Real-World Data Confirm Ibrutinib's Role in Relapsed CLL

Results of a large real-world cohort study including more than 3300 patients confirm that ibrutinib is an effective salvage treatment for relapsed/refractory chronic lymphocytic leukemia (R/R CLL). The work, published in HemaSphere, surveyed data from all patients with R/R CLL who received ibrutinib within the Italian National Health Service between 2016 and 2020, with a median follow-up of 42.2 months after treatment initiation.¹ It is the longest real-world study on this topic, the researchers said.

The patients’ median age was 72.1 years, and 42.6% had received 2 or more previous lines of treatment. Older age and number of previous therapy lines were associated with shorter time to treatment discontinuation (TTD) and shorter overall survival (OS). Other factors also linked to shorter TTD and OS were worse ECOG performance status, refractoriness to last treatment, and reduced renal function.

The coexistence of 17p deletion and TP53 mutation (ie, double-hit TP53 aberration) had an independent unfavorable impact on TTD and OS, noted the authors. Further, nonstandard doses of ibrutinib and advanced disease stage were associated with shorter TTD and shorter OS, respectively. Not surprisingly, discontinuation due to CLL progression portended a poorer outcome.

Most patients (60.9%; n = 2015) eventually discontinued treatment: 993 (49.2%) stopped because of disease progression or death, 564 (17.1%) cited toxicity or medical decision, and 458 (13.8%) were lost to follow-up.

In this study, for the entire cohort, the median time to treatment discontinuation was 31.3 months. | Image Credit: © Friends Stock-stock.adobe.com

The median OS of patients who stopped ibrutinib because of disease progression or because of other reasons was 12.9 months and 22.7 months, respectively. For the entire cohort, median TTD was 31.3 months.

The 24-month discontinuation rate was 42.1%. Overall, the estimated 24-month probabilities of being on treatment and alive were 57.9% and 76.6%, respectively, the researchers reported.The median OS was 61.9 months. Combined, the data confirm ibrutinib’s general effectiveness in this population, producing prolonged disease control, they concluded.

Subgroup Stories

The TTD and OS of patients with single-hit TP53 aberrations—17p deletion in 107 patients and TP53 mutation in 184—were not affected by these factors. However, the 203 patients with double-hit TP53 aberrations had significantly shorter TTD and OS compared with those of the 1314 patients with no aberrations.

Worth noting, said the authors, is that different centers vary in terms of methods and cutoff points for the detection of 17p deletion and TP53 mutations. That might have influenced the categorization of incidences of TP53 abnormalities in the study.

A gene dosage effect may explain the poorer prognosis for patients with R/R CLL who have double-hit TP53 aberrations, the researchers stated.² However, they recommended that further studies be done to clarify the prognostic significance of the size of the 17p-clone, of the variant allele frequency of TP53 mutations, and of specific TP53 mutations in patients receiving ibrutinib as salvage treatment.

Agents Beyond Ibrutinib

In Italy during much of the study period, salvage treatment with other Bruton tyrosine kinase inhibitors or with venetoclax was unavailable. This could help explain the low incidence of discontinuations due to unacceptable toxicity in the study, which was 3.6% of all cases and 11.6% of all discontinuation events except disease progression or death. Ibrutinib was the only targeted agent reimbursed by the Italian National Health Service for R/R CLL until early 2020, when venetoclax plus rituximab gained approval, the authors explained. They speculated that different reimbursement policies and other targeted agents’ availability could both account for higher discontinuation rates of ibrutinib reported in previous studies performed in the US and in other European countries.

Acknowledging that agents like venetoclax are more widely available now, the team nonetheless noted that “the median OS of 12.9 and 22.7 months observed in our analysis in patients who discontinued ibrutinib due to CLL progression or toxicity/other reasons underlines the importance of further analysis on subsequent therapy strategies in the different patient subgroups.”

References

1. Rigolin GM, Olimpieri PP, Summa V, et al. Outcomes and prognostic factors in 3306 patients with relapsed/refractory chronic lymphocytic leukemia treated with ibrutinib outside of clinical trials: a nationwide study. HemaSphere. 2024;8(10):e70017. doi:10.1002/hem3.70017

2. Aarup K, Rotbain EC, Enggaard L, et al. Real-world outcomes for 205 patients with chronic lymphocytic leukemia treated with ibrutinib. Eur J Haematol. 2020;105(5):646-654. doi:10.1111/ejh.1349