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Comorbidities may have greater OS impact in CML than the malignancy
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Comorbidities had a negative effect on OS but did not impact treatment success in patients with chronic myeloid leukemia, according to study results.
These results imply comorbidities may influence the survival of patients with CML more than the disease itself and, thus, OS may not be an appropriate study endpoint in this setting, according to the researchers.
“Comorbidities are known to complicate longitudinal trials in diseases with expected long OS times,” Susanne Saußele, MD, of the Medizinische Klinik at the Heidelberg University in Mannheim, Germany, and colleagues wrote. “The influence of comorbidities on outcome in CML patients has not been studied; comorbidities have only been taken into account when assessing the safety and suitability of different tyrosine kinase inhibitors for CML patients.”
Saußele and colleagues enrolled 1,519 patients in the CML-Study IV — a randomized, five-arm trial — between July 2002 and March 2012. Researchers excluded pregnant patients and patients with secondary malignancies or other serious illnesses.
Patients received one of five treatment regimens composed of imatinib (Gleevec, Novartis) with or without secondary therapy.
Median follow-up was 67.5 months.
Researchers identified comorbidities using the Charlson Comorbidity Index (CCI) in 40.3% of patients (n = 612) — including 25.3% (n = 384) with CCI relevant diseases — who had a total of 511 index comorbidities. The most commonly observed CCI relevant comorbidities included diabetes (n = 106), non-active cancer (n = 102), chronic pulmonary disease (n = 74) and myocardial infarction (n = 38).
A total of 863 patients exhibited an elevated CCI score due to age.
Researchers divided patients into four CCI-related groups based on comorbidity severity: CCI 2 (n = 589), CCI 3 to 4 (n = 599), CCI 5 to 6 (n = 229) and CCI 7 or higher (n = 102).
Researchers did not observe a link between any CCI group and time to complete cytogenetic remission, major molecular remission or deep molecular response. However, CCI group significantly contributed to long-term OS (P < .001).
Patients in the CCI 2 group demonstrated an 8-year OS rate of 93.6% (95% CI, 91-95.8), whereas patients in the CCI 3 to 4 group had an 8-year OS rate of 89.3% (95% CI, 86-92.1). OS rates further declined for patients in the CCI 5 to 6 cohort (77.6%; 95% CI, 70.4-84) and the CCI 7 or greater cohort (46.4%; 95% CI, 31.5-61.7).
In the multivariate analysis, CCI remained the most powerful predictor for OS (HR = 1.69; 95% CI, 1.06-2.69). Researchers separated the CCI into age- and comorbidity-related components and determined that the comorbidity-related component remained an important predictive factor for OS (P = .002).
Researchers identified the inclusion of patients with limited survival expectancies in the analysis as a potential limitation to these findings. Further, they noted the potential for underreporting of patients’ comorbidities.
“Since TKIs have reduced CML-related mortality so effectively, we also conclude that a sole unadjusted analysis of OS is no longer appropriate for assessing the efficacy of a new specific treatment for CML,” Saußele and colleagues concluded. “An appropriate measurement seems to be PFS, as this was at least in our cohort not influenced by comorbidities. There is a need for a consensus definition of surrogate endpoints in CML studies.” – by Cameron Kelsall
Disclosure: Saußele reports receiving honoraria and research funding from Bristol-Myers Squibb, Novartis and Pfizer. Please see the full study for a list of all other researchers’ relevant financial disclosures.
Perspective
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Michael Deininger, MD, PhD
OS is the gold-standard endpoint in oncology trials and when we think about improving therapy, we typically think about improving the efficacy of therapy or reducing adverse effects. But what if the treatment is so effective that the disease under study has lost its dominant impact on OS in favor of other factors? The study reported by Saußele and colleagues shows that this shift has happened in chronic myeloid leukemia.
Researchers analyzed the impact of co-morbidities on OS in the German CML IV study, a large prospective study of more than 1,500 patients with newly diagnosed chronic phase CML. Researchers randomly assigned patients between 400 mg daily imatinib (Gleevec, Novartis) vs. 400 mg daily imatinib in combination with interferon-alpha (IFN) vs. 400 mg daily imatinib in combination with low-dose cytarabine vs. 400 mg daily imatinib after IFN failure vs. 800 mg daily imatinib. The researchers investigated the impact of co-morbidities on OS using the Charlson Comorbidity Index (CCI), which considers not only the presence but also the severity of the comorbid condition. CCI had no impact on the response to treatment, but had a dramatic impact on OS, indicating that in the era of tyrosine kinase inhibitors, OS in CML is driven by co-morbid conditions.
This implies that OS is no longer a suitable endpoint for efficacy studies and that proper management of concomitant conditions is at the core of improving outcomes. For the CML field, this means that the emphasis needs to shift to other relevant endpoints such as treatment-free remission, and that integrated comprehensive care is needed to optimize results. Considering that 15 years ago allogeneic stem cells transplant was recommended to all eligible CML patients, it is hard to conceive of a more profound shift in the objectives of care. Again CML — an orphan disease — is breaking new ground. Other malignant conditions are likely to follow soon.
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