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Significant Rate of Febrile Neutropenia Seen in CDK 4/6 Inhibitor Based Regimens

By Katie Kosko
Cyclin D–dependent kinase (CDK) 4/6 inhibitors have proven to be effective treatment in patients with hormone receptor-positive HER2-negative metastatic breast cancer. But, much like many cancer therapies, there are challenges when it comes to toxicity.

Patients who receive CDK 4/6 treatment often experience adverse effects (AEs), which may include neutropenia, anemia, and thrombocytopenia.

“Hematologic toxicities may have potentially significant impacts on patients’ quality of life,” said Catherine Jones, MD, associate program director, internal medicine and assistant professor, hematology oncology, Texas Tech University Health Sciences Center and Southwest Cancer Center. “For example, anemia may exacerbate fatigue/weakness in someone who may also have disease or treatment related fatigue.”

To learn specifically which AEs patients are experiencing, investigators from New York and Texas examined the impact of CDK 4/6 inhibitors by performing a systematic review and meta-analysis of 5 randomized controlled trials — 4 phase III studies and 1 phase II study. They presented their findings at the 2017 Palliative and Supportive Care in Oncology Symposium in San Diego, California.

Trials incorporated into the analysis had listed AEs such as anemia, thrombocytopenia, leukopenia, neutropenia, and neutropenic fever. Investigators used the Mantel-Haenszel method to calculate the estimated pooled risk ratio with 95% confidence interval (CI).

There were 2671 patients eligible for the analysis. The study arm used palbociclib-letrozole, palbociclib-fulvestrant, ribociclib-letrozole and abemaciclib-fulvestrant, while the control arm utilized placebo in combination with letrozole or fulvestrant.

The relative risks (RR) of all-grade AEs were: anemia, 3.77 (95% CI: 2.47 – 5.75, p < 0.0001); thrombocytopenia, 9.69 (95% CI: 4.26 – 22.04, p < 0.0001); leukopenia, 11.68 (95% CI: 8.19–16.65; p < 0.0001); and neutropenia, 14.09 (95% CI: 10.73–18.49; p < 0.0001).

The RR of high-grade AEs were: anemia, 2.66 (95% CI: 1.29 – 5.45, p = 0.008); thrombocytopenia, 7.08 (95% CI: 1.95 – 25.74, p = 0.003); leukopenia, 33.58 (95% CI: 14.49–77.77; p < 0.0001); and neutropenia, 40.33 (95% CI: 19.34–84.10; p < 0.001).

The pooled risk of neutropenic fever was statistically significant at 4.26 (95% CI: 1.11–16.26; p = 0.034), noted the study.

The investigators determined that CDK 4/6 inhibitor based regimens significantly contributed to all hematological toxicities, as well as febrile neutropenia, per the study.

“Hematologic toxicities associated with CDK4/6 inhibitors are well-known including neutropenia,” Jones said. “What is significant here is the rate of febrile neutropenia, which has not previously thought to be a significant issue with these medications.”

Other AEs associated with CDK 4/6 inhibitors include: any-grade diarrhea, stomatitis, nausea, vomiting, and fatigue.

The investigators noted that toxicities, such as the ones described, can add a financial burden for patients, and may even lead to drug dosing inconsistencies. For instance, patients may require extra supportive care such as transfusions, said Jones.

“Vigilant monitoring of complete blood counts in patients on these medications is clearly warranted given the increased risk of febrile neutropenia,” she said. “For patients who develop neutropenia, proper supportive care and dose modifications should be followed.”

Zaw M, Thein KZ, Tun A, et al. Risk of hematological toxicities and febrile neutropenia in patients with hormone receptor-positive HER2-negative metastatic breast cancer treated with CDK 4/6 inhibitors: A systematic review and meta-analysis of randomized controlled trials. Presented at: 2017 Palliative and Supportive Care in Oncology Symposium; October 27-28; San Diego, CA. Abstract 207.
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