The ELN criteria (2009 version) recommended dose escalation of imatinib in case of failure or suboptimal response.21 The primary study endpoints were event-free survival (EFS) (events were defined as the first occurrence of death from any cause, progression to AP/BP of CML, or loss of an MCyR) and OS.

The median time to dose escalation was 22 months for the entire cohort. Of the patients who had dose escalation based on IRIS protocol criteria, 86% achieved or regained their hematologic response within 12 months of dose escalation, and 42% achieved or regained a CyR. Of the patients who had dose escalation according to the ELN recommendations, 67% achieved or regained a hematologic response within 12 months of dose escalation, and 38% achieved or regained a CyR.

Continue Reading

Among all patients who underwent dose escalation, the rates of freedom from progression to AP/BP and OS were 89% and 84% at 3 years after dose increase, respectively. Relative to treatment with the standard imatinib dose, an increased frequency of grade 3/4 adverse events was observed after dose escalation to $600 mg daily for superficial edema, headache, abdominal pain, hemorrhage, pyrexia, anemia, and thrombocytopenia.22

The other study reported on 74 patients with hematologic failure, cytogenetic resistance, or suboptimal response to conventional imatinib dose. In all, 54 patients received imatinib dose escalation from 400 mg to 600 mg daily and 20 patients were dose-escalated from 400 to 800 mg daily.

An MCyR was achieved in 41 patients (72%) who escalated imatinib dose for cytogenetic failure and in six patients (46%) with hematologic failure. A CCyR was achieved in 27 patients (37%): 38% of the hematologic failure patients and 42% of the cytogenetic-resistant patients.

After 3 years of follow-up, all responding patients were in sustained CCyR. The estimated 2-year PFS and OS was 87% and 85%, respectively.23 In the study by Jabbour et al, the long-term efficacy of imatinib dose escalation in 84 patients with CML-CP who met the ELN criteria of failure to standard-dose imatinib was assessed.

In all, 21 patients with hematologic failure and 63 with cytogenetic failure had their imatinib dose escalated from 400 mg to 800 mg daily (n=72) or from 300 to 600 mg daily (n=12).

After a median follow-up of 61 months from dose escalation, 69% remained alive. CMR (absence of BCR-ABL1 transcript) was achieved in 40% patients, including 52% of patients with cytogenetic failure and 5% of those with hematologic failure.

The estimated 2- and 3-year EFS and OS rates were 57% and 47%, and 84% and 76%, respectively. Responses were long lasting; 88% of patients with MCyR sustained their response beyond 2 years.

Treatment was well tolerated, with 76% of patients at 12 months continuing to receive imatinib at 100% of the intended dose.24 Taken together, the aforementioned studies show that imatinib dose escalation appears to induce sustained responses in a subset of patients with cytogenetic failure or acquired cytogenetic resistance.

In second-line therapy, HD imatinib does not significantly improve patient outcomes without a prior CyR. START-R was a Phase II randomized study comparing dasatinib with HDs of imatinib after failure of the latter at the standard dose.