Early BCR-ABL Predicts Survival in Nilotinib-Treated CML



AMSTERDAM – Measuring BCR-ABL transcript levels at 3 and 6 months can predict the outcome of treatment with nilotinib in patients newly diagnosed with chronic myeloid leukemia, according to new data from the ENESTnd study.

Patients with lower levels at these milestones had higher rates of progression-free and overall survival, whether they received nilotinib (Tasigna) or imatinib (Gleevec) in the pivotal phase III study, investigators reported at the annual congress of the European Hematology Association (EHA).

Dr. Andreas Hochhaus

"The main message is that for patients who are on imatinib, you have an early predictor of response that you may use the second-generation drugs if there is a problem – and the same now applies for second-generation drugs," the lead author Dr. Andreas Hochhaus, said in an interview.

The phase III ENESTnd [Evaluating Nilotinib Efficacy and Safety in Clinical Trials Newly Diagnosed Ph+ CML Patients] trial led to the approval of nilotinib for the first-line treatment of adult patients with newly-diagnosed, Philadelphia chromosome–positive chronic myeloid leukemia (CML) in the chronic phase. The findings, along with data from the DASISION trial, which led to comparable approval of dasatinib (Sprycel), show that second-generation tyrosine kinase inhibitors (TKIs) induce faster and deeper molecular responses than does imatinib.

With three TKIs already licensed and more potentially on the way, there is a need to compare the outcomes achievable with each available agent, observed Dr. Hochhaus of Jena (Germany) University Hospital.

"Since cytogenetics is not very popular [and] PCR [polymerase chain reaction] is standardized now, at least in Europe, PCR can be used" for the 3 months’, 6 months’, and 12 months’ assessment, he suggested

The analysis presented by Dr. Hochhaus concerned only some of the patients included in the main ENESTnd study – namely, 282 patients who were treated with nilotinib at a dose of 300 mg twice daily, and 283 who were treated with 400-mg imatinib once daily.

BCR-ABL was measured after 3 and 6 months of treatment. The investigators defined progression-free survival in terms of progression to the advanced phase of disease or blast crisis, or death due to any cause; overall survival was defined as death due to any cause.

At 3 months, significantly more nilotinib-treated patients than imatinib-treated patients achieved a BCR-ABL transcript level of 10% or less (91% vs. 67%) and 1% or less (56% vs. 16%). In contrast, 33% of the imatinib-treated patients and 9% of those given nilotinib had transcript levels higher than 10%.

These 3-month transcript levels correlated with survival outcomes at 3 years’ follow-up, Dr. Hochhaus reported. In the nilotinib-treated group, 96.9% of those who achieved 1% or less and 98.8% of those who achieved up to 10% – but only 86.7% of those whose levels exceeded 10% – were alive at that point. Corresponding values for imatinib-treated patients were 95.3%, 100%, and 84.8%.

Progression-free survival rates at 3 years showed the same pattern: 96.5%, 95.6%, and 82.9%, respectively, for nilotinib-treated patients with BCR-ABL transcript levels of 1% or less, 10% or less, and more than 10% at 3 months. In the imatinib arm at 3 years’ follow-up, progression-free survival rates were 98.5%, 95.3%, and 83.8%, respectively, based on 3-month transcript levels.

Only the differences between a BCR level of 10% or less vs. more than 10% were significant for both drugs.

Similarly, progression-free survival rates at 3 years’ follow-up correlated with BCR-ABL transcript levels at 6 months. In nilotinib-treated patients, these rates were 96.5% for levels of 1% or less, 91.3% for 10% or less, and 75% for more than 10%. Corresponding values in imatinib-treated patients were 97.6%, 96.5%, and 79.7%, respectively.

Overall survival at 6 months for nilotinib and imatinib reflected the results seen at 3 months.

"Long-term outcomes for patients with more than 10% BCR-ABL levels at 3 or 6 months are worse compared to patients with less than 10% BCR-ABL when considering both progression-free survival and overall survival," Dr. Hochhaus said.

He concluded: "Nilotinib frontline allows more patients to achieve deeper responses earlier, [which is] associated with improved long-term outcomes versus imatinib."

Dr. Richard Clark

The 3-year follow-up data from the 846-patient ENESTnd study have just been published online and were reported separately at the EHA meeting by Dr. Richard Clark, professor of hematology and consultant hematologist at the Royal Liverpool (England) University Hospital (Leukemia 2012 May 18 [doi:10.1038/leu.2012.134]).

Dr. Clark reported that – similar to previous finding – nilotinib was associated with faster and deeper molecular response rates, a lower progression to the advanced phase or blast crisis, and fewer CML-related deaths than is treatment with imatinib.

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