Case Series of Potential Wernicke's Encephalopathy in Patients Treated with Fedratinib

Introduction:

In the phase III study, JAKARTA I, the JAK2 inhibitor, fedratinib, elicited responses in 47% (400mg) and 50% (500mg) of patients with intermediate 2 or high risk myelofibrosis (MF). In JAKARTA II, 53% of MF patients who were resistant and 63% of patients who were intolerant to ruxolitinib responded to fedratinib, indicative of clinical benefit for the majority of patients not responding to standard therapy. Fedratinib development was discontinued after the FDA placed a clinical hold on November 15, 2013 as a result of neurological symptoms, suggestive of Wernicke's encephalopathy (WE) in 8 of 670 subjects, exposed to fedratinib.

WE develops in the setting of thiamine deficiency and is typified by diplopia, ataxia, confusion and characteristic brain MRI findings. Confirming a diagnosis of WE is complicated by comorbidities in patients with myeloproliferative neoplasms (MPN) including a high incidence of stroke, hepatic encephalopathy secondary to hepatic extramedullary hematopoiesis or sepsis related to marrow failure in an elderly population. While autopsy studies indicate that rates of WE range from 0.8-2.8% of the general population, the incidence in MPN patients is reportedly 3-fold higher. WE can be diagnosed based on clinical signs and specific MRI findings; prevented by ensuring that nutritional status is not exacerbated by nausea and vomiting; and treated with thiamine.

To evaluate the epidemiology of potential WE subjects treated with fedratinib, we conducted a retrospective analysis of the 8 fedratinib-treated subjects. Patient demographics, clinical signs together with thiamine levels, when available, and MRI scans were evaluated to determine the likelihood of WE and elucidate contributory factors by an independent expert panel.

Results:

Eight patients (1 male, 7 females) from 7 countries and 5 fedratinib trials were identified. Median age was 69.1 years (IQR 67-71). Of these patients, 6 had MF, 1 had polycythemia vera and 1 had metastatic head and neck cancer. Based on retrospective analysis of clinical reports, thiamine levels and MRI results the data was either inconclusive or not supportive of WE in three patients, one of which likely had hepatic encephalopathy. Of the remaining 5 patients, 1 clearly had WE, 2 likely had WE, and 2 had inconclusive diagnosis. All potential WE patients had preceding protracted nausea and vomiting suggesting this as a contributing factor to malnutrition and thiamine deficiency.

Concerning the 3 subjects thought to have WE: one was severely malnourished and refused gastrostomy during study suggesting malnutrition as a cause of thiamine deficiency. The two other likely WE patients had preceding sustained nausea and vomiting with recovery from neurological deficits while continuing fedratinib treatment suggesting fedratinib did not inhibit thiamine uptake. Consistent with that, mean patient thiamine levels from 161 patients available at end of treatment were normal and in vitro experiments in the presence of human serum show fedratinib at physiologically achievable levels does not inhibit thiamine transport.

The two other patients that may have had WE had preceding nausea and vomiting; one developed neurological symptoms while not on drug and the other developed disseminated metastases, including an edematous brain metastases, preceding neurological symptoms confounding the diagnosis.

Conclusion:

Across 9 fedratinib trials enrolling 670 MPN or solid tumor patients between 3 to 5 patients experienced WE (0.4-0.7%). The overall prevalence of WE observed was less than published levels for a patient population of this size. For the 5 potential WE patients, one subject had malnutrition related to protracted nausea and vomiting as well as clinical signs and MRI findings consistent with WE. Additionally, 2 other subjects likely experienced WE, both of which recovered without a dose interruption suggesting fedratinib does not inhibit thiamine absorption. The remaining 2 had an unclear diagnosis with 2 of 3 experts believing the data were either inconclusive or not supportive of WE. Notably, one of the patients was not on fedratinib at the time of neurological symptoms. In total, these data suggest that fedratinib does not increase the risk of thiamine deficiency beyond its potential to exacerbate malnutrition through poor management of preventable GI adverse events.