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Bristol-Myers’ leukaemia drug Sprycel (dasatinib) causes significant pleural effusions that have led patients to discontinue treatment, physicians told Pharmawire. The FDA recently approved a new dosage regimen in Sprycel tablets, from 70mg twice daily to 100mg once daily.
Dr Michael Mauro, associate professor of Medicine in the Division of Hematology and Medical Oncology at Oregon Health Science University said based on his experience, approximately 25% of his patients taking Sprycel at 70mg twice a day had to discontinue treatment due to lung abnormalities.
In a Phase 3 dose-optimization study in chronic phase CML patients, the percentage of patients that reported pleural effusions on Sprycel 100 mg once daily or Sprycel 70 mg twice daily were 10% and 18% respectively.
Although there is a reduction in frequency with the lower dose, pleural effusions still occur, physicians added. A pleural effusion is excess fluid that accumulates in the pleural cavity – in the fluid-filled space that surrounds the lungs.
Sprycel is a tyrosine kinase inhibitor that was approved last year for the treatment of chronic myeloid leukemia (CML). The drug is only to be used in CML patients who are resistant to the current industry standard, Novartis’ Gleevec (imatinib).
Dr Claude Nicaise, Vice President of Sprycel Global Development said there are relatively few patients who have this complication with Gleevec. The fluid retention is much more of a “generalized edema” with Gleevec treatment, he added.
Dr Anne Bergeron-Lafaurie, a pulmonologist and author of an independent study on lung abnormalities after Sprycel treatment for CML, added there are several types of pleural effusions, some of which are ”quite dangerous” as the symptoms are silent and easily dismissed.
Bergeron-Lafaurie cautioned that it is more likely for patients who have discontinued Gleevec treatment due to pleural effusions to develop lung complications on Sprycel. ”If a patient developed pleural infusions on Gleevec, they need to be careful with Sprycel,” she added.
”A pleural effusion can negatively affect patient’s quality of life and patients have to stop treatment punctually once it develops,” said Bergeron-Lafaurie. Physicians and patients should be wary of progressive dyspea – shortness of breath – as this could indicate that the condition is more severe. In the case of parenchymal pleural complications, patients can also develop a high fever, she said.
Mauro added that approximately 75% of patients stopped treatment because of lung abnormalities and blood count diffusions. Pleural effusions can happen unexpectedly at anytime, during the course of treatment, Mauro said. It can be a chronic toxicity that is recurrent, he added.
Pleural effusions occur most often during the first year of treatment and are most frequently reported between the second month and the end of first treatment year.
However, Bergeron-Lafaurie remained unsure as to when exactly pleural effusions occur during the course of treatment, as Sprycel is a relatively new drug.
Patients and physicians need to be aware of the signs and symptoms of lung abnormalities, and Bergeron-Lafaurie believed it is still too early to determine when the timing of pleural effusions occur during the course of treatment.
Nicaise said most patients report Grade 1 or 2 pleural effusions. “Grade 1” is defined as an asymptomatic pleural effusion, and physicians discover these minimally intrusive effusions during routine chest x-ray examinations.
Once patients report this symptom, the physician should briefly interrupt treatment and can resume treatment at a lower dose when symptoms have resolved. “In the vast majority of patients there is no need for therapeutic intervention,” added Nicaise.
However, Bergeron-Lafaurie cautioned that patients often neglect and dismiss the most common signs of pleural effusions, such as chest pain and coughing. “Maybe lung complications will become less frequent with the new way of prescribing Sprycel,” she added.
It is important to differentiate between pleural effusions and tumors, which are more likely to occur in lung cancer and breast cancer. Nicaise said pleural effusions are “relatively rare complications of cancer.”
It is important for physicians to determine whether the cells in an effusion are neoplastic (cancerous) cells or epithelial cells. Sprycel induced pleural effusions contain epithelial cells and cells from the pleura, both of which are benign. A spinal tap can help determine whether the cells are neoplastic cancerous cells or benign epithelial cells.
“When you have fluid retention like with Sprycel, it is accumulation that only contains epithelial cells or cells from pleura and there are no malignant or leukaemia cells. So it is easy to differentiate between the two,” he explained.
However, the pleural effusions disappear when a patient interrupts Sprycel treatment. “We give them a diuretic and corticosteroid to get rid of the effusions and once they disappear, the patients can continue treatment at a lower dose,” he added.
The 100 mg dose not only reduced the frequency of pleural effusions, it also reduced the presence of symptoms. “Once we have a better understanding of the symptoms and how it occurs, much fewer patients will have pleural effusions and more will continue without a problem,” said Nicaise.
Nintey percent of patients with chronic CML that were treated with Sprycel lived longer than two years.
Bristol-Myers Squibb has a current market cap of USD 55.18bn.
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