MAJIC-PV Study Indicates Ruxolitinib Treatment Yields Superior Responses for Patients With Polycythemia Vera
Claire Harrison, MD, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom, presented results from the phase 2 MAGIC-PV trial, which indicated that ruxolitinib treatment yielded superior event-free survival, complete response, molecular response, and overall durable responses compared with best available therapy for patients with hydroxycarbamide-intolerant polycythemia vera (PV).
This study also demonstrated first-time results that molecular response is linked to event-free survival, progression-free survival, and overall survival.
Transcript:
Hello, my name is Claire Harrison. I'm a hematologist from Guy's and St. Thomas' Hospital in London. I'm here today to talk about a recent study [that] we have presented and published called MAJIC-PV.
This is a study involving patients with polycythemia vera, which is a relatively rare blood cancer characterized by mutations in [Janus kinase 2] (JAK2), predisposition to thrombosis, hemorrhage, and transformation to myelofibrosis and early death. Treatment is focused on reducing thrombotic risk, and no current treatments have been shown to prolong life for patients or affect disease-free survival. Thus, no benefit has been demonstrated either for measuring minimal residual disease by quantifying JAK2 mutation levels.
Resistance or intolerance to first-line therapy with drugs such as hydroxyurea or hydroxycarbamide is the setting in which ruxolitinib has been approved. This is a JAK1 and 2 inhibitor. The trials from which ruxolitinib gained approval involved [a] crossover of patients from a control arm after a short period of time, and therefore the effect of this drug on longer events, such as those already mentioned, has not been measured.
This was the aim of the MAJIC-PV study. Here, we recruited 180 patients from across the UK who met criteria for resistance or intolerance to hydroxycarbamide and had a diagnosis of polycythemia vera. Patients were randomly allocated in an open-label fashion to either ruxolitinib at standard dosing, or best available therapy. Patients were broadly balanced across baseline demographics.
This paper presented the 5-year results from the study, and in brief, the results are as follows. We showed, as is already known, that ruxolitinib was superior to standard therapies for controlling blood counts, spleen size, and symptoms, but that this control was durable over the 5-year period, and much more durable than was seen for those patients treated with best available therapy who did respond. We also saw that time to discontinuation of treatment was superior for ruxolitinib.
However, there were several important novel findings from this study. First, ruxolitinib prolonged event-free survival, where [the] event was thrombosis, hemorrhage, transformation, or death. We also saw, among those events, that thrombosis-free survival was superior for patients treated with ruxolitinib.
For PV patients, controlling the hematocrit has been well-documented, but controlling all parameters of the blood count has always been a little bit controversial. In this study, we also showed that controlling all parameters of the blood count, regardless of therapy, was also associated with event-free survival.
Finally, we also had some pre-embedded molecular marker analysis, measuring both the JAK2 variant allele frequency at various time points during the study, but also the impact of additional non-driver mutations.
This work has demonstrated, for the first time, prospectively that reducing the JAK2 [variant allele frequency] (VAF) by a modest amount, 50%, leads to prolonged overall survival, progression-free survival, as well as event-free survival. We were also able to show with single-cell analysis that these changes that we were seeing in the peripheral blood were reflected with profound changes in the stem cell population bearing JAK2 mutations, effectively suggesting that ruxolitinib was affecting the stem cell pool and modifying disease.
Additional driver mutations were associated with worse event-free survival and less chance of obtaining a molecular response. Amongst those, SXR1 mutations were particularly poor.
In this study, we were also able to focus on adverse events of specific interest that have already arisen with ruxolitinib, including infections and squamous cell skin cancers, and overall there were no new safety signals.
In summary, this study confirms that it is necessary to do long-term studies in chronic diseases, which isn't a surprise. We have led by analyzing these results to several important insights in the field. One, ruxolitinib delivers event-free survival, not just control of the blood count. Controlling the blood count by whichever means also results in better event-free survival, so clinicians should be focusing on that for their patients.
The study points to the first time the value in measuring the JAK2 variant allele frequency, or VAF, and using this as a way of monitoring disease, although whether this is integrated in the long term will require validation in future studies. Thank you.
Source:
Harrison C, Nangalia J, Boucher R, et al. Ruxolitinib versus best available therapy for polycythemia vera intolerant or resistant to hydroxycarbamide in a randomized trial. J Clin Oncol. Published May 01, 2023. doi: 10.1200/JCO.22.01935