Survival in Imatinib-Treated CML Independent of Response Time

Nancy A. Melville

July 05, 2017

MADRID — Survival outcomes in chronic myeloid leukemia (CML) treated with imatinib (Gleevec, Novartis) as monotherapy are high and are not necessarily influenced by faster responses or disease-related factors, with outcomes more associated with comorbidities and external factors, according to 10-year survival outcomes from a randomized study.

"Imatinib 400 mg provides close to normal life expectancy," said Ruediger Hehlmann, MD, a professor of medicine at the Mannheim Medical Faculty of the University of Heidelberg and coordinator of the German CML study group, in Heidelberg, Germany. He was presenting findings from the CML-Study IV here at the European Hematology Association (EHA) 2017 Congress.

"Survival is independent of time to response," he said. "Outcomes of CML are currently more determined by patients' and disease factors, such as comorbidities and smoking, and by microeconomic elements, such as treatment center, than by initial treatment selection."

CML-Study IV was a randomized, five-group treatment optimization study conducted at 210 centers in Germany, Switzerland, and the Czech Republic. The 1551 patients had newly diagnosed CML in chronic phase and were recruited between July 2002 and March 2012.

Of the patients in the current analysis, 1536 had evaluable data, included 400 patients treated with imatinib 400 mg, 430 patients treated with imatinib plus interferon, and 420 patients treated with imatinib 800 mg. Recruitment in two other groups — imatinib plus cytarabine (n = 158) and imatinib after interferon failure (n = 128) — was halted after a pilot phase.

The median patient age was 53 years, and 61% of patients were male.

With a median observation time of 9.5 years, the study showed an overall survival rate of all patients of 82%, 10-year progression-free survival of 80%, and a relative survival rate of 92% (compared with 92% in the general population).

The 10-year overall survival rates did not differ significantly between groups, with rates of 80% with imatinib 400 mg, 84% with imatinib plus interferon, 79% for imatinib 800 mg, 84% for imatinib plus cytarabine, and 79% for imatinib after interferon.

Patients reaching the molecular response milestones at 3, 6, and 12 months had a significantly better survival, the researchers report: Patients who achieved responses of BCR-ABL on the international scale of less than 1% between 4.5 and 7.5 months (n = 594) had a somewhat higher 8-year overall survival rate (93%) compared with those who had a response greater than 1% in the same time period (n = 385 [86%]), they add.

However, the higher (800-mg) dose of imatinib, which has shown faster responses in previous research, did not show a detectable survival advantage, the researchers reported.

"Considering the previously published data showing earlier and deeper molecular responses in imatinib 800 mg, the expectation would be that survival with [the higher dose] should be better, but the message from this study is that the earlier response did not translate to better survival," Dr Hehlmann said.

The earlier response did not translate to better survival. Dr Ruediger Hehlmann

In terms of 10-year probability of cause of death, factors unrelated to CML were twice as likely to cause death (12%) as CML itself (6%).

A multivariate analysis of 1252 patients showed no significant survival differences in therapy regimen. The leading predictors included low- vs high-risk European Treatment and Outcome Study long-term survival score (P < .001), academic vs community (P = .02) or academic vs office-based (P = .004) health center, comorbidities (P < .001), smoking vs nonsmoking (P = .001), and additional chromosomal abnormalities vs no such abnormalities at diagnosis (P < .001).

The findings show the 400 mg imatinib is probably as good as we can do. Dr Ruediger Hehlmann

"The findings show the 400 mg imatinib is probably as good as we can do and the time to response is apparently not a good surrogate marker for survival — at least not in this situation," Dr Hehlmann said.

"Although improvements are needed for refractory disease, more lifetime can also be gained by carefully addressing non-CML determinants of survival," he added.

In commenting on the study, Monica Bocchia, MD, director of the Department of Hematology at the University of Siena, Italy, said she agreed that the findings suggesting that early response may not be associated with long-term survival were surprising, as were the findings on the causes of death.

"This was surprising, but it's the result of having a good drug to control the disease," she told Medscape Medical News. "Most of the time the deaths are not the consequence of the disease."

Most of the time the deaths are not the consequence of the disease. Dr Monica Bocchia

Also approached for comment, C. Michel Zwaan, MD, PhD, from the Department of Pediatric Oncology/Hematology at the Erasmus MC–Sophia Children's Hospital, Rotterdam, the Netherlands, also found the results unexpected.

"Indeed [the findings] are surprising — clearly we need very long follow-up times," he told Medscape Medical News.

As a specialist in pediatric oncology, he questioned the implications for younger patients. "I think for children the question is different: Can we stop these drugs after achieving deep remission, and how many will then remain treatment-free?" he said.

"This is the best way to avoid life-long drug exposure and perhaps not yet known long-term safety concerns," Dr Zwaan said.

Dr Hehlmann has received research support from Novartis and has consulted for Bristol-Myers Squibb. Dr Bocchia has received honoraria from Janssen, Novartis, and Bristol-Myers Squibb. Dr Zwaan is a consultant for Bristol-Myers Squibb.

European Hematology Association (EHA) 2017 Congress Abstract S424. Presented June 24, 2017.

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