Do age, fitness, and concomitant medications influence management and outcomes of patients with CLL treated with ibrutinib?

Abstract

Functional reserve of organs and systems is known to be relevant in predicting immunochemotherapy tolerance. Age and comorbidities, assessed by the cumulative illness rating scale (CIRS), have been used to address chemotherapy intensity. In ibrutinib era it is still unclear whether age, CIRS and ECOG-PS retain their predictive role on treatment vulnerability. In this 712 CLL patients series treated with ibrutinib outside clinical trials, baseline ECOG-PS and neutropenia, resulted as the most accurate predictors of treatment feasibility and outcomes. Age did not independently influence survival and ibrutinib tolerance, indicating that not age per se, but age-related conditions may affect drug management. We confirmed the role of CIRS>6 as a predictor of a poorer progression and event-free survival (PFS, EFS). The presence of a severe comorbidity was significantly associated with permanent dose reductions (PDR), not translating into worse outcomes. As expected, del(17p) and/or TP53mut and previous therapies affected PFS, EFS and overall survival. No study so far has analyzed the influence of concomitant medications and CYP3A-inhibitors with ibrutinib. In our series, these factors had no impact, though CYP3A4 inhibitors use correlated at Cox regression analysis, with an increased risk of PDR. Despite the limitation of its retrospective nature, this large study confirmed the role of ECOG-PS as the most accurate predictor of ibrutinib feasibility and outcomes and importantly neutropenia emerged as a relevant tool influencing patients vulnerability. Although CIRS>6 retained a significant impact on PFS and EFS its value should be confirmed by prospective studies.

Long-Term Efficacy and Safety of Ibrutinib in the Treatment of CLL Patients: A Real Life Experience

“…Response rates appear instead rather similar across studies (Table 5). Likewise, discrepancies observed between patients treated in second or later line in our study and in clinical trials may be in part explained by the fact that possible more comorbidities affecting patients treated on a routine basis may have affected the compliance to therapy, the emergence of AEs, and ultimately, the outcome of the treatment itself (Table 4) as previously reported [21,22]. Therefore, if on the one hand, it is important to operate a comparison between real-life data and clinical trial outcomes, on the other, the information gathered in real-world experiences is undoubtedly valuable to help clinicians acquire familiarity with the use of new agents in several contexts of treatment.…”

Treatment Options for Elderly/Unfit Patients with Chronic Lymphocytic Leukemia in the Era of Targeted Drugs: A Comprehensive Review

“…They showed that older age does not independently influence survival and ibrutinib tolerance and confirmed that CIRS > 6 is a predictor of a poorer progression-free survival (PFS) and event-free survival (EFS). Moreover, they showed that the only baseline parameters affecting overall survival are ECOG-PS ≥ 2 and neutropenia [ 22 ]. An important consideration to make is that studies in which ECOG showed a negative impact included more unfit and, on average, older patients than those in which a higher CIRS showed an impact.…”

“…In particular, in a retrospective multicentre study [ 10 ], Gordon et al showed the impact of CIRS ≥ 7 and the severe impairment of a single organ (CIRS3+) affecting OS (2-year OS 79% versus 100%) and EFS (median 24 versus 37 months), both in frontline and relapsed CLLs [ 10 ]. Tedeschi et al, in their retrospective multicentre study [ 22 ] on 712 patients on treatment with Ibrutinib, showed that ECOG-PS ≥ 2 and neutropenia are the only baseline parameters affecting overall survival. Moreover, since it is metabolized via the CYP3A4 enzyme system, they demonstrated that the influence of concomitant medications and CYP3A-inhibitors (e.g., clarithromycin, erythromycin, diltiazem, itraconazole, ketoconazole, ritonavir, verapamil) with ibrutinib has no impact on outcome, though CYP3A4 inhibitors use severe comorbidities correlated with an increased risk of permanent dose reduction.…”

“…Moreover, since it is metabolized via the CYP3A4 enzyme system, they demonstrated that the influence of concomitant medications and CYP3A-inhibitors (e.g., clarithromycin, erythromycin, diltiazem, itraconazole, ketoconazole, ritonavir, verapamil) with ibrutinib has no impact on outcome, though CYP3A4 inhibitors use severe comorbidities correlated with an increased risk of permanent dose reduction. Besides, concerning the discontinuation of treatment, definitive discontinuation of treatment due to toxicity negatively affects OS independently from age, while permanent dose reduction did not have any OS impact [ 22 ].…”

Coexisting conditions and concomitant medications do not affect venetoclax management and survival in chronic lymphocytic leukemia

“…Few studies have addressed the role of age and fitness status on BCR inhibitors management and outcome. 9 – 11 In two retrospective studies of ibrutinib-treated patients outside clinical trials, Cumulative Illness Rating Scale (CIRS) and ECOG-PS emerged as reliable tools in predicting treatment tolerance and survival. 9 , 11 Among other parameters considered at baseline, in the study published by Tedeschi et al , 11 only neutropenia independently influenced all the survival outcomes.…”