Promising Long-Term Results of Imatinib for CML
Promising Long-Term Results of Imatinib for CML
Abstract & Commentary
By Andrew S. Artz, MD, MS, Section of Hematology Oncology, University of Chicago. Dr. Artz reports no financial relationship to this field of study.
Synopsis: Imatinib inhibits the BCR/ABL tyrosine kinase in CML, leading to improved responses over standard therapy. This report provides 5 year follow-up from the seminal IRIS study of upfront imatinib for chronic phase CML among the 553 patients randomized to 400 mg of imatinib. The estimated best complete cytogenetic response was 69% and 87% at 12 and 18 months, respectively. Sixty-nine percent were still on imatinib after 5 years. Overall survival was 89% at 5 years with 7% progressing to accelerated-phase or blast crises. Grade 3 or 4 adverse events decreased with longer time on treatment. The majority of patients achieve durable remissions using imatinib as initial therapy for chronic phase CML.
Source: Druker B, et al., for the IRIS Investigators. Five-Year Follow-up of Patients Receiving Imatinib for Chronic Myeloid Leukemia. N. Eng. J. Med. 2006;355:2408-2417.
The translocation creating the Philadelphia chromosome results in the Bcr-Abl fusion protein and represents the central event in Chronic Myeloid Leukemia (CML). Imatinib (Gleevec™, originally known as STI-571) inhibits the aberrant tyrosine kinase activity of Bcr-Abl. It became quickly apparent that single agent imatinib had considerable activity in CML with low toxicity.1 These exciting results quickly translated into a definitive randomized study of CML chronic phase, comparing imatinib to the standard therapy of interferon alfa and low dose cytarabine.2 More than 1100 patients were enrolled in the Phase III International Randomized Study of Interferon and STI571 (IRIS). The estimated rates of complete cytogenetic response in the imatinib arm were 76% compared to only 14.5% with standard therapy. The long-term outcomes remained unclear in light of the relatively short follow-up of 19 months and a cross-over design. The study continued to monitor patients and thus now offers a more complete picture of the durability of responses and long-term imatinib tolerability.
The IRIS study enrolled 1106 subjects between 18 and 70 years of age with chronic phase CML within 6 months of diagnosis and not previously treated, except for hydroxyurea or anagrelide. Patients were randomized to imatinib at 400 mg daily or the combination of subcutaneous interferon alfa with low dose cytarabine. Cross-over to either arm was allowed because of poor responsiveness or toxicity. Patients were enrolled over a relatively short period of time between June 2000 and January 2001. The censor date for the analysis of January 31, 2006 allows 5 years follow-up for the last enrolled patient.
Only 3% (16/553) continued with their randomized arm of interferon alfa plus cytarabine while 69% (382/553) stayed with their initial assignment of imatinib. Thus, long-term results are reported only for the imatinib treated patients. The vast majority of the 382 imatinib treated patients were still taking 400 mg daily (82%). Grade 3 and 4 adverse events were very uncommon after year 2, primarily consisting of neutropenia (3%) and "other" drug related adverse events (4%).
The rate of major and complete cytogenetic responses for imatinib-treated patients was 89% and 82%, respectively. Among the 382 subjects still receiving imatinib at 5 years, 96% had a complete cytogenetic response. Only 6% (35/553) assigned to imatinib progressed to accelerated phase. Five percent lost a major cytogenetic response and 2% died from unrelated causes. The proportion on treatment who failed declined after year 2, from 7.5% in the second year, to 4.8%, 1.5%, and 0.9% in the third, fourth, and fifth year, respectively. Among the 350 patients who had a complete cytogenetic remission after 12 months of imatinib, 97% had not progressed, whereas 81% had not progressed among those not achieving a major cytogenetic response by 12 months of imatinib.
Five year overall survival was 89% (95% CI, 86 to 92) by intention to treat in the imatinib-assigned patients. Forty-four patients eventually underwent allogeneic transplant, of which 32% had died.
Commentary
These updated results from the IRIS study summarize outcomes for newly diagnosed chronic phase CML using imatinib as front-line therapy. The 89% survival at 5 years is excellent and better than prior studies in the pre-imatinib era. The cross-over design prevents determination of a survival benefit compared to interferon alfa with cytarabine. Nevertheless, the low toxicity and persistent control of disease solidifies the recommendation of imatinib as initial therapy for chronic phase CML for most patients.
Reaffirming the positive results was the remarkable fact that among those who achieved a major cytogenetic remission at 12 months, only 3% developed disease progression at 5 years. Among those who achieved a cytogenetic remission, only a subset of 124 was tested for BCR-ABL transcript levels. Of those with a three-fold log BCR-ABL reduction, no patient progressed. Progression rates appeared to decrease with each year on therapy. The authors postulated that the decreasing rate of disease progression is consistent with the hypothesis that BCR-ABL mutations conferring resistance are primarily present at diagnosis, rather than evolving during therapy.
A major question remains whether we can identify newly diagnosed chronic phase CML patients for whom imatinib will not induce durable remissions. The present strategy has been to follow the kinetics of response during imatinib therapy either by cytogenetics or BCR/ABL transcripts and consider novel tyrosine kinase inhibitors and/or transplant in cases of inadequate responses. Mutational sequencing may also guide therapy. The Sokal score3 helped predict responses with an 89% complete cytogenetic response rate for low-risk disease and 69% for high-risk patients. These differences may warrant closer monitoring of high-risk patients by Sokal score, but do not appear great enough to justify a different treatment strategy for patients having a high Sokal score.
Toxicity rates also decreased each year on therapy. A concern about serious cardiac toxicity was recently raised when a series of 10 cases were reported due to Imatinib.4 However, in the IRIS study, only a single case was reported. Further post-marketing surveillance will be required to define the true incidence of this complication.
In summary, imatinib as initial therapy for chronic-phase CML shows excellent 5 year disease control and tolerability.
References:
1. Druker BJ, et al. Efficacy and safety of a specific inhibitor of the BRC-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med. 2001;344:1031-1037.
2. O'Brien SG, et al. N Engl J Med. 2003;348:994-1004.
3. Sokal JE, et al. Blood. 1984;63:789-799.
4. Kerkela R, et al. Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat Med. 2006;12:908-916.
Imatinib inhibits the BCR/ABL tyrosine kinase in CML, leading to improved responses over standard therapy. This report provides 5 year follow-up from the seminal IRIS study of upfront imatinib for chronic phase CML among the 553 patients randomized to 400 mg of imatinib.Subscribe Now for Access
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