The Pharmaceutical Journal
Vol 276 No 7405 p714
17 June 2006

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Treatment options set to expand for patients with imatinib-resistant chronic myeloid leukaemia

Dasatinib and nilotinib, novel tyrosine kinase inhibitors currently in development, induce haematologic and cytogenetic responses in patients with imatinib-resistant leukaemias, two studies published this week in The New England Journal of Medicine reveal (2006;354:2531 and 2542).

Of the 84 patients enrolled in the first study, 40 had chronic-phase chronic myeloid leukaemia (CML), 11 had accelerated-phase CML, 23 had myeloid blast crisis and 10 had lymphoid blast crisis. Oral dasatinib (15mg to 240mg per day) was administered in four-week treatment cycles, once or twice daily.

A complete haematologic response was seen in 37 of the 40 chronic phase CML patients (92 per cent), with 18 (45 per cent) achieving a major cytogenetic response (substantial reduction in cells with the Philadelphia chromosome in the bone marrow).

In patients with accelerated-phase CML and blast crisis, and in patients with acute lymphoblastic leukaemia (ALL), a major cytogenetic response was reported in between 27 and 80 per cent of patients. Responses in these patients were generally short-lived.

The major adverse effect of dasatinib was myelosuppression. Importantly, the 12 patients who could not tolerate imatinib did not have a recurrence of imatinib-associated non-haematologic toxic effects.

The researchers conclude: “Successful long-term treatment of CML may require a cocktail of kinase inhibitors with activity against all drug-resistant BCR-ABL mutations, analogous to the success of highly active antiretroviral therapy in the treatment of infection with HIV.”

The second trial involved 119 patients with imatinib-resistant CML or Philadelphia-positive ALL who were given nilotinib (50mg to 1,200mg per day) once or twice daily. Results indicate that the drug improves outcomes in CML, and is most effective in chronic-phase CML. It was less active than expected in patients with ALL; only two of 13 patients responded.

Lead investigator Hagop Kantarjian, of the University of Texas M.D. Anderson Cancer Centre, Houston, commented that nilotinib appears to have fewer side effects than imatinib (Glivec). However, some patients in the trial had abnormal electrocardiograms, and one patient experienced two cardiac events.

“We believe this issue is manageable with the right dose of nilotinib and with careful monitoring,” he added.

Nilotinib is being developed by Novartis, manufacturer of Glivec (imatinib). Dasatinib is being developed by Bristol-Myers Squibb.