High-dose imatinib as a frontline treatment of CML-CP
The recommended dose of imatinib for initial therapy ofCML-CP is 400 mg daily.4 Of note, a maximum tolerateddose for imatinib has never been established.
Continue Reading
The doseof 400 mg daily was recommended based on the originalPhase I study by Druker et al as a one level higher thana dose which yielded good hematologic and cytogeneticresponses (CyRs) in patients with CML-CP.2
Nevertheless,there have been some preliminary reports suggesting thathigher imatinib dosage, such as 600 or 800 mg daily, couldbe more effective and lead to deeper and faster cytogeneticand molecular responses than the standard dose.5,6
Beforethe era of 2G-TKIs, the conception of high-dose (HD)imatinib as a frontline therapy of CML-CP was widelyexplored. There have been many clinicaltrials addressingthis issue. Kantarjianet al reported the study of 114 patientswith newly diagnosed CML-CP treated with imatinib at thedose of 400 mg twice daily.
Compared with the standarddose, HD imatinib was significantly associated with a betterrate of complete cytogenetic response (CCyR) (P=0.0005),major molecular response (MMR) (defined as BCR-ABL/ABL ratio #0.05%), (P=0.00001), and complete molecularresponse (CMR, undetectable BCR-ABL) (P=0.001). HDimatinib was well tolerated but resulted in more frequentmyelosuppression.7
The other study, 2-Arm Phase III trial,was conducted in 227 patients with CML-CP, previouslyresistant or intolerant to interferon-alpha (IFN-α). Thestudy compared the standard dose of imatinib400 mg daily(arm A) with HD imatinib (800 mg daily) for 6 months,followedby 400 mg daily as a maintenance(arm B).
Imatinibdosage of 800 mg daily resulted in a significantlyhigher rate of CCyR and MMR at 6 months but not at 12months as compared with the dose of 400 mg daily.
In contrastto non-hematologic toxicities, grade 3/4 hematologictoxicitieswere significantly more common in the HD armB.8 In TIDEL-I study, Hughes et al used a dose-optimizationapproach in a clinical trial encompassing 103 patients withnewly diagnosed CML-CP. In this study, patients weretreated with imatinib 600 mg daily with response monitoredevery 3 months.
Patients who failed to achieve a completehematologic response (CHR), major cytogenetic response(MCyR), CCyR, or MMR by 3, 6, 9, and 12 months weretreated with a high dose of 800 mg imatinib once daily.Dose interruptions were indicated for serious hematologicand non-hematologic toxicity.
Using this approach, theestimatedcumulative incidences of CCyR by 12 monthsand 24 months were 88% and 90%, respectively, and MMRrates were 47% and 73%, respectively.9
These responserates were superior to those achieved with standard doseimatinib.10,11 In patients who maintained a daily average doseof 600 mg of imatinibfor the first 6 months, MMR rates by12 months and 24 months were 55% and 77% comparedwith 32% and 53% in patients averagingless than 600 mgdaily (P=0.037 and 0.016), respectively.
Recently, the resultsof the second part of the TIDEL study have been published.The study encompassed 210 patients with newly diagnosedCML-CP divided into two equal cohorts. The initial therapywas imatinib 600 mg/day in all patients. The study endpointswere defined molecular targets: BCR-ABL1 #10%, #1%,and #0.1% at 3, 6, and 12 months, respectively.
