Not too late for imatinib

In this issue of Blood, Hochhaus and colleagues demonstrate that among chronic myeloid leukemia (CML) patients who had previously failed interferon, 76% remain alive and 44% remain on imatinib mesylate therapy after 6 years.

Imatinib mesylate was clearly shown to be the standard of care for patients with newly diagnosed chronic myeloid leukemia (CML)– chronic phase by the randomized phase III clinical trial IRIS (International Randomized Study of Interferon and STI-571).¹  The landmark trial demonstrated a complete cytogenetic response rate of 76% at 18 months in the imatinib arm, with 96.7% of patients avoiding progression to accelerated or blast phase. Long-term outcomes of the trial demonstrated durability, with 87% of patients achieving a complete cytogenetic response by 60 months, and 93% remaining in the chronic phase at that junction.²  These results are clearly astonishing in the universe of hematologic malignancies, but were achieved in the “cleanest” study population: namely untreated, newly diagnosed CML. What about everyone else who had CML prior to the widespread availability of imatinib in 2001?

In this edition of Blood, Hochhaus and colleagues report on the long-term outcomes of the single-arm phase II trial of standard dose imatinib in a large cohort (n = 532; primarily chronic phase) of CML patients who had failed interferon therapy and were a median of 34 months from diagnosis. The initial results of this trial were the basis for the initial Food and Drug Administration approval of imatinib in CML. Among the study cohort (64% with inadequate response to interferon), 57% achieved a complete cytogenetic response, of whom 41% remained in that response through the 5-year time point. In addition, 61% remained in the chronic phase 6 years after enrollment in the trial. As in the IRIS trial,²  the quality of the cytogenetic response by 12 months was predictive of long-term risks of progression.

So how does the study by Hochhaus and colleagues help us further understand the impact of imatinib therapy in CML? First, the study clearly shows that even in pretreated patients, imatinib keeps many in an excellent progression-free state for a long period of time. Indeed, the 6-year overall survival rate of 76% easily trumps historical controls of 15% to 20%.³  Second, the rates of response and progression-free survival and the percentage of patients who remain on imatinib are all lower compared with the newly diagnosed group in the IRIS trial.

The differences between this current trial and the IRIS trial suggest that disease progression in CML is probably not solely a BCR-ABL–driven phenomenon and that inadequate (or in this case delayed) suppression of the tyrosine kinase may allow disease evolution. The latter observation forms the basis for the current research agenda in CML. Will higher initial doses of imatinib, or a second-generation inhibitor such as dasatinib⁴  or nilotinib, decrease rates of progression? How can BCR-ABL be best suppressed in patients with mutations (such as the T315I) that render them insensitive to current kinase inhibitors?⁵  What is the best way to monitor response to tyrosine kinase inhibition, and what thresholds should be established for altering therapy or considering allogeneic stem-cell transplantation? Unraveling the mechanism of disease progression is crucial for guiding CML therapy, elucidating further targeted therapy beyond tyrosine kinase inhibition, and may yield insight into mechanisms of disease progression in the other chronic myeloproliferative disorders.