Age-adjusted lymphoma incidence rates continue to rise in France since the early 80's, although rates have slowed since 2010 and vary across subtypes. Recent improvements in patient survival in major ...lymphoma subtypes at population level raise new questions about patient outcomes (i.e. quality of life, long-term sequelae). Epidemiological studies have investigated factors related to lymphoma risk, but few have addressed the extent to which socioeconomic status, social institutional context (i.e. healthcare system), social relationships, environmental context (exposures), individual behaviours (lifestyle) or genetic determinants influence lymphoma outcomes, especially in the general population. Moreover, the knowledge of the disease behaviour mainly obtained from clinical trials data is partly biased because of patient selection.
The REALYSA ("REal world dAta in LYmphoma and Survival in Adults") study is a real-life multicentric cohort set up in French areas covered by population-based cancer registries to study the prognostic value of epidemiological, clinical and biological factors with a prospective 9-year follow-up. We aim to include 6000 patients over 4 to 5 years. Adult patients without lymphoma history and newly diagnosed with one of the following 7 lymphoma subtypes (diffuse large B-cell, follicular, marginal zone, mantle cell, Burkitt, Hodgkin, mature T-cell) are invited to participate during a medical consultation with their hematologist. Exclusion criteria are: having already received anti-lymphoma treatment (except pre-phase) and having a documented HIV infection. Patients are treated according to the standard practice in their center. Clinical data, including treatment received, are extracted from patients' medical records. Patients' risk factors exposures and other epidemiological data are obtained at baseline by filling out a questionnaire during an interview led by a clinical research assistant. Biological samples are collected at baseline and during treatment. A virtual tumor biobank is constituted for baseline tumor samples. Follow-up data, both clinical and epidemiological, are collected every 6 months in the first 3 years and every year thereafter.
This cohort constitutes an innovative platform for clinical, biological, epidemiological and socio-economic research projects and provides an opportunity to improve knowledge on factors associated to outcome of lymphoma patients in real life.
2018-A01332-53, ClinicalTrials.gov identifier: NCT03869619 .
Tumor-associated macrophages (TAMs) in chronic lymphocytic leukemia (CLL) are also called nurse-like cells (NLC), and confer survival signals through the release of soluble factors and cellular ...contacts. While in most patient samples the presence of NLC in co-cultures guarantees high viability of leukemic cells in vitro, in some cases this protective effect is absent. These macrophages are characterized by an "M1-like phenotype". We show here that their reprogramming towards an M2-like phenotype (tumor-supportive) with IL-10 leads to an increase in leukemic cell survival. Inflammatory cytokines, such as TNF, are also able to depolarize M2-type protective NLC (decreasing CLL cell viability), an effect which is countered by IL-10 or blocking antibodies. Interestingly, both IL-10 and TNF are implied in the pathophysiology of CLL and their elevated level is associated with bad prognosis. We propose that the molecular balance between these two cytokines in CLL niches plays an important role in the maintenance of the protective phenotype of NLCs, and therefore in the survival of CLL cells.
Objective
Hematological treatment decisions in older adults with hematological malignancies are complex. Our objective is to study the impact of a comprehensive geriatric assessment on hematological ...treatment decision in older patients and the factors associated with change in treatment plan.
Methods
We conducted a cross‐sectional analysis of patients aged 65 years and above with hematological malignancies, hospitalized between 2008 and 2019 at the University Cancer Institute of Toulouse. They were assessed by a geriatrician/nurse team using a comprehensive geriatric assessment (CGA). A penalized logistic regression model with elastic net regularization was used to identify factors associated with change in hematological treatment plan.
Results
A total of 424 patients were included. Main hematological malignancies were lymphoma (36.1 %), acute myeloid leukemia (26.9 %) and myelodysplastic syndrome (19.8%). Change in hematological treatment plan was suggested after CGA for 92 patients (21.7%). Factors associated with change in treatment plan were functional impairment according to ADL and IADL scale, mobility impairment, the presence of comorbidity defined by the Charlson score >1 and increasing age.
Conclusion
A CGA has a significant impact on hematological treatment decision in older patients. Functional and mobility impairment, comorbidities and age are predictive factors of change in treatment plan.
Follicular lymphoma (FL) is a common non Hodgkin's lymphoma subtype in which immune escape mechanisms are implicated in resistance to chemo-immunotherapy. Although molecular studies point to ...qualitative and quantitative deregulation of immune checkpoints, in depth cellular analysis of FL immune escape is lacking. Here, by functional assays and in silico analyses we show that a subset of FL patients displays a 'high' immune escape phenotype. These FL cases are characterized by abundant infiltration of PD1
+
CD16
+
TCRVγ9Vδ2 γδ T lymphocytes. In a 3D co-culture assay (MALC), γδ T cells mediate both direct and indirect (ADCC in the presence of anti-CD20 mAbs) cytolytic activity against FL cell aggregates. Importantly, PD-1, which is expressed by most FL-infiltrating γδ T lymphocytes with ADCC capacity, impairs these functions. In conclusion, we identify a PD1-regulated γδ T cell cytolytic immune component in FL. Our data provide a treatment rational by PD-1 blockade aimed at boosting γδ T cell anti-tumor functions in FL.
The development of targeted therapy drugs acting on tumor growth and progression is greatly expanding these last years. Among them kinase inhibitors have a prominent position and have demonstrated ...efficacy and clinical benefits in solid and hematologic malignancies. Compared to conventional systemic cytotoxic chemotherapeutic agents, their specific mechanism of action limits the occurrence of adverse events. However, as targeted kinases are shared by normal cells, their inhibition can affect physiological cell function. In this review we will focus on the side effects of kinase inhibitors on blood platelets which actively use kinase-related signalling pathways to prevent haemorrhages following vessel injury. Major functions of platelets are to adhere to the subendothelial matrix and to aggregate to form a haemostatic plug preventing excessive blood loss upon vascular lesion. Several kinase inhibitors including dasatinib and ibrutinib have been reported to affect specific steps of platelet activation process and to increase bleeding risk. This has important clinical implications particularly in patients treated with antithrombotic drugs. We will describe the effect of kinase inhibitors known to affect platelet activation and discuss the potential impact of those under development that may also interfere with platelet functions.
Findings among a cohort of 26 patients who had hematologic malignancies and hepatitis E virus (HEV) infection support that HEV can induce chronic hepatitis. However, a 3-month course of ribavirin can ...induce a rapid viral clearance, reducing the risk for chronic hepatitis and enabling continuation of cytotoxic treatments for underlying malignancies.
Complex karyotype identified by chromosome-banding analysis has been shown to have prognostic value in chronic lymphocytic leukemia (CLL). Genomic arrays offer high-resolution genomewide detection of ...copy-number alterations (CNA) and could therefore be well equipped to detect the presence of a complex karyotype. Current knowledge on genomic arrays in CLL is based on outcomes of single-center studies, in which different cutoffs for CNA calling were used. To further determine the clinical utility of genomic arrays for CNA assessment in CLL diagnostics, we retrospectively analyzed 2,293 arrays from 13 diagnostic laboratories according to established standards. CNA were found outside regions captured by CLL fluorescence
in situ
hybridization probes in 34% of patients, and several of them, including gains of 8q, deletions of 9p and 18p (
P
<0.01), were linked to poor outcome after correction for multiple testing. Patients (n=972) could be divided into three distinct prognostic subgroups based on the number of CNA. In multivariable analysis only high genomic complexity, defined as ≥5 CNA, emerged as an independent adverse prognosticator for time to first treatment (hazard ratio: 2.15; 95% confidence interval: 1.36-3.41;
P
=0.001) and overall survival (hazard ratio: 2.54, 95% confidence interval: 1.54-4.17;
P
<0.001; n=528). Lowering the size cutoff to 1 Mb in 647 patients did not significantly improve risk assessment. Genomic arrays detected more chromosomal abnormalities and, in terms of risk stratification, performed at least as well as simultaneous chromosome banding analysis as carried out in 122 patients. Our findings indicate that genomic array is an accurate tool for CLL risk stratification.
Introduction: Ibrutinib is an irreversible first-in-class inhibitor of BTK (Bruton tyrosine kinase) approved for the therapy of relapsed/refractory chronic lymphocytic leukemia (R/R CLL). The drug ...mediates a transient increase in circulating CLL cells together with reduction in spleen and lymph node size, by both cellular mobilization and apoptosis of resident CLL cells (Herman SE, et al. Blood 2014;123:3286-95). These events occur with important patients' inter-variability (Herman SE, et al. Leukemia 2014;28:2188-96), one cluster of patients presents with greater peak lymphocytosis (resolving between 1 to more than 6 months), while another cluster presents with rapid resolution of lymphocytosis and lymph node/spleen size within 2 months.
Upon such dramatic shifts in disease distribution the first 2 months of therapy (and sometimes lasting >6-12 months), the question of phenotypic changes, sensitivity to monoclonal antibodies (MoAbs), and subclonal diversity of circulating cells remains central for further combination studies. In this study, we evaluated changes in CD5, CD19, and CD20 expression in vitro/in vivo, and peripheral blood side population (SP) cells (a fraction highly enriched in chemorefractory cells, Gross E, et al. Leukemia 2010;24:1885-92) upon ibrutinib therapy. We also investigated whether patterns of lymphocytosis may predict for response to rituximab (RTX) or obinutuzumab (GA101).
Methods: R/R CLL patients (n=25) median prior lines=4, range=2-8), PBMCs were collected before ibrutinib initiation and after 1 and 2 months of therapy. PBMC were seeded at 10 x 106 cells/mL in culture medium and treated for 7 days with 10µg/mL control IgG1 (trastuzumab), RTX or obinutuzumab. The specific percentage of remaining B cells in MoAbs-treated samples was calculated as (absolute number in treated samples/absolute number in control samples) x 100. For each condition, absolute number of remaining B cells =total viable cell number (trypan blue exclusion determination) x % of viable CD19+/CD5+ lymphocytes (flow cytometry determination). For statistical analyses, Student's test (paired, two-sided) was used (*p<0.05;**p<0.01;***p<0.001).
Results: We firstanalyzed patterns ofabsolute lymphocytes count ( ALC) across 23 patients receiving ibrutinib (Fig 1a) to classify them into two clusters as previously published (Fig 1b): Cluster 1 and cluster 2 did not differ significantly in terms of initial lymphocytosis, line of therapy, gender, karyotype, IgHV. Interestingly, the SP fraction in peripheral blood was significantly increased (median: 5/microL before ibrutinib, 10/microL at peak lymphocytosis), suggesting mobilization of resident SP cells, although no apoptosis was detected (in vitro or in vivo) with ibrutinib.
We next assessed CD5, CD19 and CD20 levels in vitro (n=22) and in vivo (n=15) upon ibrutinib therapy. In vitro, ibrutinib significantly reduced CD20 (Fig 2a) and CD19 surface expression, but not CD5; nevertheless anti-CD20 MoAbs still had activity in vitro (Fig 2b). Expression levels were not linked to clusters 1 or 2.
Finally we compared RTX- and obinutuzumab-induced B-cell depletion before administration of ibrutinib, and at various sampling time points (1 to 6 months). Obinutuzumab induced significantly superior depletion at various timepoints than RTX. More interestingly, when analysis was performed from paired samples before/during ibrutinib therapy from the same ibrutinib-exposed patients, only obinutuzumab-induced depletion was increased in cluster 2 (Fig 3).
Conclusions: Ongoing and planned clinical studies evaluate the combination of ibrutinib and obinutuzumab in CLL (first-line and relapsed). Some concerns have emerged due to published preclinical data showing that ibrutinib can interfere with efficacy of therapeutic antibodies. Here, we suggest that ibrutinib-exposed CLL cells, despite wide inter-patient heterogeneity, are targetable with obinutuzumab.
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Klein:Roche: Employment.
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