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• W2063055276 abstract "Bruton tyrosine kinase (BTK) is involved in the signalling pathway of the B-cell receptor (BCR). Signal regulation within this pathway is critical for the maturation and functioning of normal B cells (Gauld et al, 2002). Functional BCR signalling has been shown to be necessary for maintaining the viability of malignant B cells in varied non-Hodgkin lymphoma subtypes (Davis et al, 2010; Cinar et al, 2013). Ibrutinib is a selective inhibitor of the BTK protein that irreversibly binds to cysteine-481 within the active site (Honigberg et al, 2010). In vitro, ibrutinib blocks B-cell activation, arrests cell growth and induces apoptosis in human B-lymphocyte cell lines (Davis et al, 2010; Honigberg et al, 2010; Cinar et al, 2013). In clinical trials, ibrutinib has exhibited significant activity in certain B-cell malignancies, including chronic lymphocytic leukaemia (CLL) and mantle cell lymphoma (MCL) (Advani et al, 2013; Byrd et al, 2013; Wang et al, 2013). Peripheral blood lymphocytosis was a significant feature observed with ibrutinib therapy during phase 1 and 2 studies in CLL (Byrd et al, 2013) and MCL (Wang et al, 2013). In a phase 2 study of single-agent ibrutinib (PCYC-1104-CA; NCT01236391), 34% of the enrolled patients with MCL (n = 111) experienced a transient increase (to ≥50% of baseline and >5 × 109/l) in peripheral absolute lymphocyte count (ALC). This lymphocytosis peaked at a median of 4 weeks of treatment and gradually decreased over 15–18 weeks of therapy (Wang et al, 2013). The circulating lymphocytes were characterized as CD19+CD3−CD5+, with reduced expression of CXCR4 (which is involved in the homing of B cells to lymphoid tissues). Reductions in plasma chemokines CCL22, CCL4, and CXCL13 were also noted (Chang et al, 2013). These results, combined with the finding that lymphocytosis occurred during a period of reduction in tumour volume, led to the postulation that the circulating tumour cells were moving from involved lymph nodes into the peripheral circulation. Full details of the phase 2 MCL trial have been reported previously (Wang et al, 2013). In this trial, patients with relapsed or refractory MCL received oral ibrutinib at a dose of 560 mg daily until disease progression or development of unacceptable toxicity. Patients received a median of nine cycles of therapy (one cycle is 4 weeks of continuous therapy), with a median follow-up time of 15 months. The overall response rate (ORR) was 68%, with 21% of patients achieving complete remission (in a median of 5·5 months). We examined whether lymphocytosis, which occurred in 34% of the patients (38 of 111) in the phase 2 trial, was associated with either a change in tumour volume or disease involvement of the bone marrow. The present analysis included data from 110 patients for whom we had baseline and at least 1 post-baseline ALC measurement. We observed a significantly greater change in mean maximum ALC in patients with disease involving the bone marrow (n = 53) compared with those with no bone marrow involvement (n = 57) (Fig 1A, 25·8 × 109/l vs. 3·1 × 109/l respectively; P < 0·0001, Wilcoxon nonparametric rank sum test). In patients exhibiting bone marrow disease, the degree of marrow involvement was important, with a mean maximum ALC change of 9·6 × 109/l in those with ≤30% marrow involvement (n = 25) compared with 39·5 × 109/l for those with >30% marrow involvement (n = 20) (Fig 1B, P = 0·0078, Wilcoxon nonparametric rank sum test). In addition, we analysed the kinetics of the ALC change. For those patients with bone marrow involvement, the median time to peak ALC was 21·5 d with a median time to resolution (return to baseline ALC) of 115 d (Fig 1C). For patients without marrow involvement, no clinically relevant ALC peak was observed, and the mean ALC remained relatively stable over the course of ibrutinib treatment (Fig 1C). Moreover, there were no significant differences in independently assessed ORR or duration of response (DOR) with ibrutinib treatment between patients with lymphocytosis and those without lymphocytosis in our MCL study (ORR 75·7% vs. 73·8%; median DOR 18·8 vs. 20·9 months, respectively). In CLL, there appears to be a correlation between the rise in lymphocytes and a reduction in tumour volume, as shown in a phase 2 trial of single-agent ibrutinib, in which the median percentage ALC change from baseline occurred simultaneously with the fastest reduction in the sum of the products of lymph node diameters (Byrd et al, 2013). In contrast to findings from the CLL study, changes in tumour volume in our MCL study did not correlate with involvement of bone marrow with disease (Table 1, P = 0·1222 permutation test) or the degree of lymphocytosis (P = 0·6164 Spearman's rank test). These findings are compatible with the current knowledge regarding the effects of ibrutinib. In CLL, ibrutinib-associated lymphocytosis has been differentiated from disease progression (Cheson et al, 2012), and it has already been postulated that the redistribution of CLL cells into the peripheral blood may occur due to the effect of the drug on the signalling of receptors, such as CXCR4 and CXCR5, which are both important in B-cell migration and adhesion (Burger & Buggy, 2013). It may be that the drug facilitates the release of cells from different tissue compartments in CLL compared with MCL. These results may also explain why the circulating MCL cells examined by Chang et al (2013) were CD38lo rather than CD38hi, as would be expected of lymphocytes from lymph nodes. Because it is often difficult to clear disease from the bone marrow, it is conceivable that the use of ibrutinib as an adjunct to other therapies could help to deepen the responses achieved. The lymphocytosis that occurs in MCL during ibrutinib treatment can be dramatic, and this is the first report showing a clear association between lymphocytosis and bone marrow disease involvement. The information presented here may help clinicians predict which patients may potentially develop lymphocytosis during ibrutinib therapy and thereby alleviate concerns when it occurs. Robert Rydzewski, MS, CMPP, provided medical writing assistance with copy-editing, author comment compilation, and incorporation of revisions for this manuscript, which was supported by Pharmacyclics, Inc. BM, JM, and DMB declare employment by and ownership interest in Pharmacyclics; SR has consulted for Johnson & Johnson, Pharmacyclics, Roche, Napp and Celgene; SR has received research funding from Celgene, GlaxoSmithKline and Johnson & Johnson; MF and MLW declare no conflicts. All authors contributed to the study design; BM contributed to data collection and analysis; all authors contributed to the writing and final approval of this manuscript." @default.
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• W2063055276 date "2015-01-06" @default.
• W2063055276 modified "2023-09-23" @default.
• W2063055276 title "Ibrutinib-associated lymphocytosis corresponds to bone marrow involvement in mantle cell lymphoma" @default.
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