Novel drug targets imatinib-refractory leukemia: two studies suggest that nilotinib could provide an alternative for patients not benefiting from imatinib.
Two studies at the annual meeting of the American Society of Hematology demonstrated the efficacy and safety of nilotinib in imatinib-resistant or -intolerant patients with blast-phase or chronic-phase chronic myelogenous leukemia (CML) and in patients with acute lymphocytic leukemia (ALL) who tested positive for the Philadelphia chromosome (Ph+). Both studies were sponsored by Novartis.
Imatinib was a breakthrough in leukemia treatment, but resistance to this compound appears to be increasing, said Dr. Michael J. Mauro of the Oregon Health and Science University, Portland.
"ABL kinase mutations, which alter imatinib binding or favor kinase conformations inaccessible to imatinib, are a common finding associated with clinical resistance. Dasatinib and nilotinib, alternate ABL kinase inhibitors, restore hematologic and cytogenetic remission in the majority of patients with primary failure or acquired resistance in chronic-phase disease; in advanced disease and Philadelphia chromosome ALL, responses are more limited and relapse is common," Dr. Mauro said.
Dr. Philipp le Coutre of Humboldt University, Berlin, and his colleagues conducted a phase II, open-label study to evaluate the safety and efficacy of nilotinib in CML patients with chronic-phase disease. A total of 316 patients who were resistant or intolerant to imatinib were treated with 400 mg nilotinib twice daily, which could be increased to 600 mg twice daily for patients not responding adequately.
Of 132 patients who had 10 months follow-up, 77% had a complete hematologic response, 49% had a major cytogenetic response, and 32% had a complete cytogenetic response. The median time to complete hematologic response was 1 month, and the median time to major cytogenetic response was 2.8 months.
The most frequent grade 3-4 myelosup-pressive adverse events included thrombocytopenia (29%, with 24% requiring dose interruption or reduction, and 6% requiring discontinuation), neutropenia (28%, with 10% requiring dose interruption or reduction, and 6% requiring discontinuation), and anemia (9%). The most common grade 3-4 biochemical abnormalities were alanine transferase elevation (13%), bilirubin (25%), hypophosphatemia (32%), lipase elevation (44%), and hyperglycemia (33%), Dr. le Coutre reported.
"Nilotinib showed excellent tolerability as evidenced by high-dose intensity and minimal cross tolerance in imatinib-intolerant patients. There were negligible rates of fluid retention; elevations in serum lipase, AST, ALT, and bilirubin were transient and manageable," he said. "Nilotinib, in conclusion, is a selective, potent inhibitor of BCR-ABL, which has significant efficacy with low rates of myelosuppression."
In a related study, Dr. Oliver Ottman, of the Johann Wolfgang Goethe Universitat in Frankfurt-am-Main, Germany, and his colleagues conducted an open-label, phase II study to evaluate the efficacy of nilotinib in patients with imatinib-resistant or -intolerant CML in blast crisis (CML-BC) or relapsed/refractory Ph+ ALL. Patients received oral nilotinib 400 mg twice daily, which could be increased to 600 mg twice daily if patients failed to respond adequately.
Hematologic responses were seen in 36% of patients with myeloid disease, in 37% of those with lymphoid disease, and in 17% of those with an unknown type. (See box.)
In Ph+ ALL patients without minimum residual disease, there was a 24% complete response rate, and 30% had hematologic improvement, 19% had stable disease, and 38% had progressive disease. Six patients (18%) were missing or not evaluable.
In CML-BC patients, the most frequent grade 3-4 nonhematologic adverse events were pneumonia (11%), pyrexia (6%), diarrhea (4%), and asthenia (4%). Corresponding adverse events in patients with Ph+ ALL were increased alanine transferase (7%), hypokalemia (7%), headache (5%), vomiting (5%), fatigue (5%), asthenia (5%), bone pain (5%), back pain (5%), and pain in the extremities (5%).
The data show that nilotinib had significant clinical activity and was well tolerated, as shown by the high median dosage delivered (800 mg/day). "No patient in this study developed CNS disease, a common development in patients with Ph+ ALL," Dr. Ottman noted.
BY BRUCE WILSON
Investigator Assessment of Best Response to Nilotinib in Patients With CML-BC Myeloid Lymphoid Unknown Type (n = 87) (n = 27) (n = 6) Hematologic response 36% 37% 17% Stable disease 31% 26% 33% Progressive disease 18% 19% 33% Not evaluable 8% 4% 0% Missing 7% 15% 17% Note: Percentages may not add up to 100% because of rounding. Source: Dr. Ottman ELSEVIER GLOBAL MEDICAL NEWS
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|Publication:||Internal Medicine News|
|Date:||Jan 15, 2007|
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