib had a longer survival than patients that were not exposed to ruxolitinib. In addition, I would say that the analysis showed that the care for the patients in general improved over time because patients in later years had a better outcome than the patients in earlier years. So, ruxolitinib gave this extra kick and prolonged their life for a number of extra years. That is indirect but very solid data that sheds light on that claim for a survival benefit. It appears to be a real and throughout analysis of just the common practice, exposure to ruxolitinib leads a longer survival.

TARGETED ONCOLOGY: How do you think these data will impact practice in clinical settings?

VERSTOVSEK: The real benefits in every practice that count for its use are improving quality-of-life and decrease in spleen size. With a longer-term follow up as we described, you can see that prolongation of life and it was questionable because the study so far did not really have the primary aim to prolong survival. This is was discovered during a post hoc analysis. There is some worry about people not really endorsing that benefit. The data that we prsented at ASH 2020 should certainly move the mind of the treating doctors in a community setting from focusing just on a quality-of-life and a degree of a spleen reduction to prolongation of life. In fact, our understanding of that benefit will, I hope, lead to better improvement in the spleen response. The spleen response may be the one to emphasize more because in other studies published so far, the degree of spleen reduction actually correlates very well with the prolongation of life. So, in other words, moving from improving quality-of-life, which is very valuable to moving to control the spleen size in a safe way during the first 6 months of therapy may eventually lead to prolongation of life. I think these data will enhance understanding of that benefit and I hope it will improve the management of patients.

TARGETED ONCOLOGY: Are there any next steps with this research maybe on the safety front with confirming those data from the COMFORT studies?

VERSTOVSEK: The safety is always paramount for its use. Initially, we all know that myelosuppression, decrease of red blood cells and platelets, is something to deal with and requires some engagement on the part of the treating doctor to adjust the dose of ruxolitinib to account for that undesirable effect of anemia and thrombocytopenia. However, to connect to previous comments on the need for control of the spleen, one needs to find a balance between the desirable effect on quality-of-life and maximum effort on the spleen in a safe way, meaning not to cause too much anemia or thrombocytopenia. That balance between the spleen and anemia or thrombocytopenia needs to be optimized to get that spleen under control to get that survival benefit.

Other long-term side effects are rare. We already know about occasional opportunistic infections that happen. And now more recently, about six months ago, there was a publication from a long-term follow up of patients with polycythemia vera (PV) that were previously exposed to hydroxyurea as a cytotoxic agent that is usually used for therapy of PV, we learn about increased risk of non-melanoma skin cancer possibly. This is something to perhaps evaluate in the patients with MF over a long period of time as well. I don't have much concern over a long-term period for patients treated with ruxolitinib.

TARGETED ONCOLOGY: What other settings is ruxolitinib being explored in right now and where is it showing promise?

VERSTOVSEK: As many know, ruxolitinib is already approved as a second-line agent for hydroxyurea-refractory disease in intolerance patients. We have some new findings as well on its use again in PV. But a utility of ruxolitinib in MPNs is also noted in essential thrombocythemia (ET). Although not approved, there are studies and observational studies, not just the sponsored studies perspective by the maker of ruxolitinib, but also by academic physicians to really position ruxolitinib in the setting of ET. Remember, these patients have a high platelet count. They may, in the advanced setting, have a bad quality-of-life and a large spleen. These are the characteristics certainly that can be controlled and improved with ruxolitinib. Outside of MPNs, ruxolitinib is being used and is approved in graft-versus-host disease after transplant. It's being explored in the combination with other agents in more aggressive forms of MPNs accelerated in the ballistic phase where it's used for quality-of-life influence specifically. This is endorsed because these patients don't do well in that particular aspect either.

_REFERENCE:

_{Verstovsek S, Parasuraman S,Yu J, et al. Real-world survival among patients with intermediate- to high-risk myelofibrosis in the United States: Impact of ruxolitinib approval. Blood. 2020; 136 (Suppl 1): 46-47. doi: 10.1182/blood-2020-140820}