Ibrutinib in Previously Treated Waldenström’s Macroglobulinemia

Key Points• BDR is a chemotherapy-free, non-stem-cell-toxic regimen associated with high response rates and long-term remissions.• The long-term safety profile of BDR is favorable, with high probability of response to reintroduction of rituximabbased regimens at relapse.In this phase 2 multicenter trial, we evaluated the efficacy of the combination of bortezomib, dexamethasone, and rituximab (BDR) in 59 previously untreated symptomatic patients with Waldenström macroglobulinemia (WM), most of which were of advanced age and with adverse prognostic factors. BDR consisted of a single 21-day cycle of bortezomib alone (1.3 mg/m 2 IV on days 1, 4, 8, and 11), followed by weekly IV bortezomib (1.6 mg/m 2 on days 1, 8, 15, and 22) for 4 additional 35-day cycles, with IV dexamethasone (40 mg) and IV rituximab (375 mg/m 2 ) on cycles 2 and 5, for a total treatment duration of 23 weeks. On intent to treat, 85% responded (3% complete response, 7% very good partial response, 58% partial response). After a minimum follow-up of 6 years, median progression-free survival was 43 months and median duration of response for patients with at least partial response was 64.5 months. Overall survival at 7 years was 66%. No patient had developed secondary myelodysplasia, whereas transformation to high-grade lymphoma occurred in 3 patients who had received chemoimmunotherapy after BDR. Thus, BDR is a very active, fixedduration, chemotherapy-free regimen, inducing durable responses and with a favorable long-term toxicity profile (www.

Section: Methodsmentioning

confidence: 99%

BDR in newly diagnosed patients with WM: final analysis of a phase 2 study after a minimum follow-up of 6 years

Gavriatopoulou

García‐Sanz

Kastritis

et al. 2017

“…3,4 Ibrutinib is an irreversible, small-molecule inhibitor of BTK with efficacy in B-cell malignancies, including chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma, lymphoplasmacytic lymphoma, marginal zone lymphoma, and mantle cell lymphoma. [5][6][7][8][9][10] Follicular lymphoma (FL) cells exhibit enhanced BCR activation via both antigen-dependent and -independent mechanisms. [11][12][13] In a phase 1 study of ibrutinib in relapsed B-cell malignancies, 6 (54%) of 11 patients with FL who received doses $2.5 mg/kg achieved an objective response.…”

Section: Introductionmentioning

confidence: 99%

Single-agent ibrutinib in relapsed or refractory follicular lymphoma: a phase 2 consortium trial

Bartlett

Costello

LaPlant

et al. 2018

142

115

“…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.…”

mentioning

confidence: 99%

“…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.…”

mentioning

confidence: 99%

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

Leong

Caron

Hillis

et al. 2016

206

117

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...