Patients with mantle cell lymphoma failing ibrutinib are unlikely to respond to salvage chemotherapy and have poor outcomes

Cheah, Chan Yoon; Chihara, Dai; Romaguera, Jorge; Fowler, Nathan; Seymour, John F.; Hagemeister, Fredrick B.; Champlin, Richard E.; Wang, Michael L.

doi:10.1093/annonc/mdv111

Cited by 149 publications

(125 citation statements)

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“…The results of this large international observational study are consistent with a recent single-center study of MCL 8 and multicenter study of CLL, 7 and highlight the challenges that people with MCL and their treating physicians face on a daily basis. Although the RR and side-effect profile of ibrutinib are unprecedented in MCL, long-term remissions remain elusive, and the outcomes of patients that experience ibrutinib appears to be poor.…”

Section: Discussionsupporting

confidence: 86%

Postibrutinib outcomes in patients with mantle cell lymphoma

Martin

Maddocks

Leonard

et al. 2016

Blood

238

204

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Section: Discussionsupporting

confidence: 86%

Postibrutinib outcomes in patients with mantle cell lymphoma

Martin

Maddocks

Leonard

et al. 2016

Blood

238

204

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“…Thirteen articles reported on the incidence of overall bleeding 6,8,[15][16][17][18][19][20][21][22][23][24][25] with a pooled annual incidence of any bleeding of 20.8 per 100 patient-years (95% confidence interval [CI], 19.1-22.1) in ibrutinibtreated patients. Two RCTs 6,15 compared the incidence of overall bleeding between ibrutinib and an alternative therapy ( Figure 1).…”

Section: Overall Bleedingmentioning

confidence: 99%

Current understanding of bleeding with ibrutinib use: a systematic review and meta-analysis

Caron

Leong

Hillis³

et al. 2017

Blood Advances

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Ibrutinib therapy was associated with an increased risk of bleeding in previous trials. In this systematic review and meta-analysis of published trials including patients treated with ibrutinib, the relative risk (95% confidence interval [CI]) of overall bleeding was significantly higher in ibrutinib recipients (2.72 [1.62-6.58]), but major bleeding did not show a significant difference (1.66 [0.96-2.85]). The incidences (95% CI) of major bleeding and any bleeding were 3.0 (2.3-3.7) and 20.8 (19.1-22.1) per 100 patient-years, respectively. This analysis is limited by reporting bias from variable ascertainment of bleeding and lack of allocation concealment in some studies and differing exposures between groups, leading to potential overestimation of event rates in the ibrutinib group. CaseA 65-year-old man with chronic lymphocytic leukemia (CLL) with 17p deletion on first-line ibrutinib 420 mg daily for 8 weeks presented with a 2-week history of easy bruising and epistaxis. He was previously healthy with no personal or family history of a bleeding disorder and no regular antithrombotic drug use. Laboratory testing revealed a hemoglobin concentration of 8 g/dL, lymphocyte count of 13 3 10 9 /L, and normal platelet count, international normalized ratio, and activated partial thromboplastin time. What is the role of ibrutinib in this patient's bleeding symptoms?

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“…Thus, 20 manuscripts, reporting on the occurrence of AF in individuals treated with ibrutinib, contributed to the meta-analysis (Table 1). [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21] Four of these studies were randomized controlled trials, 10 phase II studies, one prospective cohort study, and 5 retrospective cohort studies. In total, 14 studies included CLL/SLL patients; 5 studies included mantle cell lymphoma patients; 2 studies included Waldenström macroglobulinemia patients, and one study included follicular lymphoma patients.…”

mentioning

confidence: 99%

The risk of atrial fibrillation with ibrutinib use: a systematic review and meta-analysis

Leong

Caron

Hillis

et al. 2016

Blood

204

121

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Ibrutinib is an irreversible inhibitor of Bruton tyrosine kinase in the B-cell receptor signaling pathway. In randomized trials, ibrutinib is effective as first-line treatment of chronic lymphocytic leukemia (CLL)/ small lymphocytic lymphoma (SLL) (compared with chlorambucil), 1 for relapsed/refractory CLL/SLL (compared with ofatumumab or combined with bendamustine/rituximab), 2,3 or for relapsed/refractory mantle cell lymphoma (compared with temsiroliums), 4 with promising results in the treatment of Waldenström macroglobulinemia. 5 It is anticipated that ibrutinib will become an important part of the therapeutic armamentarium for these conditions. Randomized trials suggest that ibrutinib may increase the risk of atrial fibrillation (AF) as compared with chlorambucil 1 or ofatumumab. 2 In the general population, AF is strongly associated with heart failure and arterial thromboembolism, which result in substantial morbidity and mortality. There is uncertainty over the magnitude of the increase in AF risk attributable to ibrutinib because the absolute numbers of incident AF cases are small in individual studies.We undertook a systematic review and meta-analysis to (1) estimate the magnitude of the increase in AF risk among ibrutinib recipients, as compared with alternative therapies and (2) quantify the frequency of AF reported among ibrutinib recipients. We searched MEDLINE and EMBASE, and proceedings from the American Society of Hematology, the European Haematology Association, and the American Society of Clinical Oncology for articles describing AF rates in recipients of ibrutinib. The following search terms were used: ibrutinib; imbruvica; or PCI-32765. Animal studies, case reports, case series (ie, that reported on consecutive AF cases), cross-sectional studies, editorials, phase I/dose-finding studies, and conference abstracts more than 12 months old were excluded.Two independent reviewers screened the articles' titles and abstracts for eligibility. Cases of disagreement were resolved by a third reviewer. Papers identified after title and abstract screening were obtained in full. When data from the same cohort of participants were presented in different papers, only the manuscript with the larger sample size was included in the meta-analysis. The following data were extracted from eligible full text manuscripts: design, disease, sample size, treatments, participant age and sex, follow-up duration, AF rates, and where reported, AF ascertainment strategies, past history of cardiovascular disease, AF, or hypertension.Statistical analysis was performed using STATA 14 (StataCorp, College Station, TX). To evaluate the increase in the risk of incident AF, the primary meta-analytic approach was a fixed effects model using the Mantel-Haenszel method. A sensitivity analysis was performed using a DerSimonian and Laird random effects model. Heterogeneity of studies was evaluated by Cochran's Q and the I 2 statistic. Pooled AF rates were estimated as follows: we multiplied the median follow-up duration by the sample siz...

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Patients with mantle cell lymphoma failing ibrutinib are unlikely to respond to salvage chemotherapy and have poor outcomes

Abstract: The outcome of patients with MCL who experience disease progression following ibrutinib therapy is poor, with both low response rates to salvage therapy and short duration of responses. Further studies to better understand and overcome ibrutinib resistance are urgently needed.

Cited by 149 publications

References 10 publications

Postibrutinib outcomes in patients with mantle cell lymphoma

Postibrutinib outcomes in patients with mantle cell lymphoma

Current understanding of bleeding with ibrutinib use: a systematic review and meta-analysis

The risk of atrial fibrillation with ibrutinib use: a systematic review and meta-analysis

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