The vast majority of patients with chronic myeloid leukaemia (CML) have a chromosomal aberration known as the "Philadelphia chromosome", a translocation of part of chromosome 22 with part of chromosome 9. This fuses part of the BCR gene on chromosome 22 with part of the ABL gene on chromosome 9, forming the oncogenic tyrosine kinase BCR-ABL. Prospects for patients with this disease were transformed about ten years ago by the development of the specific BCR-ABL inhibitor imatinib (Gleevec® /Glivec®). This is a very effective drug, particularly when given during the initial chronic phase of the disease when symptoms are mild, but in a minority of cases the drug is either ineffective (imatinib resistance) or patients exhibit severe side effects (imatinib intolerance). The structurally similar second-generation BCR-ABL inhibitors dasatinib and nilotinib were designed rationally using information from the crystal structure of the imatinib-enzyme complex to counteract this resistance.

Nilotinib is known to be effective in treating patients with CML following failure of imatinib. An international group of researchers led by Jorge Cortes at the M.D. Anderson Cancer Center, University of Texas, Houston, USA has now investigated whether patients with imatinib intolerance (that is, patients in whom treatment with imatinib failed due to adverse effects) are cross-intolerant to nilotinib¹ using data from a Phase II registration study of nilotinib². Imatinib-intolerant patients were selected from this study of Philadelphia chromosome positive CBL patients, all of whom were in the chronic or acute phase and had experienced resistance or intolerance to imatinib. Out of 458 enrolled patients, a total of 95 with chronic phase leukaemia (CML-CP) and 27 in the acute phase (CML-AP) who exhibited imatinib intolerance and had 24 months nilotinib treatment or discontinued the study, were included in this post hoc analysis.

Seventy-five of these 122 patients had experienced either severe (grade 3/4) or long-lasting (persistent grade 2) non-haematological side effects when treated with imatinib; 60 of these had CML-CP and 15 had CML-AP. Only four of these experienced the same severe or persistent toxicity with nilotinib, and none of these withdrew from the trial or reduced their dose because of this toxicity. Interestingly, all four patients who experienced this toxicity were in the chronic phase of the disease. Out of thirty-one patients with CML-CP and nine with CML-AP who discontinued imatinib due to severe or persistent adverse effects, more – 17 of those in the chronic phase and four of those in the acute phase – experienced severe or persistent adverse effects with nilotinib, but only seven in the chronic phase and none in the acute phase discontinued nilotinib on account of these effects.

The overall safety profile of nilotinib in these patients was similar to that in patients with imatinib resistance, with rash, pruritus, nausea and vomiting the most commonly reported non-haematological side effects. Haematological side effects, particularly neutropenia, thrombocytopenia, and anemia, were more common. The drug was also effective, with 90% of chronic phase patients in the chronic phase who were not in complete haematological response when nilotinib treatment was initiated achieving such a response on the drug, and a major cytogenetic response achieved by 66% of chronic phase and 41% of acute phase patients respectively. These responses were rather better than those experienced by patients with prior imatinib resistance.

Taken together, these results confirm that nilotinib is an effective treatment for CML that exhibits minimal cross-intolerance with imatinib. Cortes and his co-workers conclude that nilotinib should be considered as a second-line or subsequent treatment for patients in the chronic or acute phase of CML who have discontinued imatinib treatment due to unacceptable side effects.

References

1. Cortes, J.E., Hochhaus, A., le Coutre, A.D. and 9 others Minimal cross-intolerance with nilotinib in patients with chronic myeloid leukemia in chronic or accelerated phase who are intolerant to imatinib Blood published online ahead of print 4 April, 2011 DOI 10.1182/blood-2010-11-318949

2. Kantarjian HM, Giles F, Gattermann N, et al. Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance Blood 110(10): 3540-6;

le Coutre P, Ottmann OG, Giles F, et al. Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is active in patients with imatinib-resistant or –intolerant accelerated-phase chronic myelogenous leukemia Blood 111(4): 1834-9 (2008)