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Analysis shows ‘no clear signal’ linking fedratinib to Wernicke’s encephalopathy in myeloproliferative neoplasms
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ATLANTA — Incidence of Wernicke’s encephalopathy appeared quite low among patients with myeloproliferative neoplasms treated with fedratinib, according to study results presented at ASH Annual Meeting and Exposition.
An analysis of nine trials that included 877 patients with myeloproliferative neoplasms or solid tumors treated with fedratinib (Impact Biomedicines) showed there were one to three patients (0.1% to 0.4%) with suspected Wernicke’s encephalopathy, a neurological disorder that develops in the setting of thiamine deficiency.
Only one patient had clinical signs and MRI findings that supported the diagnosis of Wernicke’s encephalopathy. The observed prevalence was less than previously published levels for a patient population of similar size.
The findings suggest fedratinib — which the FDA previously had on clinical hold — does not appear to increase risk for thiamine deficiency beyond its potential to exacerbate malnutrition through poor management of preventable gastrointestinal adverse events, researchers wrote.
“This intense analysis with longer-term follow-up showed no clear signal that fedratinib leads to the development of Wernicke’s encephalopathy,” researcher Ruben A. Mesa, MD, director of UT Health San Antonio Cancer Center and a HemOnc Today Editorial Board member, said in an interview. “We identified only one confirmed case, but it seems likely that this individual had Wernicke’s encephalopathy before enrollment in the study. Perhaps that individual’s condition worsened while on trial, but it is difficult to know whether that really was a side effect of the medication.”
Prevalence of Wernicke’s encephalopathy is estimated at 0.8% to 2.8% in the general population, but incidence among individuals with myeloproliferative neoplasms is projected to be three times greater.
The condition — preventable by ensuring nausea and vomiting do not exacerbate malnutrition — can be diagnosed based on MRI findings and clinical signs.
However, confirmation of diagnosis among patients with myeloproliferative neoplasms is difficult due to comorbidities, such as high incidence of stroke or hepatic encephalopathy secondary to hepatic extramedullary hematopoiesis.
Fedratinib — a highly selective JAK2 kinase inhibitor — is in development for myelofibrosis and polycythemia vera.
Results of the randomized phase 3 JAKARTA I study showed half of patients with intermediate-2- or high-risk myelofibrosis responded to first-line fedratinib. In the phase 2 JAKARTA II trial — which evaluated the agent in the second-line setting — 53% of patients with myelofibrosis who were resistant to standard-of-care ruxolitinib (Jakafi, Incyte) responded to fedratinib, as did 63% of patients who were intolerant to ruxolitinib.
However, the FDA placed a clinical hold on fedratinib in November 2013 after eight of 877 patients exposed to the agent experienced neurological symptoms suggestive of Wernicke’s encephalopathy.
Six of those eight patients had myelofibrosis, one had polycythemia vera, and one had metastatic head and neck cancer.
Mesa and colleagues retrospectively analyzed those eight patients (women, n = 7; median age, 69.1 years; interquartile range, 67-71) to evaluate demographics, clinical signs, thiamine levels and MRI scans to determine the likelihood of Wernicke’s encephalopathy. The investigators also worked with an independent expert panel to identify other possible contributory factors.
They concluded data either did not support Wernicke’s encephalopathy diagnosis or was inconclusive for three of the eight evaluated patients. One of those three individuals likely had hepatic encephalopathy, researchers wrote.
Mesa and colleagues determined one of the remaining five patients clearly had Wernicke’s encephalopathy.
That person — who had experienced protracted nausea and vomiting — was severely malnourished and refused gastrostomy during the study, suggesting malnutrition as a cause of thiamine deficiency. Clinical signs and MRI findings were consistent with Wernicke’s encephalopathy. The individual received treatment with thiamin and Wernicke’s encephalopathy resolved, Mesa said.
Two other patients considered likely to have the condition experienced “preceding sustained nausea and vomiting” but recovered from neurological deficits while they continued fedratinib treatment with no dose interruption.
The final two patients analyzed — for whom Wernicke’s encephalopathy diagnosis was inconclusive — also experienced preceding nausea and vomiting.
One developed disseminated metastases from a separate malignancy — including an edematous brain metastases — prior to experiencing neurological symptoms, thereby confounding the diagnosis. The other developed neurological symptoms while not on fedratinib treatment.
The FDA lifted the clinical hold on fedratinib in August.
“In that context, there is a desire to circle back to take another look at an efficacious drug, and the data are being analyzed to see whether it fits in the paradigm for myeloproliferative neoplasms,” Mesa told HemOnc Today.
“This drug demonstrated significant efficacy in an arena where we have only one FDA-approved therapy — ruxolitinib,” Mesa added. “Personally, I think the data we have available now suggest a role for fedratinib for patients with myelofibrosis, but it will be up to regulatory agencies to determine what a potential indication may look like. ... There are individuals who are having suboptimal response to ruxolitinib, and I can say with certainty that another available agent certainly would be very attractive for them.” – by Mark Leiser
Reference:
Harrison CN, et al. Abstract 4197. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2017; Atlanta.
Disclosure: Mesa reports consultant roles with Ariad, Galena Biopharma and Novartis, as well as research funding from Celgene, CTI BioPharma, Gilead, Incyte and Promedico. Please see the abstract for all other authors’ relevant financial disclosures.
Perspective
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Aaron T. Gerds, MD, MS
Janus — the Roman god of beginnings, endings, gates and dualism — is routinely evoked when dis-cussing myeloproliferative neoplasms because of the central role that Janus kinase (JAK) mutations play in the pathogenesis of the disease. However, the duality of clinical trial results also can conjure Janus as not only the efficacy, but the safety of a new medication is evaluated. As a critical element of any trial, the ruling of whether an adverse event is due to the study drug is as important as determining remissions and relapses. However, the process by which this is done can be very unscientific. Once an adverse event is recognized, the investigator caring for the patient takes the clinical scenario and makes the call based on his or her experience with the study drug.
The Common Terminology Criteria for Adverse Events — formerly known as the Common Toxicity Criteria — has done much by defining the severity of induvial adverse events. But we still rely on the Likert-invoking scale of not related, unlikely related, possibly related, probably related or definitely related to the study treatment. Once the attribution is made, it is logged in a ream of study documents that often are aggregated and condensed into a table for the resulting manuscript. Investigators rarely dig deeper into the “who, what, where, why and how” of an adverse event.
In this ASH abstract, Harrison and colleagues did dig deeper into why this devastating adverse event was occurring at such a seemingly high rate, finding that a simple table cataloguing adverse events did not tell the whole story. They were able to explain that — in all of these cases — either Wernicke’s encephalopathy was not the diagnosis, or there were extreme nutritional situations that led to thiamine deficiency among these individuals.
Their results created a reasonable doubt, if not exonerated fedradtinib from this devastating adverse event.
Looking forward, there is great interest in how this efficacious medication can move forward to reach patients who could benefit now that the clinical hold has been lifted. Looking back, this also can serve as an example of not taking data at face value, and how to dig deeper to get the whole story of patient safety.
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