Many agents are in development to fight resistance to Gleevec (imatinib, Novartis) in patients with chronic myeloid leukemia (CML). That was one of the issues highlighted at the recent meeting of the American Society of Hematology (ASH), held in Orlando, Fla. The meeting drew 20,000 attendees seeking news of improved treatments for blood cancer.
Said investigator Charles A. Linker M.D., clinical professor of medicine, University of California, San Fran- Francisco, "The expanding anti-resistance research is very important for patients who relapse on imatinib therapy. [The research] not only shows the efficacy of certain new imatinib-like drugs, but it encourages us to study each patient's mutation pattern to tailor his/her course of therapy."
Imatinib treatment originally allowed CML patients to experience a 90% five-year survival rate; the agent inhibited BCR-ABL, an abnormal protein driving the overproduction of white blood cells characteristic of leukemia. But as cancer cells mutated and adapted, resistance appeared, followed by relapse. "The new drug nilotinib (Tasigna, Novartis), a tyrosine kinase inhibitor like Gleevec, was specifically designed for patients resistant to or intolerant of Gleevec," Linker said.
After nilotinib treatment twice a day (400 mg) for three to six months, more than 70% of the patients with mutations had a hematologic response (control of white blood cells), and about half had a major cytogenic response (elimination of cancer-carrying cells).
Suggested lead author Andreas Hochhaus, M.D., professor of internal medicine, University of Heidelberg, Mannheim, "Nilotinib helps, when imatinib fails, by overcoming the mutations that cause resistance.... Response to nilotinib depends on the type of BCR-ABL mutations in each individual CML patient after imatinib failure."
The recently Food & Drug Administration-approved dasatinib (Sprycel, Bristol-Myers Squibb) is an oral inhibitor of multiple tyrosine kinases. It blocks BCR-ABL production so that both imatinib-resistant CML and acute lymphocytic leukemia ( ALL) respond dramatically to it.
Hochhaus also presented results from a randomized phase III study showing that resistant CML patients receiving dasatinib 100 mg once a day achieved similar cytogenic responses at six months with fewer adverse events than patients receiving three other dosing schedules-including the FDA-approved dose of 70 mg twice a day.
"Thus, many patients resistant to Gleevec respond to a once-daily dose of Sprycel with an improved safety and tolerability profile," Hochhaus said.
Researchers from the M. D. Anderson Cancer Center, Houston, were excited about results from a phase I trial of Merck & Co.'s complex new tyrosine kinase inhibitor MK-0457. The agent is clinically active against multiple target mutations in several leukemias and myeloproliferative disorders, they said, yet produces only minor side effects.
MK-0457 targets chronic myeloid leukemia by inhibiting aurora kinases (cell-development enzymes) as well as BCR-ABL kinases, including those with the baffling T315l mutation. It also fights the refractory JAK-2 mutation found in myeloproliferative diseases (MPD).
The dose escalation trial looked at 44 patients with advanced leukemias and MPD who received MK-0457 as a five-day IV infusion every two or three weeks. Of the 15 patients with refractory CML, nine had a T3151 BCR-ABL mutation. Of these, eight responded positively to MK-0457.
"MK-0457 produces clinical and biologic activity where we have not seen it before," emphasized lead investigator Francis J. Giles, M.D., from M. D. Anderson's department of leukemia. "A broader phase II trial in these patients is under way."
In more ASH treatment news, information on more than a dozen new or updated agents for patients suffering from idiopathic thrombocytopenic purpura (ITP) was presented. Here is a sampling: