High-dose imatinib as a second-line therapy for standard dose imatinib failure in CML-CP

Before the 2G-TKIs have become widely used in second-line therapy, imatinib dose escalation was one of very few available options in patients with CML-CP resistant to standard dose imatinib (400 mg daily).

Mechanisms of imatinib resistance that could be potentially overcome with dose escalation include, but are not limited to, over-expression of BCR-ABL1 and gene amplification.

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Several clinical studies have tried to identify whether and which imatinib-resistant CML-CP patients might benefit from such an intervention. Marin et al reported on the outcome of 36 patients with CML-CP in CHR in whom imatinib dosage was increased when they failed to achieve CCyR. Fourteen patients (39%) improved their CyR and seven (19%) achieved CCyR.

The responses were short lasting, and six patients (43%) lost their best response and, at latest follow-up, only nine patients (25%) had sustained improvement with five of them (14%) remaining in CCyR.19

Furthermore, in the study conducted by Zonder et al, patients with CML-CP who had imatinib dose increased from 400 mg daily to 600–800 mg daily because of progressive disease (due to clonal evolution in majority of them) or inadequate CyR, after at least 1 year of therapy did not achieve significantly better responses.20 Six patients achieved MCyR (three complete and three partial).

Two others had minor cytogenetic responses (mCyRs). Two patients with clonal evolution transiently lost the additional clonal aberrations. Almost all of the responses occurred within 6 months, and were typically 3–6 months in duration.20

However, studies that provide rationale for HD imatinib in patients resistant to conventional dose have also been published in the literature. Kantarjian et al reported on 106 patients with newly diagnosed CML-CP who had been enrolled on the International Randomized Study of Interferon and STI571 (IRIS) trial, who began treatment with imatinib at a dose of 400 mg daily, and who subsequently underwent dose escalation to either 600 or 800 mg daily.

Reasons for dose escalation were evaluated retrospectively based on two sets of criteria: the IRIS protocol-defined criteria and the ELN recommendations.

The IRIS protocol allowed dose escalation of imatinib to 600 mg and then, 1 month later, to 800 mg for the following reasons: 1) failure to achieve CHR by 3 months, 2) failure to achieve at least an mCyR (36%–65% Philadelphia chromosome [Ph]-positive metaphases) by 12 months, 3) loss of an MCyR (<35% Ph-positive metaphases) at any time, and 4) progression.