Imatinib Effective in CML Patients Who Failed Interferon

Roxanne Nelson

February 27, 2012

February 27, 2012 — Patients with chronic myeloid leukemia (CML) who do not respond to treatment with interferon alpha can experience long-term benefits when switched to imatinib (Gleevec).

A study, published online February 27 in Cancer, found that receiving imatinib after interferon failure was associated with a 10-year survival rate of 68%. In patients who failed interferon therapy and had no access to imatinib, long-term survival was 20% to 30%.

These results suggest that the majority of patients can be managed safely and effectively with imatinib after failing interferon therapy, the authors note, and do not have to consider allogeneic stem cell transplantation (SCT) as long as they are in complete cytogenetic response.

"The major thrust of this study is to reassure patients and their physicians that if they are currently on imatinib after previously failing interferon therapy, their long-term outlook on imatinib is quite good and the majority of them will likely not have to contemplate other treatment strategies," said Peter Emanuel, MD, chair of the Winthrop P. Rockefeller Cancer Institute at the University of Arkansas for Medical Sciences in Little Rock.

Interferon is no longer used as first-line therapy for CML, explained Dr. Emanuel, who was not involved in the study. However, even though it has been replaced with tyrosine kinase inhibitors such as imatinib, there are many CML patients still alive who were diagnosed with CML years before the switch in first-line treatment occurred.

"Many of those patients started on interferon therapy and were later switched to imatinib after they failed interferon," he told Medscape Medical News.

In the United States, there could be 15,000 to 20,000 patients with CML initially treated with interferon and then switched to imatinib.

We knew from previous studies that these patients would respond well to imatinib in the short-term; how they would do in the long-term was not known, Dr. Emanuel explained.

This study answers those questions, he said. "The good news...is that these CML patients who received first interferon and then imatinib can look forward to prolonged disease control and a generally favorable outlook."

Efficacy and Safety Confirmed

In their study, Hagop Kantarjian, MD, from the Department of Leukemia at the University of Texas M.D. Anderson Cancer Center in Houston, and colleagues analyzed 368 adults with Ph-positive CML in the chronic phase who received treatment with imatinib after failing to respond to interferon.

The median age of the cohort was 54 years, and the median follow-up was 114 months (range, 1 to 132 months). Overall, 247 patients (67%) achieved a complete cytogenetic response; of the 326 patients who had undergone molecular studies, 207 (63%) achieved a major molecular response (BCR-ABL ratio on the international scale, ≤0.1%). In addition, 99 patients (30%) had undetectable levels at some point during their therapy.

The authors note that the cumulative incidence of major molecular response at 7 years was 55%, whereas the cumulative incidence of undetectable BCR levels was 35%. In an intent-to-treat analysis of all 368 patients at 7 years, 129 (35%) were in complete cytogenetic response, 116 (32%) were in major molecular response, and 40 (11%) had undetectable BCR-ABL levels.

At the most recent follow-up, the estimated 10-year survival rate was 68%, the progression-free survival rate was 67%, and event-free survival was 51%.

To date, 104 patients (28%) have died — 13 from accelerated-phase complications and 39 from blast-phase disease.

In addition, 118 patients stopped using imatinib for reasons other than drug resistance — 95 because they received no further follow-up at the institution, 4 because of patient request, 3 because of a physician decision, 5 because of socioeconomic factors, 3 because of noncompliance, and 8 because of other malignancies or diseases. Imatinib failure was observed in 127 patients — 86 patients who remain in chronic phase and 41 who have transformed to blastic-phase (n = 14) or accelerated-phase CML (n = 27).

Of those who failed imatinib therapy, 62 (49%) received salvage treatment with second-generation tyrosine kinase inhibitors as first salvage (14 with nilotinib, 34 with dasatinib, and 14 with other agents), and 27 received second salvage therapy with these agents. Estimated 5-year survival for this group was 60%.

A total of 10 patients were referred for allogeneic SCT after developing imatinib resistance in chronic-phase CML (n = 4) and in transformation (n = 6). Currently, 3 of these patients remain alive without evidence of disease.

"In summary, the current analysis confirms the efficacy and safety of continued imatinib therapy in patients with Ph-positive CML after interferon failure and reassures patients who are currently on such therapy in the oncology community, and their treating physicians, that continuation of this therapy is reasonable," write the authors. "Undertaking allogeneic SCT should be considered only in patients who develop imatinib resistance."

This study was supported by the National Institutes of Health and the Betty Foster Leukemia Research Fund. Dr. Kantarjian and coauthor Jorge Cortes, MD, report serving as consultants for Novartis, the manufacturer of imatinib, and receiving research funding from Novartis, BMS, and Pfizer. Coauthor Elias Jabbour, MD, reports being a speaker for Novartis.

Cancer. Published online February 27, 2012. Abstract

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