Predictors of atrial fibrillation in ibrutinib-treated CLL patients: a prospective study

Reda, Gianluigi; Fattizzo, Bruno; Cassin, Ramona; Mattiello, Veronica; Tonella, Tatiana; Giannarelli, Diana; Massari, Ferdinando; Cortelezzi, Agostino

doi:10.1186/s13045-018-0626-0

Cited by 34 publications

(24 citation statements)

References 9 publications

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“…[37][38][39][40][41] Of 5 patients with atrial fibrillation, three had events within the first year of treatment, consistent with previous reports that atrial fibrillation typically occurs within the first year of ibrutinib treatment and remains constant or declines over time. [39][40][41][42][43][44][45][46] Atrial fibrillation was Previous MZL studies have identified NF-kB and Notch as 2 major signaling pathways that are disrupted through genetic alterations in key pathway genes. 47 In this analysis, mutation of A20, a known negative regulator gene in the NF-kB pathway, was shown to be correlated to clinical efficacy (increased tumor shrinkage).…”

Section: Discussionmentioning

confidence: 99%

Durable ibrutinib responses in relapsed/refractory marginal zone lymphoma: long-term follow-up and biomarker analysis

et al. 2020

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Advanced marginal zone lymphoma (MZL) is an incurable B-cell malignancy dependent on B-cell receptor signaling. The phase 2 PCYC-1121 study demonstrated the safety and efficacy of single-agent ibrutinib 560 mg/d in 63 patients with relapsed/refractory MZL treated with prior rituximab (RTX) or rituximab-based chemoimmunotherapy (RTX-CIT). We report the final analysis of PCYC-1121 with median follow-up of 33.1 months (range: 1.4-44.6). Overall response rate (ORR) was 58%; median duration of response (DOR) was 27.6 months (95% confidence interval [CI]: 12.1 to not estimable [NE]); median progression-free survival (PFS) was 15.7 months (95% CI: 12.2-30.4); and median overall survival (OS) was not reached (95% CI: NE to NE). Patients with prior RTX treatment had better outcomes (ORR: 81%; median DOR: not reached [95% CI: 12.2 to NE]; median PFS: 30.4 months [95% CI: 22.1 to NE]; median OS: not reached [95% CI: 30.3 to NE]) vs those with prior RTX-CIT treatment (ORR: 51%; DOR: 12.4 months [95% CI: 2.8 to NE]; PFS: 13.8 months [95% CI: 8.3-22.5]; OS: not reached [95% CI: NE to NE]). ORRs were 63%, 47%, and 62% for extranodal, nodal, and splenic subtypes, respectively. With up to 45 months of ibrutinib treatment, the safety profile remained consistent with prior reports. The most common grade ≥3 event was anemia (16%). Exploratory biomarker analysis showed NF-κB pathway gene mutations correlated with outcomes. Final analysis of PCYC-1121 demonstrated long-term safety and efficacy of ibrutinib in patients with relapsed/refractory MZL, regardless of prior treatment or MZL subtype. This trial was registered at www.clinicaltrials.gov as #NCT01980628.

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Section: Discussionmentioning

confidence: 99%

Durable ibrutinib responses in relapsed/refractory marginal zone lymphoma: long-term follow-up and biomarker analysis

et al. 2020

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“…Left atrial remodelling is a crucial element in the pathogenesis of AF and this observation is confirmed in patients treated with ibrutinib. Small preliminary studies previously suggested that signs of left atrial dilatation on the ECG or TTE pattern were associated with a higher risk of IRAF 26 27. However, these studies did not assess LAVI, which is the reference measure for left atrial remodelling.…”

Section: Discussionmentioning

confidence: 99%

High incidence of atrial fibrillation in patients treated with ibrutinib

et al. 2019

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ObjectiveAtrial fibrillation (AF) is one of the most common side effects of ibrutinib, a drug that has dramatically improved the prognosis of chronic B-cell malignancies such as chronic lymphocytic leukaemia (CLL). The true incidence of ibrutinib-related AF (IRAF) is not well known and its therapeutic management poses unique challenges especially due to the inherent risk of bleeding. We aimed to determine the incidence and predictors of IRAF, and to analyse its management and outcome.MethodsA standardised monitoring was applied at two cardio-oncology clinics in consecutive patients referred before and during ibrutinib therapy. The primary endpoint was the incidence of IRAF. The excess of AF incidence with ibrutinib was studied by comparing the incidence of IRAF with the expected incidence of AF in general population and in patients with CLL not exposed to ibrutinib.Results53 patients were included. The incidence of IRAF was 38% at 2 years and the risk was 15-fold higher than the AF risk in both the general population and patients with CLL not exposed to ibrutinib (p<0.0001). The majority of cases occurred in asymptomatic patients within the first 6 months. Left atrial volume index ≥40 mL/m2 at treatment initiation identified patients at high risk of developing IRAF. No major bleeding events occurred in patients on ibrutinib, although the majority of patients with IRAF were treated with anticoagulants.ConclusionsThis cardio-oncology study showed that the risk of IRAF was much higher than previously reported. The majority of cases occurred in asymptomatic patients justifying close monitoring.

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“…At 7 years, 55% of patients developed a serious infection and 9% a major hemorrhage 18. However, observational studies of ibrutinib clearly showed that elderly patients with comorbidities and/or an ECOG PS >1 were more likely to discontinue treatment due to toxicity34–38 and that atrial fibrillation occurred more frequently in elderly patients with previous arterial hypertension and pre-existing cardiologic comorbidities 39. In the real world experience of the Swedish registry36 an updated analysis at 30-month follow-up of 95 R/R patients (median age of 69 years, del(17p)/TP53 mutation in 63% of the patients, PS grade 2–3 in 27%) showed that 51% of patients had a grade 3–4 infection, 15% developed any grade atrial fibrillation and 20% discontinued due to adverse events.…”

Section: Treatment Until Progressionmentioning

confidence: 99%

Relapsed/Refractory Chronic Lymphocytic Leukemia: Chemoimmunotherapy, Treatment Until Progression With Mechanism-Driven Agents or Finite-Duration Therapy?

Cuneo

Foà

2019

Mediterr J Hematol Infect Dis

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Treatment of relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) has dramatically improved thanks to the development of mechanism-driven agents including drugs that inhibit kinases in the BCR pathway or BCL2. The treating physician has now the opportunity to decide i) which patient can be still offered chemoimmunotherapy as salvage treatment, ii) which patient is a candidate to receiving at relapse continuous treatment with ibrutinib, idelalisib and rituximab or venetoclax and iii) which patient may benefit from a fixed-duration treatment using the BCL2 antagonist venetoclax in association with rituximab. Ibrutinib is the most actively investigated drug in R/R CLL and data at a 7-year follow-up were reported, showing durable efficacy and favorable efficacy profile. The patients with cardiac disease, hypertension and on anticoagulant therapy are not ideal candidates for continuous therapy with this agent. Idelalisib and rituximab was tested in patients with unfavorable characteristics including cytopenias. The short follow-up and treatment emergent adverse events limit its role to patients unlikely to get a benefit with other agents. Venetoclax and rituximab is the only effective chemo-free approach for the treatment of R/R with a fixed duration (up to 24 months) schedule capable of inducing deep responses in the majority of cases with a reassuring safety profile. While a deep knowledge of the growing body of scientific evidence is required to inform and guide the appropriate treatment choice and management, physicians cannot disregard the growing problem of sustainability

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Predictors of atrial fibrillation in ibrutinib-treated CLL patients: a prospective study

Cited by 34 publications

References 9 publications

Durable ibrutinib responses in relapsed/refractory marginal zone lymphoma: long-term follow-up and biomarker analysis

Durable ibrutinib responses in relapsed/refractory marginal zone lymphoma: long-term follow-up and biomarker analysis

High incidence of atrial fibrillation in patients treated with ibrutinib

Relapsed/Refractory Chronic Lymphocytic Leukemia: Chemoimmunotherapy, Treatment Until Progression With Mechanism-Driven Agents or Finite-Duration Therapy?

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