Weight Gain, Hypertension Seen With Ruxolitinib

Alexander M. Castellino, PhD

November 18, 2019

Real-world data from a retrospective study suggest that patients who are taking ruxolitinib (Jakafi, Incyte), which is approved for the treatment of myeloproliferative neoplasms such as polycythemia vera and myelofibrosis, experience weight gain that is much higher than previously reported in short-term clinical trials. The data also suggest that patients may develop hypertension and increases in liver enzyme levels with long-term use of the drug.

The study was published online November 12 in Scientific Reports.

"This study details the real-world effects of ruxolitinib on weight and metabolic factors in patients with myeloproliferative neoplasms," commented lead study author Emily J. Gallagher, MD, PhD, assistant professor of medicine specializing in onco-endocrinology at the Icahn School of Medicine at Mount Sinai, New York City.

"It demonstrates that ruxolitinib treatment is associated with increased prevalence of obesity as measured by BMI [body mass index]. Interestingly, despite the increase in the percent of patients with obesity, we did not find any change in the prevalence of hyperglycemia, although an increase in systolic blood pressure was observed," she told Medscape Medical News.

Gallagher noted that previous clinical studies have reported weight gain in patients treated with ruxolitinib. Although many healthcare providers perceive that patients with cancer are underweight or cachectic and consider the weight gain to be beneficial, Gallagher pointed out that a major cause of morbidity and possible mortality in patients with myeloproliferative neoplasms is cardiovascular disease.

"In contrast to the perception of many health care providers, patients are not going from being underweight to being a normal weight. Instead, a significant number of patients are developing obesity. Based on these results, physicians should be aware of the potential effects and counsel patients accordingly," Gallagher said in a statement released from the institution.

Details of the Study

Gallagher and researchers identified patients who were treated with ruxolitinib between January 2010 and 2017 at their institution by accessing the hospital's electronic medical records. They extracted data on sex, age, weight, laboraory test results, blood test results, initiation and discontinuation of ruxolitinib, presence of comorbidities, medications taken for comorbidities, and imaging information.

Only patients with information at baseline and at 72 weeks' follow-up were included in the analysis. Of 127 patients initially identified, 69 were included in the analysis.

Fifty-two (75.3%) patients were treated with ruxolitinib for myelofibrosis; 14 (20.3%) were treated for polycythemia vera.

The mean BMI was 25.8 kg/m2 (range: 16.8 – 41.1). Obesity was defined as BMI ≥30; overweight was defined as BMI 25 – 29.9. In the patients with myelofibrosis who were obese (patients typically present with cachexia), splenomegaly and fluid retention did not contribute to increased weight; most of these patients had low or intermediate 1 DIPSS [Dynamic International Prognostic Scoring System] scores.

After taking ruxolitinib for 72 weeks, the number of obese patients doubled — from 14.7% at the start of treatment to 29.6% after 72 weeks.

Mean glucose level did not change: 100 mg/dL at baseline and 101 mg/dL after 72 weeks.

Prevalence of hypertension increased from 64.7% at baseline to 69.1% at 72 weeks. Mean systolic blood pressure was 124 mmHg at baseline and 129 mmHg after 72 weeks of taking ruxolitinib. Mean diastolic blood pressure was lower: 72 mmHg at the start of therapy and 70 mmHg at week 72.

Liver enzyme levels also increased from baseline to week 72: aspartate aminotransferase levels rose by 4.5 IU/L, and alanine transaminase levels rose by 6.3 IU/L.

Speculating as to why weight gain occurred with this drug, Gallagher explained that ruxolitinib is a JAK inhibitor, and the JAK1/2 enzymes are intracellular mediators of cytokine signaling as well as the signaling of hormones such as leptin and growth hormone. Blocking this signaling pathway may lead to weight gain through inhibition of cytokine signaling or inhibition of growth hormone and leptin signaling, she suggested.

The weight gain was not due to steroids. "Patients treated with ruxolitinib were not on glucocorticoid therapy, which is well known to be associated with weight gain in patients with various cancers," she said.

The researchers did not have detailed dietary records and are undertaking prospective studies to determine whether changes in appetite or hormone levels are associated with weight changes.

"With improvement in therapies, cancer is gradually becoming a chronic disease. Patients with a number of different cancers are increasingly living for many years, and both patients and physicians are becoming aware of the adverse metabolic consequences of a number of cancer therapies," Gallagher said. In some cases, the adverse metabolic consequences of targeted therapies may actually lead to resistance to the cancer treatment, she observed.

The study did not include long-term morbidity and mortality data for these patients, which will be important to include in a follow-up study, Gallagher said. At this point, it is not clear whether weight gain associated with ruxolitinib is beneficial (eg, whether patients who experience weight gain have a better response to therapy and live longer) or is associated with more long-term adverse cardiovascular effects (due to an increase in systolic blood pressure), she noted.

"At present, we advise counseling patients on the potential for weight gain and increased blood pressure with this therapy. In patients who experience weight gain, we recommend testing for and treating other metabolic conditions (hypertension, dyslipidemia) to reduce the risk of cardiovascular events," Gallagher said.

Gallagher served on the advisory board for Novartis. Conflict of interest information for the other study authors is available in the original article.

Sci Rep. Published online November 12, 2019. Full text

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