Nilotinib active, safe in imatinib resistant/intolerant CP-CML

ASCO—Nilotinib (Tasigna), a second-generation tyrosine kinase inhibitor currently under FDA review, is highly active and safe in imatinib (Gleevec)-resistant or intolerant patients with chronic myeloid leukemia in chronic phase (CP-CML).

In updated results of a phase II open-label trial, major cytogenetic responses were reported in 55.6% of patients treated for at least 6 months, Gianantonio Rosti, MD, of the University of Bologna, Italy, reported at the American Society of Clinical Oncology 43rd Annual Meeting (abstract 7007).

"The news from this trial," said discussant Charles A. Schiffer, MD, of the Karmanos Cancer Institute, "is that nilotinib results are holding up with large numbers of patients. . . . It's clearly an alternative drug that is suitable for those who have failed imatinib therapy."

The study included 320 adult Philadelphia chromosome positive (Ph+) CML patients in first chronic phase who were imatinib resistant or intolerant.

The study patients received nilotinib at a dose of 400 mg orally twice a day. Dose escalation to 600 mg twice daily was allowed if there was no complete hematologic response (CHR) at 3 months, no minimal cytogenetic response (CyR) at 6 months, no major CyR (MCyR) (complete or partial) at 12 months, loss of hematologic or cytogenetic response, or disease progression. The primary endpoint was MCyR. Imatinib-resistant patients made up the largest part (70.6%) of the population.

The hematologic response rate in patients lacking a CHR at baseline was 75.7%. Time to first CHR in these patients was 1 month, Dr. Rosti reported. In all patients, the major CyR and complete CyR rates were 55.6% and 40%, respectively. MCyR rates were similar in imatinib-resistant patients (54%) and imatinib-intolerant patients (59.6%). Time to first MCyR was 2.8 months. Median duration of MCyR had not been reached at the data cutoff. The Kaplan-Meier 1-year survival estimate for all patients was 95% with only 19 patients failing.

"Nilotinib is a very nicely tolerated drug," Dr. Rosti said. Among nonhematologic adverse events, rash, nausea, and headache were most common at approximately 33% each, with headache the most common grade 3-4 event at 2.5%. "Most of these events are of early onset and early disappearance," he noted. Among hematologic laboratory abnormalities, anemia, neutropenia, and thrombocytopenia of any grade were reported in 50.2%, 52.1%, and 61.3% of patients, respectively; grade 3-4 in 9.1%, 30.5%, and 33.0%, respectively.

Regarding other laboratory abnormalities, Dr. Rosti pointed to a notable rise in total bilirubin in 70.6% of patients (8.5% grade 3-4), which, he said, was related to the Gilbert's syndrome genotype. Lipase elevation occurred in 43.9% of patients and was severe in 15.3%, he said, "but only one patient abandoned the treatment due to acute pancreatitis." Grade 3-4 adverse events associated with fluid retention were rare (less than 1%).

"Nilotinib is highly active and safe in CP-CML patients with imatinib resistance or intolerance," Dr. Rosti concluded. The high dose intensity (median, 792.6 mg/d), he added, is evidence of nilotinib's excellent tolerability.