Investigators at Mount Sinai Find Strong Association of Kidney Injury with Dasatinib, a Commonly Used Oncological Therapeutic

Investigators at Mount Sinai Find Strong Association of Kidney Injury with Dasatinib, a Commonly Used Oncological Therapeutic

Findings suggest an update may be warranted for current clinical care, screening guidelines, and FDA guidance on adverse events

Principal Investigator: Evren U. Azeloglu, PhD, Associate Professor of Medicine (Nephrology), Icahn School of Medicine at Mount Sinai

First Author: Benjamin Adegbite, MD, Internal Medicine Resident, Mount Sinai West

Journal: Clinical Journal of the American Society of Nephrology – September Issue

Bottom Line:  Investigators found that dasatinib, a drug commonly used to treat chronic myeloid leukemia, is strongly associated with kidney injury.

Why the Study Is Important: The study team strongly believes this study will impact clinical practice significantly, changing standard of care and possibly introducing new black box warnings for dasatinib.

Furthermore, the researchers point out that the incidence of kidney injury is a previously unknown severe side effect for this drug. This side effect, they report, is advertised to be rare; however, they observed it in 10 percent of all participants taking dasatinib. Of concern, they say, is that patients taking dasatinib are currently not screened for kidney injury or dysfunction, making them susceptible to chronic kidney disease.

What the Study Found: Eighty-two participants who have been on long-term tyrosine-kinase inhibitor treatment for chronic myeloid leukemia were part of the study; 32 participants were treated with dasatinib and 50 were treated with other, similar drugs. Significantly elevated levels of kidney injury (measured as elevated protein in the urine, or proteinuria) were identified in dasatinib patients, with 10 percent of participants exhibiting severe levels that were later seen to decrease upon cessation of dasatanib use. No participant in the non-dasatinib cohort showed severe proteinuria. Widespread kidney damage in dasatinib patients was also confirmed by kidney biopsy. 

How the Study Was Conducted: With the help of Dr. Adegbite and researchers at Memorial Sloan Kettering Cancer Center, the lead investigator, Dr. Azeloglu, led a multi-center clinical study to determine the incidence of kidney injury in patients taking dasatinib. The investigators examined glomerular injury through urine albumin-creatinine ratio (UACR) in 82 patients with chronic myelogenous leukemia who have been continuously taking a tyrosine-kinase inhibitor for at least 90 days. They compared mean differences in UACR, in addition to studying proteinuria. In addition to other blood tests, they also described a case study of a patient who experienced nephrotic-range proteinuria while on dasatinib.

What These Findings Mean: Based on these findings, oncologists prescribing dasatinib may be advised to monitor patients for kidney function or proteinuria and engage a nephrologist to assist in their care. It is also likely that the presence of proteinuria in this setting may result in changes in therapy, especially if proteinuria is severe. Furthermore, the researchers say that these findings suggest that current clinical care, screening guidelines, and Food and Drug Administration guidance on adverse events may need to be updated.

WHAT’S NEXT: Earlier clinical trials reported proteinuria in only less than 1 percent of patients. This may be due to the shorter windows associated with clinical trials versus the lengthier time frame afforded by Dr. Azeloglu’s  retrospective study. Larger prospective clinical studies can help identify which patients are susceptible to this type of injury and design alternative treatment strategies. 

Funding: This work was supported by National Institutes of Diabetes and Digestive and Kidney Diseases (R01 DK118222).

Quotes:  “Ten percent of patients in our study exhibited severe levels of kidney injury, which is striking. Earlier clinical trials reported proteinuria, or high levels of protein in the urine, in less than one percent of patients only, which may be due to their shorter follow-up. Larger prospective clinical studies can help us identify which patients are susceptible to this type of injury and design alternative treatment strategies,” says Principal Investigator Evren U. Azeloglu, PhD, Associate Professor of Medicine (Nephrology), Icahn School of Medicine at Mount Sinai.

“We think our study will impact clinical practice significantly, changing standard of care and possibly introducing new black box warnings for the drug that is being studied,” says Dr. Azeloglu.

 

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About the Icahn School of Medicine at Mount Sinai

The Icahn School of Medicine at Mount Sinai is internationally renowned for its outstanding research, educational, and clinical care programs. It is the sole academic partner for the

eight member hospitals* of the Mount Sinai Health System, one of the largest academic health systems in the United States, providing care to a large and diverse patient population. 

Ranked No. 14 nationwide in National Institutes of Health funding and in the 99th percentile in research dollars per investigator according to the Association of American Medical Colleges, Icahn Mount Sinai has a talented, productive, and successful faculty. More than 3,000 full-time scientists, educators, and clinicians work within and across 34 academic departments and 44 multidisciplinary institutes, a structure that facilitates tremendous collaboration and synergy. Our emphasis on translational research and therapeutics is evident in such diverse areas as genomics/big data, virology, neuroscience, cardiology, geriatrics, and gastrointestinal and liver diseases.

Icahn Mount Sinai offers highly competitive MD, PhD, and master’s degree programs, with current enrollment of approximately 1,300 students. It has the largest graduate medical education program in the country, with more than 2,600 clinical residents and fellows training throughout the Health System. In addition, more than 535 postdoctoral research fellows are in training within the Health System.

A culture of innovation and discovery permeates every Icahn Mount Sinai program. Mount Sinai’s technology transfer office, one of the largest in the country, partners with faculty and trainees to pursue optimal commercialization of intellectual property to ensure that Mount Sinai discoveries and innovations translate into health care products and services that benefit the public.

Icahn Mount Sinai’s commitment to breakthrough science and clinical care is enhanced by academic affiliations that supplement and complement the School’s programs. Through Mount Sinai Innovation Partners (MSIP), the Health System facilitates the real-world application and commercialization of medical breakthroughs made at Mount Sinai. Additionally, MSIP develops research partnerships with industry leaders such as Merck & Co., AstraZeneca, Novo Nordisk, and others.

The Icahn School of Medicine at Mount Sinai is located in New York City on the border between the Upper East Side and East Harlem, and classroom teaching takes place on a campus facing Central Park. Icahn Mount Sinai’s location offers many opportunities to interact with and care for diverse communities. Learning extends well beyond the borders of our physical campus, to the eight hospitals of the Mount Sinai Health System, our academic affiliates, and globally.

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* Mount Sinai Health System member hospitals: The Mount Sinai Hospital; Mount Sinai Beth Israel; Mount Sinai Brooklyn; Mount Sinai Morningside; Mount Sinai Queens; Mount Sinai South Nassau; Mount Sinai West; and New York Eye and Ear Infirmary of Mount Sinai.

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