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Imatinib Continues to Impress in Long-Term CML Analysis

Silas Inman @silasinman
Published: Friday, Mar 10, 2017

Dr. Brian Druker

Brian Druker, MD

Imatinib (Gleevec) continued to show dramatic overall survival (OS) benefits after nearly 11 years of follow-up and despite crossover for patients with Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML), according to long-term findings published in The New England Journal of Medicine.

At a 10.9 year assessment of the phase III IRIS trial, the 10-year OS rate was 83.3% for 400-mg imatinib (95% CI, 80.1-86.6). Overall, 65.6% of patients crossed over to the imatinib arm from the control arm of interferon alfa plus cytarabine. The median time to crossover was 0.8 years. The OS rate after 10 years for those treated with interferon alfa plus cytarabine was 78.8% (95% CI, 75.0-82.5). Despite the crossover, there was still a 26% reduction in the risk of death with imatinib (HR, 0.74; 95% CI, 0.56-0.99; P = .04).

"The long-term success of this treatment confirms the remarkable success we've seen since the very first Gleevec trials," senior study author Brian Druker, MD, director of the OHSU Knight Cancer Institute, said in a statement. "This study reinforces the notion that we can create effective and non-toxic therapies."

Earlier findings from the phase III trial changed practice for patients with CML, ushering in an era of precision medicine. At the 18-month analysis of the trial, which was also known as STI571, the complete cytogenetic response (CCyR) was 76.2% with imatinib versus 14.5% with interferon alfa plus cytarabine. After this analysis, most patients in the control arm crossed over to receive imatinib.

Overall, the trial included 1106 patients with newly-diagnosed chronic phase CML. There were 553 patients in each arm, with 48.3% of patients completing treatment with imatinib compared with just 1.3% of those in the control arm. Patients primary crossed over from the control arm to imatinib due to disease progression or lack or loss of response (31.5%), unacceptable adverse events (26.2%), or reluctance to continue taking interferon alfa plus cytarabine (8.0%).

In the imatinib arm, just 6.9% of patients experienced progression of their disease to accelerated phase or blast crisis. The 10-year freedom from progression rate was 92.1% (95%, 89.6-94.5). In the interferon alfa/cytarabine arm, 12.8% of patients progressed to accelerated phase or blast crisis CML. Most of the disease progression events occurred within the first 4 years (89% for imatinib and 90% in the control arm).

The 10-year event-free survival rate with imatinib was 79.6% (95% CI, 75.9-83.2) compared with 56.6% with interferon alfa plus cytarabine (95% CI, 51.5-61.6). Sokal score synchronized with OS, with those having a high score experiencing a worse 10-year survival rate. In the imatinib group, the 10-year OS rates were 68.6%, 80.3%, and 89.9% for those with high, intermediate, and low Sokal scores.

In the imatinib arm, 89 patients had died at the 10.9-year follow-up (16.1%). Of these events, 37 were related to CML in patients who had not undergone a stem cell transplant. In the control arm, 105 patients died (19%), with 48 deaths related to CML in those who did not undergo a transplant. Additionally, 165 patients had unknown survival status (29.8%).

At the 10-year mark, 91.8% of patients in the imatinib had a CCyR. A major molecular response (MMR) was noted in 93.1% of patients and 63.2% had an MMR 4.5. In those with a MMR at 12 months, the 10-year OS rate was 91.1% with imatinib, as compared with 85.3% for those who did not achieve MMR at this time point (P = .15). MMR at 18 months was also predictive of better long-term OS (93.0% vs 85.6%; P = .04).

Treatment-related serious adverse events (AEs) were experienced by 9.3% of those in the imatinib arm. These events were most common during the first year of treatment and declined with time. Overall, 7.1% of patients experienced a cardiac serious AE and 11.3% were diagnosed with a second neoplasm.

"Our results demonstrating Gleevec's high efficacy in CML tell us to realize the full promise of precision cancer medicine, we need to diagnose and treat patients earlier in the disease course," Druker concluded.

Imatinib, which is broadly considered the first precision cancer medicine, was approved for the treatment of CML in 2001, based on phase II findings. The phase III IRIS study began enrolling patients in June 2000, with the last patient accrued in 2012. Since its approval, several other BCR-ABL TKIs have also gained approval for patients with CML, completely altering the natural history of the disease.
Hochhaus A, Larson RA, Guilhot F, et al. Long-Term Outcomes of Imatinib Treatment for Chronic Myeloid Leukemia. N Engl J Med. 2017;376:917-927.

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