Evidence ‘encouraging’ for venetoclax in elderly with relapsed, refractory CLL

New evidence supporting the efficacy and safety of venetoclax in elderly patients with relapsed, refractory chronic lymphocytic leukaemia (CLL) is encouraging and may inform prescribing choices in this patient group who otherwise may have few clear therapeutic options, researchers suggest.

The team from the UK and US looked at key safety measures and efficacy in 342 venetoclax-treated patients outside of clinical trials, comparing patients aged 75 years and over to those aged under 75 years [see journal paper here].

Progression-free survival (PFS), overall survival (OS), tumour lysis syndrome (TLS), adverse events (AE) and reasons for discontinuation were all shown to be similar in both cohorts.

Dr Toby Eyre from Oxford University Hospitals NHS Foundation Trust who led the study said: “We demonstrate that venetoclax has equivalent efficacy and safety in relapsed/refractory CLL patients who are elderly, the majority of whom are previous ibrutinib-exposed and therefore may otherwise have few clear therapeutic options.”

He added that the new findings corroborate those from a pooled analysis of 350 venetoclax-treated trial patients, which showed that adverse event (AE) rates, including grade 3/4 AEs, serious AEs and AEs leading to venetoclax dose reduction, interruption or discontinuation did not differ according to age (<75 or ≥75 years).

According to Dr Eyre, the provision of effective and tolerable therapy in elderly patients is a clear priority for the CLL community.

He says elderly CLL patients treated outside of trials have notably greater toxicity with ibrutinib compared to younger patients, noting that in contrast to trial reports large retrospective series have documented higher discontinuation rates attributable to ibrutinib-related AEs.

“As novel agents including ibrutinib and venetoclax rapidly move from the relapsed setting into the frontline elderly CLL setting, selecting which agent(s) to utilise up-front will be challenging and debated.

“The tolerability profile of ventoclax in elderly patients demonstrated in this analysis and in pooled trial data is encouraging and may inform its use in the elderly,” he said in the paper published in the British Journal of Haematology.

More discontinuations due to toxicity in elderly

Results showed the overall response rate for patients aged under 75 years was 82% and 81.6% for patients aged 75 years and over, and there was no difference between one-year PFS or OS.

Toxicity was assessed by measuring the number of dose reductions, biochemical and clinical TLS events, cytopenias (CTCAE Grade ≥ 3) and neutropenic fever. Clinical tumour lysis syndrome (TLS) was 3% in both cohorts, and there were no significant differences in toxicity.  Although rates of Grade ≥ 3 thrombocytopenia and neutropenia were higher in older patients, this did not clearly translate into higher rates of neutropenic infection, the researchers noted.

Across all patients, 42% discontinued venetoclax. The proportion discontinuing due to toxicity (20% of discontinuations) was lower than due to progressive disease or Richter’s transformation (48% of discontinuations).

Overall, 14% of older patients stopped venetoclax due to toxicity compared to 6.6% of younger patients.

According to the researchers, although the proportion of patients aged 75 years and over stopping due to toxicity was proportionally higher than that in the younger cohort, there were considerably more reasons for younger patients to discontinue therapy, for example, CAR-T or stem cell transplant. Overall, 20.7% of younger patients stopped due to progressive disease or Richter’s transformation compared to 14% of older patients.

Taking into account previous reports with immunochemotherapy and ibrutinib where tolerance may be inferior in elderly patients, the researchers speculate that the maximal tolerated dose in the elderly may be lower.

“Alternate dosing strategies and further study of drug-drug interactions should be conducted in elderly patients to possibly mitigate toxicity,” the study authors said.

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