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Imatinib: Time to Rethink 400 mg Starting Dose?

Carlson, Robert H.

doi: 10.1097/01.COT.0000368426.42926.06


NEW ORLEANS—For adult patients who present with chronic myeloid leukemia (CML) in chronic phase it is now generally agreed that initial treatment should start with the tyrosine kinase inhibitor (TKI) imatinib at a dose of 400 mg daily. But experts in an Educational Session here at the ASH Annual Meeting titled “Chronic Myeloid Leukemia: After a Decade of Imatinib” said that a higher starting dose of 600 mg a day could be appropriate for select patients.

John M. Goldman, DM, Emeritus Professor of Hematology at Imperial College in London, explained that the standard starting dose of 400 mg/d is based on the starting dose in the Phase III International Randomized Study of Interferon and STI571 (IRIS) study for newly diagnosed chronic-phase CML—“This was despite the fact that the maximum tolerated dose was never reached in preliminary studies.”

Dr. Goldman cited two single-arm studies of patients who started imatinib at 800 mg/d (Kantarjian el al: Blood 2004;103: 2873–2878; and a study led by Jose Cortes reported at the 2006 ASH Annual Meeting).

Some patients were unable to tolerate this higher dosage, Dr. Goldman said, but complete cytogenic responses and major molecular responses were achieved more rapidly with the higher dose of imatinib compared with the results for patients receiving 400 mg/day daily. Still, it appears that while response to the higher dose is clearly more rapid, no survival benefit has yet been seen with the higher dose at 18 months, he said.

Dr. Goldman cited the “TOPS” study, which he said continues to confirm the safety and efficacy of imatinib at 400 mg/day for newly diagnosed patients with chronic-phase CML, with results very similar to those in the IRIS study (study reported by Michele Baccarani as Abstract 337 at the 2009 ASH Meeting).

“The essential question here is whether the speed of response is critically important for the long-term survival and the long-term event survival,” Dr. Goldman said.

The data presented at the ASH meeting suggest that the speed of response is an important prognostic factor for subsequent events, he added.

“One might speculate that the best starting dose for the individual patient who is not in a prospective trial might possibly be something between 400 and 800 mg/d—namely 600 mg/d. But at the moment the recommended basic starting dose for chronic-phase patients is 400 mg/d.”

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Predicting Response at 400 mg/day

Dr. Goldman said there are possible pre-therapy predictors of response to imatinib at 400 mg/d, including the Sokal score (combining age, spleen size, platelet count, and the percentage of myoblasts in blood), the IC50 for imatinib, and organic cation transporter 1 (hOCT1) level.

After starting therapy, the indicators of response to imatinib might be plasma imatinib levels, early molecular response, and the adherence of the individual patients.

“It's interesting that 25 years after Joseph Sokal produced this scoring system, that it still has significance in predicting good or bad response on imatinib,” Dr. Goldman said.

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Higher Risk, Higher Dose

Asked after the session for his opinion, Brian Druker, MD, the moderator of the session, whose research led to the development of imatinib, said, “What I've done over the years has been to look at Sokal features, and by that I mean if somebody's in a higher risk group, or I know that their complete cytogenetic response rate is lower on 400 milligrams, I actually will try to start at 600, as opposed to 400.”

He said if the patient is in the standard-risk group with a lower Sokal score, he will likely start therapy at 400 mg/d.

“But in addition, if I'm concerned about a patient or if they're not seeing an early response and I'm checking a drug level, if it's lower than 1,000 ng/mL, I will up their imatinib dose.”

Much less is known about appropriate dosing for nilotinib or dasatinib, Dr. Druker added, “so we have lots more to do in that area.”

© 2010 Lippincott Williams & Wilkins, Inc.
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