NEW YORK – Researchers are investigating genetic correlates of vulnerability to kidney injury in patients with Philadelphia chromosome-positive chronic myeloid leukemia after finding high rates of elevated protein in the urine of those treated with Bristol Myers Squibb's Bcr-Abl tyrosine kinase inhibitor Sprycel (dasatinib).
An elevated urine protein level, known as proteinuria, is a sign of kidney injury which in the early stages may not have any other symptoms. In a study published in the September issue of the Clinical Journal of the American Society of Nephrology, a team of researchers from Mount Sinai and Memorial Sloan Kettering Cancer Center tested urine protein levels in 82 patients with CML who had been on a Bcr-Abl tyrosine kinase inhibitor therapy for a median duration of 41 months and found a high prevalence of elevated protein in the patients who had taken Sprycel (32 of the 82 patients studied), but not in those that had received any of the other drugs.
"We were quite surprised to find that 50 percent of the patients had some form of kidney dysfunction and 10 percent had severe kidney dysfunction," Evren Azeloglu, first author on the study and an associate professor of nephrology at the Icahn School of Medicine at Mount Sinai, said. Furthermore, Azeloglu noted, this was the first time any of the patients had been diagnosed with a kidney injury. "Not a single one knew. Per clinical protocol, they would not be followed because these drugs are known to be safe. There was no reason."
In 2006, the US Food and Drug Administration granted accelerated approval of Sprycel as a second-line therapy for adults with all forms of chronic myeloid leukemia and full approval as a second-line therapy for Philadelphia chromosome-positive acute lymphoblastic leukemia. The accelerated approval in CML was converted to full approval in that same setting in 2009. In 2010, the FDA approved the drug as a first-line therapy for adults with Philadelphia chromosome-positive CML, and in 2017, it expanded the drug's approval in that indication to include children. The drug's label, which is informed by at least eight Phase I-III clinical studies in CML, includes warnings for myelosuppression, bleeding, fluid retention, QT prolongation, and heart complications but does not mention kidney injury or proteinuria.
Patients in the study who had taken other tyrosine kinase inhibitors — Novartis' Gleevec (imatinib) and Tasigna (nilotinib), Pfizer's Bosulif (bosutinib), and Ariad Pharmaceuticals’ Iclusig (ponatinib) — did not have signs of kidney injury. This finding is in line with work Azeloglu and his colleagues published in 2019 in Nature Communications characterizing the mechanisms of Sprycel-induced injury to kidney cells. In that study, the researchers obtained adverse event frequencies from the FDA Adverse Event Reporting System and analyzed risks associated with FDA-approved protein kinase inhibitors, establishing that Sprycel had one of the highest reporting odds ratios for adverse events related to certain aspects of kidney function. In other words, the odds of kidney injury occurring with Sprycel were higher compared to the odds of it occurring with other kinase inhibitors. In animal and cell studies, they demonstrated that Sprycel has unique effects on the podocyte cells in the kidney, which Azeloglu explained have somewhat fragile connections to the to the capillaries that form the glomerulus, the functional unit of the kidney.
"We saw that these connections were severely injured or severely compromised with" Sprycel, Azeloglu said, "and we did not see similar injury with any of the other tyrosine kinase inhibitors."
Azeloglu noted that Sprycel is gaining popularity as a first-line therapy choice for patients with Philadelphia chromosome-positive CML, due to the high efficacy rates it has shown in clinical trials and a generally favorable safety profile with few adverse events. And, he explained, as it gains in popularity, rates of kidney injury and kidney failure could become much more widespread.
In the case of one patient in the new study who had received Sprycel, her urine protein levels were so high that she was referred to a nephrology clinic for follow-up and received a biopsy to rule out underlying kidney disease. Like the other patients on Sprycel who had proteinuria, this patient discontinued the drug and her kidney function improved within two weeks. Azeloglu contrasts that with the earlier study, which was based on FDA reports of kidney failure connected with Sprycel use, suggesting that when this type of kidney injury goes undiagnosed, it could contribute to more severe events later.
"Hopefully, we'll be able to alert hematology oncologists to involve nephrologists early on, or at least start testing [kidney function] in these patients," Azeloglu said.
"We don't think it's necessary to withhold this medication. It's one of the best targeted therapeutics indicated for CML and [acute lymphoblastic leukemia]," Azeloglu said. But, he added, doctors should monitor kidney function in patients taking Sprycel. Bristol Myers Squibb did not respond to a request for an interview by press time for this story.
Azeloglu believes the association of Sprycel with kidney injury was missed in clinical trials due to the relatively long period of time over which it develops. In fact, in analyzing the data, his group found that the trend toward kidney injury in patients on Sprycel doesn't show a clear statistical divergence from the trend line in the non-Sprycel group, which is flat, until 15 years of treatment. "This is an effect that's difficult to detect," Azeloglu said, emphasizing that the long delay does not mean that each case of kidney injury will take 15 years to develop. "Some may develop it in a few years, some may take a little longer."
Sprycel isn't the only drug to have serious safety issues emerge after approval, despite exhaustive clinical trials. A study published in 2017 in JAMA found that among 222 novel therapeutics approved between 2001 and 2010, 32 percent had a post-market safety event. Azeloglu hopes that studies such as these will raise awareness, particularly in the oncology field, that drugs deemed safe for the kidney may have under-the-radar adverse effects. In general, Azeloglu pointed out, follow-up safety studies tend to "look under the light," meaning that if an event isn't initially identified as a concern and isn't monitored, it will usually not be included in post-market safety monitoring.
While about 50 percent of patients in the Sprycel group had some level of kidney injury, the other half had none. The factors contributing to that variation are unknown and could include environmental influences such as lifestyle or known nephrotoxic prescription drugs such as certain antibiotics. There could also be a genetic susceptibility involved — a thread Azeloglu is picking up in a new study for which he is seeking funding. In that study, he is screening Sprycel and dozens of other kinase inhibitors against a library of induced pluripotent stem cells from a diverse patient population to find variations between patients, including genetic variations, that contribute either to vulnerability or resilience to Sprycel-induced kidney injury.
"If we can identify what particularly makes this group susceptible, this may hold the key to many other adverse events, not just of this drug in this context, but potentially other similar adverse events caused by these targeted therapeutics," Azeloglu said.