Abstract
Causes of death, in particular deaths due to infection, have not been widely studied in randomised trials in chronic lymphocytic leukaemia. With long-term follow-up (median 13 years) we examined the cause of death in 600/777 patients in the LRF CLL4 trial. Blood samples, taken at randomisation from 499 patients, were available for identifying gene mutations. Infection was a cause of death in 258 patients (43%). Patients dying of infection were more likely than those who died of other causes to have received ≥2 lines of treatment (194/258 [75%] versus 231/342 [68%], P = 0.04) and to have died in the winter months (149/258 [58%] versus 166/342 [49%], P = 0.03), respectively. In patients with mutation data, the factors significantly associated with death from infection versus all other deaths were 11q deletion (47/162 [29%] versus 40/209 [19%], P = 0.03) and mutations of the BRAF, FBXW7, NRAS and XPO1 genes. Death was caused by an infection in 46/67 assessable patients (69%) who had a mutation of one or more of these four genes versus only 129/333 patients (39%) without any of these mutations (odds ratio: 3.46 [95% CI 1.98–6.07] P < 0.0001). Careful management of infection risk, including prophylaxis against infection, may be important in patients who carry these mutations.
Highlights
Overall survival (OS) has been an endpoint in many clinical trials in chronic lymphocytic leukaemia (CLL), the specific causes of patients’ deaths have not been widely studied in randomised trials
A study of 10,455 patients with CLL from the Danish Cancer Registry demonstrated a significant improvement in overall survival (OS) between 1978 and 2013, in parallel with the introduction of chemoimmunotherapeutic agents, but the risk of death from infections in CLL patients did not change over this time period
Deaths tended to have more than one cause, but CLL was a cause in at least 520/600 patients (87%), including 258 deaths (43%) from infection (Fig. 1A)
Summary
Overall survival (OS) has been an endpoint in many clinical trials in chronic lymphocytic leukaemia (CLL), the specific causes of patients’ deaths have not been widely studied in randomised trials. The LRF CLL4 trial is uniquely appropriate for this investigation for two reasons It has long-term follow-up (median 13 years), which allowed us to examine the cause of death in 600 of the 777 patients randomised. A study of 10,455 patients with CLL from the Danish Cancer Registry demonstrated a significant improvement in OS between 1978 and 2013, in parallel with the introduction of chemoimmunotherapeutic agents, but the risk of death from infections in CLL patients did not change over this time period. It remained 50% higher than for a matched cohort of 508,995 individuals without CLL [4]. It has been suggested that the newer tyrosine kinase inhibitor ibrutinib might reduce the rate of infections [7,8,9]
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