Safety and activity of BTK inhibitor ibrutinib combined with ofatumumab in chronic lymphocytic leukemia: a phase 1b/2 study

Jaglowski, Samantha; Jones, Jeffrey A.; Nagar, Veena; Flynn, Joseph M.; Andritsos, Leslie A.; Maddocks, Kami J.; Woyach, Jennifer A.; Blum, Kristie A.; Grever, Michael R.; Smucker, Kelly A.; Ruppert, Amy S.; Heerema, Nyla A.; Lozanski, Gerard; Stefanos, Mona; Munneke, Brian; West, Jamie-Sue; Neuenburg, Jutta K.; James, Danelle F.; Hall, Nathan C.; Johnson, Amy J.; Byrd, John C.

doi:10.1182/blood-2014-12-617522

Cited by 127 publications

(95 citation statements)

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“…This may explain why early clinical results showed an enhanced effect when adding rituximab or ofatumumab to ibrutinib in treatment for chronic lymphocytic leukemia (20,21). Anti-CD20 antibodies such as rituximab and obinutuzumab are key components of therapy for diseases such as chronic lymphocytic leukemia or non-Hodgkin lymphoma, and these results suggest a potential mechanism by which their effectiveness would not be compromised by concurrent treatment with a Btk inhibitor.…”

Section: Discussionmentioning

confidence: 84%

“…Therefore, although ibrutinib can block Btk (and Itk) in isolated cultures, proinflammatory intercellular communication is sufficient to overcome its inhibitory effects on monocytes and NK cells. These results suggest that ibrutinib may not be detrimental to patients undergoing antibody therapy and may explain early clinical results showing an enhanced effect when CD20 antibodies such as rituximab or ofatumumab are added to ibrutinib in chronic lymphocytic leukemia (20,21).…”

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confidence: 65%

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Analysis of the Effects of the Bruton's tyrosine kinase (Btk) Inhibitor Ibrutinib on Monocyte Fcγ Receptor (FcγR) Function

Campbell²,

Fang³

et al. 2016

Journal of Biological Chemistry

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The irreversible Bruton's tyrosine kinase (Btk) inhibitor ibrutinib has shown efficacy against B-cell tumors such as chronic lymphocytic leukemia and B-cell non-Hodgkin lymphoma. Fc␥ receptors (Fc␥R) on immune cells such as macrophages play an important role in tumor-specific antibody-mediated immune responses, but many such responses involve Btk. Here we tested the effects of ibrutinib on Fc␥R-mediated activities in monocytes. We found that ibrutinib did not affect monocyte Fc␥R-mediated phagocytosis, even at concentrations higher than those achieved physiologically, but suppressed Fc␥R-mediated cytokine production. We confirmed these findings in macrophages from Xid mice in which Btk signaling is defective. Because calcium flux is a major event downstream of Btk, we tested whether it was involved in phagocytosis. The results showed that blocking intracellular calcium flux decreased Fc␥R-mediated cytokine production but not phagocytosis. To verify this, we measured activation of the GTPase Rac, which is responsible for actin polymerization. Results showed that ibrutinib did not inhibit Rac activation, nor did the calcium chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N,N-tetraacetic acid tetrakis(acetoxymethyl ester). We next asked whether the effect of ibrutinib on monocyte Fc␥R-mediated cytokine production could be rescued by IFN␥ priming because NK cells produce IFN␥ in response to antibody therapy. Pretreatment of monocytes with IFN␥ abrogated the effects of ibrutinib on Fc␥R-mediated cytokine production, suggesting that IFN␥ priming could overcome this Btk inhibition. Furthermore, in monocyte-natural killer cell co-cultures, ibrutinib did not inhibit Fc␥R-mediated cytokine production despite doing so in single cultures. These results suggest that combining ibrutinib with monoclonal antibody therapy could enhance chronic lymphocytic leukemia cell killing without affecting macrophage effector function.

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Section: Discussionmentioning

confidence: 84%

mentioning

confidence: 65%

Analysis of the Effects of the Bruton's tyrosine kinase (Btk) Inhibitor Ibrutinib on Monocyte Fcγ Receptor (FcγR) Function

Campbell²,

Fang³

et al. 2016

Journal of Biological Chemistry

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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

200

117

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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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“…Ibrutinib is also tested in the frontline setting and has improved OS compared to chlorambucil in elderly patients [125]. Other trials of ibrutinibmainly comparison with ofatumumab (RESONATE) [95], combination with rituximab in high risk patients [97], combination with ofatumumab [98], in patients with TP53 mutations [96], with BR [99] Rai and Jain are summarized in Table III. CLL12 trial is first in kind trial as this trial will study ibrutinib in patients with early stage CLL who have high risk of progression depending upon the comprehensive prognostic index [126].…”

Section: Ibrutinibmentioning

confidence: 99%

Chronic lymphocytic leukemia (CLL)—Then and now

Kanti

Jain²

2016

American J Hematol

130

108

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The field of chronic lymphocytic leukemia (CLL) has witnessed considerable change since the time clinical staging was introduced in clinical practice in 1975. Over the years, the prognostication in CLL has expanded with the addition in late 90s of mutational status of variable region of immunoglobulin heavy chain (IGHV), and chromosomal analyses using fluorescent in situ hybridization (FISH). More recently, stereotypy of BCR (B cell receptor) and whole exome sequencing (WES) based discovery of specific mutations such as NOTCH1, TP53, SF3B1, XPO-1, BIRC3, ATM, and RPS15 further refined the current prognostication system in CLL. In therapy, the field of CLL has seen major changes from oral chlorambucil and steroids prior to 1980s, to chemo-immunotherapy (CIT) with fludarabine, cyclophosphamide, rituximab (FCR) to the orally administered targeted therapeutic agents inhibiting kinases in the B cell receptor (BCR) signaling pathway such as Ibrutinib (BTK inhibitor) and Idelalisib (p110 PI3Kd inhibitor) and novel anti-CD20 mAb's (monoclonal antibodies) such as obinutuzumab. This progress is continuing and other targeted therapeutics such as Bcl2 antagonists (Venetoclax or ABT-199) and finally chimeric antigen receptor against T cells (CART) are in the process of being developed. This review is an attempt to summarize the major benchmarks in the prognostication and in the therapy of CLL. The topic allocated to us by Dr Ayalew Tefferi and Dr Carlo Brugnara is very appropriate to reminisce what our understanding of chronic lymphocytic leukemia (CLL) was in 1976 and how rapidly have the advances occurring in this field affected the patients with CLL. It is a disease of progressive accumulation of lymphocytes. CLL lymphocytes are morphologically indistinguishable from a normal mature lymphocyte CLL lymphocytes are functionally inert and perhaps as a direct consequence, their life-span is longer than of normal lymphocytes. It was also believed that CLL lymphocytes are not rapidly proliferating. CLL is a disease of elderly population In some cases, chronic lymphocytic leukemia (CLL) closely resembled leukemic Brill Symmers disease (leukemic form of follicular lymphoma). In an elegant study on 88 patients, the temporal profile of the clinical course of CLL was described by Galton et al.[1] Disease progression was assessed in relation to lymphadenopathy, splenomegaly and bone marrow infiltration. CLL was considered as an immunoproliferative disorder with low immunoglobulin levels, striking response to therapy with steroids and exaggerated skin reaction to arthropod bites. Management of CLL (then in 1976)Most clinicians recognized that at the time of initial diagnosis, patients with CLL, generally, were free of disease-related symptoms. Therefore, virtually all patients were followed on a wait-and-watch regimen, withholding any cytotoxic therapy. When, on clinical grounds, initiation of any therapy was considered appropriate, oral alkylating agents such as chlorambucil with/without steroids [3,4] or cyclophosphamide [5] with or...

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Safety and activity of BTK inhibitor ibrutinib combined with ofatumumab in chronic lymphocytic leukemia: a phase 1b/2 study

Abstract: Key Points Ibrutinib combined with ofatumumab in relapsed CLL had had an ORR of 83% with median time to response of <3 months in all groups. All 3 sequences of administration were acceptably tolerated and active; responses were durable, and median PFS was not yet reached.

Cited by 127 publications

References 42 publications

Analysis of the Effects of the Bruton's tyrosine kinase (Btk) Inhibitor Ibrutinib on Monocyte Fcγ Receptor (FcγR) Function

Analysis of the Effects of the Bruton's tyrosine kinase (Btk) Inhibitor Ibrutinib on Monocyte Fcγ Receptor (FcγR) Function

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

Chronic lymphocytic leukemia (CLL)—Then and now

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