ATLANTA—Updated results from the landmark International Randomized Interferon vs STI 571 [imatinib] (IRIS) study, which prospectively compared imatinib therapy with interferon-alfa plus cytarabine in newly diagnosed adult patients with Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) in chronic phase, show that 90.3% of patients who were initially randomized to take imatinib were still alive at 54 months.
Bengt Simonsson, MD, PhD, of University Hospital in Uppsala, Sweden, reported the results here at the American Society of Hematology Annual Meeting.
In addition, the yearly risk of progressing to advanced disease fell to less than 1% in the fourth year, the lowest rate seen in this study so far, he said.
Also, 100% of patients who achieved a major molecular response to treatment at 12 months were free of progression to accelerated phase or blast crisis at 54 months. “Once patients achieve a complete cytogenetic response at 12 months, their prognosis of survival is the same throughout all risk groups,” he said.
At 54 months, 98% of patients had a complete hematologic response, 92% had a major cytogenetic response, and 86% had a complete cytogenetic response. The tolerance to imatinib continues to be good, with most Grade 3/4 toxicities including neutropenia and thrombocytopenia, he said.
“Imatinib continues to demonstrate good tolerability and efficacy as a first-line therapy. Only 3% of patients who achieved a complete cytogenetic response at 12 months progressed to advanced disease at 54 months.”
All of the patients who showed more than a 3-log reduction in BCR-ABL transcripts within 12 months did not progress to advanced disease at 54 months.
The yearly risk of progressing to advanced disease fell to less than 1% in the fourth year of follow-up, the lowest rate seen in the IRIS data so far.
Extends Survival in Newly Diagnosed Philadelphia Chromosome-Positive Chronic-Phase CML Patients
New data from a retrospective comparative analysis based partially on imatinib data from IRIS showed for the first time that imatinib significantly extended overall survival in newly diagnosed Ph+ CML patients in chronic phase compared with historical treatment of interferon plus cytarabine, reported François Guilhot, MD, of the Clinical Research Centre at University Hospital in Poiters, France.
A large number of IRIS patients who received interferon plus cytarabine switched to imatinib early in the study, making it difficult to perform an adequate long-term prospective comparative analysis, Dr. Guilhot explained.
He and his colleagues then compared the 551 patients from IRIS who took imatinib with 325 patients who took interferon plus cytarabine in a French multicenter trial began in 1991 before imatinib became available.
The duration of treatment was 42 months for the IRIS patients and 31 months for patients in the French study, with a follow-up time of 42 months for both groups.
At 36 months, the overall survival rate for patients receiving imatinib as a first-line treatment was 92% compared with 84% for patients receiving first-line interferon plus cytarabine. Similarly, the progression-free survival rate was 90% for imatinib-treated patients and 82% for patients receiving interferon plus cytarabine—all difference that were highly statistically significant, Dr. Guilhot said.
The estimated probability of a complete cytogenetic response at 36 months was 87% for imatinib-treated patients and 47% for those receiving interferon and cytarabine.
For patients who achieved a complete cytogenetic response at one year, 96% of imatinib patients were still alive at 36 months compared with 92% of patients receiving interferon plus cytarabine.
“For the first time, we begin to see that initial therapy with imatinib improves overall survival in addition to halting disease progression,” Dr. Guilhot said. “The survival benefit was significant when patients received imatinib from the start, as opposed to initial treatment with [interferon plus cytarabine.
He said that imatinib is still the first choice for the treatment of CML, but interferon plus cytarabine is a reasonable option for patients without a bone marrow transplant donor and who are unable to tolerate imatinib.
Long-time CML researcher Hagop Kantarjian, MD, Professor of Medicine and Chair of the Department of Leukemia at the University of Texas M. D. Anderson Medical Center, noted that there has been a drastic change in the prognosis and management of CML in recent times, with the annual mortality rate dropping from the rate of several years ago of about 15% to 20% to the current rate of less than 1%. “Between 90% and 95% of CML patients are alive,” he said.
The annual US prevalence of CML, which previously had been about 3,500 patients, is now more than 100,000 patients, he added. “Chronic-phase CML has turned into an indolent disorder analogous to hypertension and diabetes. If patients take the right treatment, they will do extremely well. Patients will die with CML, not from CML.”
Second-Generation TK Inhibitors
Researchers are refining their knowledge and treatments of CML with second-generation tyrosine kinase inhibitors, including AMN107 and dasatinib, which are now in Phase II studies, Dr. Kantarjian continued.
“The advantage of imatinib is that it has a follow-up of six years. We will watch the long-term follow-up of new drugs. They may have toxicities that appear in two years, and then imatinib will remain the standard.
As data mature, new kinase inhibitors may be as safe and effective as imatinib, and we will feel more comfortable prescribing those drugs as front-line therapy. They may ultimately replace imatinib as the standard of care.”