Summarized in this article are recommendations from a Canadian Myeloproliferative Neoplasms (MPNs) Group consensus statement on the recognition and management of patients with ruxolitinib failure occurring in the setting of myelofibrosis. These recommendations were published in JCO Oncology Practice.
Primary myelofibosis is a type of Philadelphia chromosome-negative MPN that is associated with the buildup of scar tissue in the bone marrow, and often characterized by splenomegaly. Myelofibrosis can also occur following progression of polycythemia vera and essential thrombocythemia.
Although the JAK inhibitor, ruxolitinib, is approved for the treatment of patients with myelofibrosis, this is neither a curative approach nor one associated with a complete or partial response. Patients with this disease can experience ruxolitinib failure due to multiple underlying causes related to the development of either drug resistance or drug intolerance. Moreover, subsequent treatment options for these patients are not well defined, and prognosis is poor following ruxolitinib failure.
To address this practice gap, the Canadian MPN Group has developed an algorithm-based approach to facilitate both the early recognition and subsequent management of patients with myelofibrosis experiencing different types of ruxolitinib failure patterns. Four main ruxolitinib failure patterns were identified:
1. A suboptimal spleen response (ie, <25% reduction in spleen size) or loss of spleen response (ie, spleen size ≥50% from best response) in patients who are not responsive to or able to receive an increase in ruxolitinib dose.
2. Refractory transfusion-dependent anemia after 24 weeks of ruxolitinib without signs of bleeding or other causes in patients who do not respond to a ruxolitinib dose reduction.
3. Patients with severe thrombocytopenia do not respond to a reduction in ruxolitinib dose.
4. Disease transforms to an accelerated or blast phase.
The recommended management approach for patients exhibiting ruxolitinib failure patterns 1, 2, or 3 is to consider hematopoietic cell transplantation (HCT) if criteria for transplant eligibility are met.
Approaches for those with ruxolitinib failure pattern 1 who are ineligible for HCT include enrollment in a clinical trial evaluating an alternative JAK inhibitor, such as fedratinib, or other agents that do not target the JAK/STAT pathway.
Consideration of clinical trial enrollment is also recommended for patients with ruxolitinib failure patterns 2 and 3 who were not candidates for HCT. Furthermore, supportive care measures directed toward the clinical manifestations of the disease, as well as consideration of splenectomy are also recommended for those ineligible for clinical trial enrollment in the setting of ruxolitinib failure patterns 1, 2, and 3.
For those experiencing disease transformation to an accelerated or blast phase who are candidates for HCT, initiation of treatment with a hypomethylating agent is recommended unless a transplant donor is readily available. In the latter case scenario, either acute myeloid leukemia-type induction therapy if <5% blasts followed by HCT or clinical trial enrollment if blasts >5% is recommended.
For those patients not considered candidates for HCT, cytoreduction is recommended if progressive leukocytosis is present, whereas molecular profiling followed by targeted therapy or clinical trial enrollment and hypomethylating therapy are considered options for those without progressive leukocytosis.
In summarizing these recommendations, the authors of the consensus statement noted that “the outcome of patients in whom ruxolitinib treatment fails is heterogenous and depends on the cause of failure. It is important to recognize the pattern of ruxolitinib failure, because treatment will depend predominantly on the cause.”
Gupta V, Cerquozzi S, Foltz L, et al. Patterns of ruxolitinib therapy failure and its management in myelofibrosis: perspectives of the Canadian Myeloproliferative Neoplasm Group [published online March 5, 2020]. JCO Oncol Pract. doi:10.1200/JOP.19.00506