High-dose imatinib improves cytogenetic and molecular remissions in patients with pretreated Philadelphia-positive, BCR-ABL-positive chronic phase chronic myeloid leukemia: first results from the randomized CELSG phase III CML 11 "ISTAHIT" study

Safety and efficacy of switching to nilotinib 400 mg twice daily for patients with chronic myeloid leukemia in chronic phase with suboptimal response or failure on front-line imatinib or nilotinib 300 mg twice daily

“…10 Several studies have shown that imatinib dose escalation may provide additional benefit in some patients with suboptimal responses /treatment failure on standard-dose imatinib; [11][12][13] however, high-dose imatinib is associated with an increased risk of adverse events (AEs), particularly grade 3/4 hematologic toxicity. 14,15 The safety and efficacy of nilotinib in patients with imatinib-resistant or -intolerant CML are well established. [16][17][18][19][20] However, prospective clinical data evaluating the benefits of switching patients with suboptimal response on front-line imatinib to nilotinib are limited.…”

High-dose imatinib induction followed by standard-dose maintenance in pre-treated chronic phase chronic myeloid leukemia patients - final analysis of a randomized, multicenter, phase III trial

“…The eligibility criteria have been described in detail elsewhere. 18 In brief, CML patients in CP aged over 18 years had to have been pretreated with drugs other than a bcr-abl-specific tyrosine kinase inhibitor for at least 12 months and should not have achieved a MCyR or anything better by study entry. All patients provided written informed consent to their participation in the study in accordance with the Declaration of Helsinki.…”

“…Events were defined as death from any cause during treatment, progression to accelerated phase or blast crisis, loss of a complete hematologic response, or loss of a MCyR. According to the protocol and due to an interim analysis, 18 final analysis was set at 0.048. All tests were two-sided.…”

Role of High Dose Imatinib in BCR/ABLpos/Phpos CML

“…The reasons for choosing this strategy were a "hit hard and early" concept in order to achieve rapid and deep cytogenetic and molecular responses on the one hand and concerns on reported hematotoxicity on the long term on the other hand, especially in regard to this pre-treated patient population in later chronic phase . A report on a planned interim analysis (after half of the patients had been treated for 12 months) demonstrated significant improvements in the rates of MCyR and CCyR at early time points such as 3 and 6 months as well as in MMR IS at 6 months in favour of HD imatinib compared to the standard dose (400 mg once daily) (Petzer et al, 2010a). As expected for this heavily pre-treated patient population, WHO grade 3 and 4 hematotoxicity was significantly increased during the first 6 months in HD imatinib arm, whereas WHO grade 3 and 4 non-hematotoxic AEs were comparable.…”

“…A different approach was tested by the Central European Leukemia Study Group (CELSG) in the international multicentre Imatinib STAndard dose versus High dose Induction Trial ("ISTAHIT") ( Petzer et al, 2010a). Different from the other phase III trials that tested HD imatinib versus the standard dose they tested pre-treated CML patients in CP.…”