NILOTINIB SUPERIOR THAN IMATINIB FOR CML?

June 9, 2009 (Berlin, Germany) — New results from a phase 2 trial with nilotinib (Tasigna) used first-line in patients with early chronic-phase chronic myeloid leukemia (CML) showed responses that were superior and faster than those seen historically with the current standard of care, imatinib (Gleevec).

"These early results are very encouraging," said lead investigator Gianantonio Rosti, MD, from St. Orsola-Malpighi University Hospital in Bologna, Italy, who presented the findings here at the 14th Congress of the European Hematology Association.

Currently, nilotinib is approved only for second-line use in patients who have become resistant or intolerant to imatinib. But in the long term, only 70% of CML patients taking imatinib maintain a perfect response, so other therapies are needed, Dr. Rosti explained.

The new results come from a multicenter study, conducted by the Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) CML working party, investigating the use of nilotinib 400 mg twice daily as a first-line treatment for early chronic-phase CML for 1 year.

Blood counts and differential and serum chemistry were assessed at baseline, every 15 days for 3 months, and then every 30 days for 9 months. A bone-marrow aspirate was taken after 3 and 6 months for cytology and cytogenetics, and after 12 months for cytology, cytogenetics, quantitative molecular biology, and mutational analysis. After the end of the study, data were collected every 6 months.

Nilotinib showed a complete cytogenetic response (CCgR) of 96% at 6 months. The achievement of the first major molecular response, after 1, 2, 3, 6, 9, and 12 months, was 3%, 21%, 52%, 66%, 73%, and 85%, respectively.

Results from this uncontrolled intervention study were compared with data for imatinib. For reference, the 400 mg imatinib group of a study known as the IRIS trial showed cumulative rates of CCgR of 51%, 69%, and 87% at 6, 12, and 60 months, respectively. However, one quarter of all imatinib-treated patients fail to acheive or maintain a stable CCgR because of upfront resistance, refractoriness, or intolerance.

"Clearly, the results with nilotinib in CML show that the response is superior to imatinib in terms of rapidity and molecular quality. It is difficult to do better than imatinib, with which we see 60% to 80% CCgR after 1 year of treatment or more, but these results show that improvement is very clear. This study only had 73 patients . . . from 18 centers, but these early results are very encouraging," Dr. Rosti emphasized.

CML is characterized by a chromosomal marker called the Philadelphia chromosome. This carries the BCR-ABL gene, which codes for a specific leukemic BCR-ABL protein. Imatinib selectively inhibits the action of the BCR-ABL protein, but nilotinib has a higher binding affinity and selectivity for the oncoprotein than imatinib, and is highly effective in imatinib-resistant patients across all 3 disease phases. Furthermore, nilotinib inhibits nearly all the imatinib-resistant BCR-ABL mutants.

"At the moment, we aim to have most patients alive with minimal or no trace of the disease at a molecular level. Ultimately, we want a proportion of patients to stop treatment altogether. Even with new drugs, nothing acts in such a way as to eliminate the last leukemia stem cell. As yet it is unknown, but a combination of [tyrosine kinase inhibitor] with interferon, for example, might help cure the disease or at least enable a patient to remain without treatment for 4 or 5 years," explained Dr. Rosti.

Dr. Rosti pointed out that nilotinib is well tolerated and adverse effects are manageable. "From a biochemical point of view, we see increased bilirubin, a transitory increase in liver enzymes, and some hyperglycemia, but most side effects are short lived and nearly all patients continue treatment." One patient discontinued treatment because of an increase in the pancreatic enzymes amylase and lipase without pancreatitis. A second patient progressed to the blastic phase after 6 months on nilotinib.

Commenting on the results, John Goldman, MD, senior research investigator at Imperial College London in the United Kingdom, told to Medscape Oncology that imatinib was facing competition from 2 promising new tyrosine kinase inhibitors. "Nilotinib is a chemical modification of imatinib. It fits into the binding pocket [of the BCR-ABL protein] with less extraneous material than imatinib. In vitro studies show it is more powerful than imatinib and it is 1 of the 2 or 3 second-generation [tyrosine kinase inhibitors] that, in my view, will replace imatinib in the next couple of years as primary therapy. Dasatinib is [as] effective as nilotinib against leukemia, so for a new patient who can afford either of these new drugs, I expect they will become the treatment of choice."