Ibrutinib has revolutionized the management of chronic lymphocytic leukemia and is now being increasingly used. Although considered to be less immunosuppressive than conventional immunochemotherapy, ...the observation of a few cases of invasive fungal infections in patients treated with ibrutinib prompted us to conduct a retrospective survey. We identified 33 cases of invasive fungal infections in patients receiving ibrutinib alone or in combination. Invasive aspergillosis (IA) was overrepresented (27/33) and was associated with cerebral localizations in 40% of the cases. Remarkably, most cases of invasive fungal infections occurred with a median of 3 months after starting ibrutinib. In 18/33 cases, other conditions that could have contributed to decreased antifungal responses, such as corticosteroids, neutropenia, or combined immunochemotherapy, were present. These observations indicate that ibrutinib may be associated with early-onset invasive fungal infections, in particular IA with frequent cerebral involvement, and that patients on ibrutinib should be closely monitored in particular when other risk factors of fungal infections are present.
•Ibrutinib may be associated with invasive fungal infections especially IA.•Most infections usually occur during the first months of treatment, often in patients with other risk factors for fungal infections.
Chronic lymphocytic leukaemia (CLL) has several unique features that distinguish it from other cancers. Most CLL tumour cells are inert and arrested in G0/G1 of the cell cycle and there is only a ...small proliferative compartment; however, the progressive accumulation of malignant cells will ultimately lead to symptomatic disease. Pathogenic mechanisms have been elucidated that involve multiple external (for example, microenvironmental stimuli and antigenic drive) and internal (genetic and epigenetic) events that are crucial in the transformation, progression and evolution of CLL. Our growing understanding of CLL biology is allowing the translation of targets and biological classifiers into clinical practice.
Pneumococcal (PC) vaccination is recommended for patients with chronic lymphocytic leukemia (CLL). However, response to vaccines has been investigated in a small series of CLL patients. We analyzed ...the antibody response and outcomes of 112 CLL patients who received the 13-valent pneumococcal conjugate vaccine (PCV13). An immune response was defined by a twofold increase in the PC-IgG levels assessed by ELISA. The median age of patients was 68 years, 23.2% showed IgG levels ≤ 400 mg/L, 6.3% progressive disease, 52% unmutated IGHV. Twenty-two (19.6%) patients were treatment-naïve and 90 (80.4%) previously treated (40.2% front-line chemoimmunotherapy; ibrutinib first/advanced-line, 9.8%/21.4%; idelalisib advanced-line, 8.9%). Nine (8%) patients developed an immune response, eight treatment-naive, and one on front-line ibrutinib. No responses were observed in patients previously treated with chemoimmunotherapy. Age ≥ 60 years (p = 0.007), IgG levels < 400 mg/L (p < 0.0001), prior treatment (p < 0.0001), and signs of disease progression (p = 0.04) were associated with a lower response rate. Pneumonia-free survival was significantly shorter in patients with clinical signs of progressive disease (HR, 8.39), prior pneumonia (HR, 7.03), and TP53 disruption (HR, 2.91). In conclusion, our results suggest that vaccination should be offered at diagnosis to CLL patients with early stage and stable disease who have better resources for an effective immune response.
The Bruton tyrosine kinase inhibitor ibrutinib induces high rates of clinical response in chronic lymphocytic leukemia (CLL). However, there remains a need for adjunct treatments to deepen response ...and to overcome drug resistance. Blinatumomab, a CD19/CD3 bispecific antibody (bsAb) designed in the BiTE (bispecific T-cell engager) format, is approved by the US Food and Drug Administration for the treatment of relapsed or refractory B-cell precursor acute lymphoblastic leukemia. Because of its short half-life of 2.1 hours, blinatumomab requires continuous intravenous dosing for efficacy. We developed a novel CD19/CD3 bsAb in the single-chain Fv-Fc format (CD19/CD3-scFv-Fc) with a half-life of ∼5 days. In in vitro experiments, both CD19/CD3-scFv-Fc and blinatumomab induced >90% killing of CLL cells from treatment-naïve patients. Antileukemic activity was associated with increased autologous CD8 and CD4 T-cell proliferation, activation, and granzyme B expression. In the NOD/SCID/IL2Rγnull patient-derived xenograft mouse model, once-weekly treatment with CD19/CD3-scFv-Fc eliminated >98% of treatment-naïve CLL cells in blood and spleen. By contrast, blinatumomab failed to induce a response, even when administered daily. We next explored the activity of CD19/CD3-scFv-Fc in the context of ibrutinib treatment and ibrutinib resistance. CD19/CD3-scFv-Fc induced more rapid killing of CLL cells from ibrutinib-treated patients than those from treatment-naïve patients. CD19/CD3-scFv-Fc also demonstrated potent activity against CLL cells from patients with acquired ibrutinib-resistance harboring BTK and/or PLCG2 mutations in vitro and in vivo using patient-derived xenograft models. Taken together, these data support investigation of CD19/CD3 bsAb's and other T cell-recruiting bsAb's as immunotherapies for CLL, especially in combination with ibrutinib or as rescue therapy in ibrutinib-resistant disease.
•A CD19/CD3 single-chain Fv-Fc bsAb mediated potent killing of CLL cells by autologous T cells in vitro and in vivo.•bsAb-mediated cytotoxicity was enhanced by prior therapy with ibrutinib and extended to ibrutinib-resistant disease.
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Anti-CD19 chimeric antigen receptor (CAR) T cells have caused remissions of B cell malignancies, but problems including cytokine-mediated toxicity and short persistence of CAR T cells in vivo might ...limit the effectiveness of anti-CD19 CAR T cells. Anti-CD19 CARs that have been tested clinically had single-chain variable fragments (scFvs) derived from murine antibodies. We have designed and constructed novel anti-CD19 CARs containing a scFv with fully human variable regions. T cells expressing these CARs specifically recognized CD19+ target cells and carried out functions including degranulation, cytokine release, and proliferation. We compared CARs with CD28 costimulatory moieties along with hinge and transmembrane domains from either the human CD28 molecule or the human CD8α molecule. Compared with T cells expressing CARs with CD28 hinge and transmembrane domains, T cells expressing CARs with CD8α hinge and transmembrane domains produced lower levels of cytokines and exhibited lower levels of activation-induced cell death (AICD). Importantly, CARs with hinge and transmembrane regions from either CD8α or CD28 had similar abilities to eliminate established tumors in mice. In anti-CD19 CARs with CD28 costimulatory moieties, lower levels of inflammatory cytokine production and AICD are potential clinical advantages of CD8α hinge and transmembrane domains over CD28 hinge and transmembrane domains.
Hinge and transmembrane regions in anti-CD19 chimeric antigen receptors (CARs) have an important impact on the function of CAR-expressing T cells. CARs with hinge and transmembrane regions from CD8-alpha lead to lower levels of cytokine release and less activation-induced cell death than CARs with hinge and transmembrane regions from CD28.
Aryl hydrocarbon receptor (AHR) activation by tryptophan (Trp) catabolites enhances tumor malignancy and suppresses anti-tumor immunity. The context specificity of AHR target genes has so far impeded ...systematic investigation of AHR activity and its upstream enzymes across human cancers. A pan-tissue AHR signature, derived by natural language processing, revealed that across 32 tumor entities, interleukin-4-induced-1 (IL4I1) associates more frequently with AHR activity than IDO1 or TDO2, hitherto recognized as the main Trp-catabolic enzymes. IL4I1 activates the AHR through the generation of indole metabolites and kynurenic acid. It associates with reduced survival in glioma patients, promotes cancer cell motility, and suppresses adaptive immunity, thereby enhancing the progression of chronic lymphocytic leukemia (CLL) in mice. Immune checkpoint blockade (ICB) induces IDO1 and IL4I1. As IDO1 inhibitors do not block IL4I1, IL4I1 may explain the failure of clinical studies combining ICB with IDO1 inhibition. Taken together, IL4I1 blockade opens new avenues for cancer therapy.
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•A pan-tissue AHR signature identifies IL4I1 as a major AHR-activating enzyme•IL4I1-mediated Trp catabolism yields indoles and kynurenic acid that activate the AHR•IL4I1 promotes AHR-driven cancer cell motility and suppresses adaptive immunity•IL4I1 enhances CLL progression and is induced by immune checkpoint blockade
Immune checkpoint blockade therapy induces the AHR-activating enzyme IL4I1, which promotes tumor progression, through its effects on tumor cell motility and adaptive immunity.
Complex karyotype, defined as ≥3 cytogenetic abnormalities, is prognostic of survival in patients treated with ibrutinib or venetoclax in relapsed/refractory (RR) chronic lymphocytic leukemia (CLL). ...Recent studies re-evaluating this dichotomous variable have shown that higher numbers of cytogenetic abnormalities (ie, ≥5) have a worse overall survival in patients treated with chemoimmunotherapy. We sought to determine if increasing karyotypic complexity, treated as a continuous variable, was prognostic of survival for patients treated with ibrutinib for CLL. We conducted a retrospective analysis of all patients with CLL treated with single-agent ibrutinib or in combination with an anti-CD20 antibody at our institution. We included 456 patients with both treatment-naive and RR disease. Median number of prior therapies was 2 (range, 0-13), 30% of patients had presence of del(17p), and 75% expressed unmutated IGHV. Fifty percent had ≥3 cytogenetic abnormalities, including 30% with ≥5. In a multivariable analysis, increasing karyotypic complexity was an independent predictor of shorter progression-free survival (hazard ratio, 1.07; 95% confidence interval, 1.04-1.10; P < .0001) and overall survival (hazard ratio, 1.09; 95% confidence interval, 1.05-1.12; P < .0001). Furthermore, we found that presence of clonal evolution determined by cytogenetic analysis at progression was prognostic of subsequent survival (P = .02). This solidifies karyotypic complexity as an important prognostic factor for patients with CLL treated with ibrutinib. Further research should consider sequential karyotypic analysis as a determination of risk of progression and death in patients with CLL.
Summary Background The TP53 gene, encoding tumour suppressor protein p53, is located on the short arm of chromosome 17 (17p). Patients with 17p deletion (del17p) chronic lymphocytic leukaemia have ...poor responses and survival after chemoimmunotherapy. We assessed the activity and safety of ibrutinib, an oral covalent inhibitor of Bruton's tyrosine kinase, in relapsed or refractory patients with del17p chronic lymphocytic leukaemia or small lymphocytic lymphoma. Methods We did a multicentre, international, open-label, single-arm study at 40 sites in the USA, Canada, Europe, Australia, and New Zealand. Patients (age ≥18 years) with previously treated del17p chronic lymphocytic leukaemia or small lymphocytic lymphoma received oral ibrutinib 420 mg once daily until progressive disease or unacceptable toxicity. The primary endpoint was overall response in the all-treated population per International Workshop on Chronic Lymphocytic Leukaemia 2008 response criteria modified for treatment-related lymphocytosis. Preplanned exploratory analyses were progression-free survival, overall survival, sustained haematological improvement, and immunological improvement. Patient enrolment is complete, but follow-up is ongoing. Treatment discontinuation owing to adverse events, unacceptable toxicity, or death were collected as a single combined category. This study is registered with ClinicalTrials.gov , number NCT01744691. Findings Between Jan 29, 2013, and June 19, 2013, 145 patients were enrolled. The all-treated population consisted of 144 patients with del17p chronic lymphocytic leukaemia or small lymphocytic lymphoma who received at least one dose of study drug, with a median age of 64 years (IQR 57–72) and a median of two previous treatments (IQR 1–3). At the prespecified primary analysis after a median follow-up of 11·5 months (IQR 11·1–13·8), 92 (64%, 95% CI 56–71) of 144 patients had an overall response according to independent review committee assessment; 119 patients (83%, 95% CI 76–88) had an overall response according to investigator assessment. In an extended analysis with median follow-up of 27·6 months (IQR 14·6–27·7), the investigator-assessed overall response was reported in 120 patients (83%, 95% CI 76–89). 24-month progression-free survival was 63% (95% CI 54–70) and 24-month overall survival was 75% (67–81). Sustained haematological improvement was noted in 72 (79%) of 91 patients with any baseline cytopenia. No clinically relevant changes were noted from baseline to 6 months or 24 months in IgA (median 0·4 g/L at baseline, 0·6 g/L at 6 months, and 0·7 g/L at 24 months), IgG (5·0 g/L, 5·3 g/L, and 4·9 g/L), or IgM (0·3 g/L at each timepoint) concentrations. Common reasons for treatment discontinuation were progressive disease in 34 (24%) patients and adverse events, unacceptable toxicity, or death in 24 (17%) patients. Major bleeding occurred in 13 (9%) patients (11 8% grade 3–4). Grade 3 or worse infections occurred in 43 (30%) patients, including pneumonia in 19 (13%) patients. In the extended analysis, 38 patients died, 18 as a result of adverse events (four pneumonia, three chronic lymphocytic leukaemia, two Richter's syndrome, two sepsis, and one each of acute myocardial infarction, septic shock, encephalopathy, general deterioration in physical health, abnormal hepatic function, myocardial infarction, and renal infarction). Interpretation A high proportion of patients had an overall response to ibrutinib and the risk:benefit profile was favourable, providing further evidence for use of ibrutinib in the most difficult subset of patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma. Ibrutinib represents a clinical advance in the treatment of patients with del17p chronic lymphocytic leukaemia and has been incorporated into treatment algorithms as a primary treatment for these patients. Funding Pharmacyclics LLC, an AbbVie Company.
Treatment of chronic lymphocytic leukemia (CLL) has shifted from chemo-immunotherapy to targeted agents. To define the evolutionary dynamics induced by targeted therapy in CLL, we perform serial ...exome and transcriptome sequencing for 61 ibrutinib-treated CLLs. Here, we report clonal shifts (change >0.1 in clonal cancer cell fraction, Q < 0.1) in 31% of patients during the first year of therapy, associated with adverse outcome. We also observe transcriptional downregulation of pathways mediating energy metabolism, cell cycle, and B cell receptor signaling. Known and previously undescribed mutations in BTK and PLCG2, or uncommonly, other candidate alterations are present in seventeen subjects at the time of progression. Thus, the frequently observed clonal shifts during the early treatment period and its potential association with adverse outcome may reflect greater evolutionary capacity, heralding the emergence of drug-resistant clones.
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