Health-related quality of life profile of newly diagnosed patients with Hodgkin and non-Hodgkin lymphomas: A real-world study including 3922 patients from the French REALYSA cohort.

INTRODUCTION: Considering the notable advances made in the treatment of lymphoma, assessment of health-related quality of life (HRQoL) of lymphoma patients has become a critical aspect to consider both in clinical research and routine practice. However, there is paucity of information about lymphoma specific HRQoL profile at diagnosis. PATIENTS AND METHODS: HRQoL at diagnosis was assessed for 3922 adult patients with newly diagnosed high-grade (HG) (n = 1994), low-grade (LG) (n = 1053) non-Hodgkin (NHL) and Hodgkin (HL) (n = 875) lymphomas included in REal world dAta in LYmphoma and Survival in Adults (REALYSA, NCT03869619), a prospective non-interventional multicentric cohort in France. Disease-specific HRQoL aspects were assessed with three validated EORTC questionnaires, namely, the QLQ-NHL-HG29, the QLQ-NHL-LG20 and the QLQ-HL27, for patients with NHL-HG, NHL-LG and HL, respectively. RESULTS: We confirmed the high-level of completion of these questionnaires in REALYSA cohort, ranging from 84 % for QLQ-HG29 to 88 % for QLQ-HL27. The proportion of patients with impaired global health status was as follows: T-cell NHL, 67 %; diffuse large B-cell (DLBCL), 62 %; Burkitt, 61 %; HL, 53 %; marginal zone, 49 %; mantle cell, 48 %; follicular, 47 %. Multivariable regression analyses for DLBCL, follicular and HL showed that gender, performance status and B symptoms were independently associated with all HRQoL dimensions. However, a variable effect of age and stage were observed among these three subtypes. CONCLUSIONS: A comprehensive analysis was made describing the HRQoL profile of newly diagnosed patients with different types of lymphomas. Our data may help to enhance the interpretation of HRQoL results in future studies using the recently validated EORTC lymphoma specific questionnaires.

Redefining Histological Cell Counts Using a Standardized Method: The Leuven Intestinal Counting Protocol.

INTRODUCTION: The diagnosis of eosinophilic gastrointestinal diseases is largely based on mucosal eosinophil counts, but thresholds and normal ranges beyond the esophagus are debated, calling for much-needed methodological standardization. We aimed to develop a standardized workflow for duodenal cell quantification and estimate duodenal eosinophil and mast cell numbers in healthy controls. METHODS: Software-based histological cell quantification using free-sized or fixed-sized regions was developed and applied to digitized hematoxylin and eosin (H&E)-stained slides from 58 individuals (healthy controls [HCs] and patients with functional dyspepsia). Intraclass correlation coefficients (ICCs) compared inter-rater reliability between software-based and microscopic quantification. Reproducibility of the software-based method was validated in an independent cohort of 37 control and functional dyspepsia subjects. Eosinophil identification on H&E staining was compared to immunohistochemistry (IHC). Normal eosinophil (H&E) and mast cell (cKit) ranges were determined in 70 adult HCs. RESULTS: Eosinophil quantification on digitized slides demonstrated excellent (ICC = 0.909) and significantly improved reproducibility over microscopic evaluation (ICC = 0.796, P = 0.0014), validated in an independent cohort (ICC = 0.910). Duodenal eosinophils were more abundant around crypts than in villi ( P < 0.0001), while counts were similar on matched H&E- and IHC-stained slides ( P = 0.55). Mean ± SD (95th percentile) duodenal eosinophils and mast cells in HC were 228.8/mm 2 ± 94.7 (402.8/mm 2 ) and 419.5/mm 2 ± 132.2 (707.6/mm 2 ), respectively. DISCUSSION: We developed and validated a standardized approach to duodenal histological cell quantification, generalizable to various mucosal cell types. Implementation of software-based quantification identified 400 eosinophils/mm 2 and 700 mast cells/mm 2 as thresholds for abnormal duodenal infiltration.

Challenges for quality and utilization of real-world data for diffuse large B-cell lymphoma in REALYSA, a LYSA cohort.

ABSTRACT: Real-world data (RWD) are essential to complement clinical trial (CT) data, but major challenges remain, such as data quality. REal world dAta in LYmphoma and Survival in Adults (REALYSA) is a prospective noninterventional multicentric cohort started in 2018 that included patients newly diagnosed with lymphoma in France. Herein is a proof-of-concept analysis on patients with first-line diffuse large B-cell lymphoma (DLBCL) to (1) evaluate the capacity of the cohort to provide robust data through a multistep validation process; (2) assess the consistency of the results; and (3) conduct an exploratory transportability assessment of 2 recent phase 3 CTs (POLARIX and SENIOR). The analysis population comprised 645 patients with DLBCL included before 31 March 2021 who received immunochemotherapy and for whom 3589 queries were generated, resulting in high data completeness (<4% missing data). Median age was 66 years, with mostly advanced-stage disease and high international prognostic index (IPI) score. Treatments were mostly rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisone (R-CHOP 75%) and reduced dose R-CHOP (13%). Estimated 1-year event-free survival (EFS) and overall survival rates were 77.9% and 90.0%, respectively (median follow-up, 9.9 months). Regarding transportability, when applying the CT's main inclusion criteria (age, performance status, and IPI), outcomes seemed comparable between patients in REALYSA and standard arms of POLARIX (1-year progression-free survival 79.8% vs 79.8%) and SENIOR (1-year EFS, 64.5% vs 60.0%). With its rigorous data validation process, REALYSA provides high-quality RWD, thus constituting a platform for numerous scientific purposes. The REALYSA study was registered at www.clinicaltrials.gov as #NCT03869619.

Resurgence of myeloproliferative neoplasm in patients in remission from blast transformation after treatment with hypomethylating agents.

Subsequent blast (BP) or accelerated phase (AP) is a severe complication of Philadelphia-negative myeloproliferative neoplasms (MPNs). The prognosis is generally dismal, but hypomethylating agents (HMAs) may induce a long-lasting response in a minority of patients. Here, we report a cohort of six patients with BP/AP-MPN who experienced MPN relapse after a leukemia response was obtained with azacytidine. Five of the patients achieved complete remission despite the presence of characteristics associated with poor prognosis, such as complex and monosomal karyotypes, TP53 mutations, and EVI1 overexpression. These remissions persisted for over five years in four of the 6 patients. All patients showed rapid reemergence of MPN within a median of two months with thrombocytosis requiring the addition of anagrelide, hydroxyurea, or ruxolitinib given continuously in parallel with the azacytidine cycle. Serial JAK2 V617F allelic burden measurements showed little variation. Thromboembolic events occurred in 3 patients, one leading to death. These findings confirm that HMA may reverse the disease course in AP/BP-MPN to a more chronic phase that may last for years but also lead to morbidity and mortality. Combining maintenance therapy with HMA and MPN-specific drugs appears to be a possible approach to avoiding leukemia relapse and controlling MPN disease.

Lenalidomide maintenance for diffuse large B-cell lymphoma patients responding to R-CHOP: quality of life, dosing, and safety results from the randomised controlled REMARC study.

Lenalidomide maintenance therapy prolonged progression-free survival (PFS) versus placebo in elderly patients with diffuse large B-cell lymphoma (DLBCL) responding to induction chemotherapy in the phase 3 REMARC study. This subpopulation analysis assessed the impact of lenalidomide maintenance and treatment-emergent adverse events (TEAEs) on health-related quality of life (HRQOL). Global health status (GHS), and physical functioning and fatigue subscales were evaluated in patients who completed the European Organisation for Research and Treatment of Cancer quality-of-life questionnaire-C30 v3.0. The impact of TEAEs classified post hoc as subjective (patients can feel) or observable (only measurable by physicians) on dose reductions and discontinuations was assessed. Among 457 patients (lenalidomide, n = 229; placebo, n = 228), mean (standard deviation) GHS was similar between treatment arms [68·2 (20·7) Versus 72·0 (17·8)] at randomisation and remained similar during maintenance. Patients receiving lenalidomide experienced no meaningful changes in GHS, physical functioning, or fatigue. Observable TEAEs were more common (81·1% Versus 66·3%) and more likely to lead to dose reductions, than subjective TEAEs in both arms. PFS was superior in the lenalidomide arm regardless of dose reduction. Lenalidomide maintenance prolonged PFS and did not negatively impact HRQOL in patients with DLBCL despite TEAEs being more common, when compared with placebo.

Epstein-Barr virus infection induces an increase of T regulatory type 1 cells in Hodgkin lymphoma patients.

Epstein-Barr Virus (EBV) is present in the neoplastic cells of around 20-30% of patients with Hodgkin Lymphoma (HL). Although, an immunosuppressive environment is currently described in HL patients, little is known concerning the regulatory mechanism induced by EBV proteins expression in tumour cells. This study aimed to investigate an association between regulatory Type 1 cells (Tr1) and EBV tissue positivity in HL patients. Transcriptomic analysis of both EBV-positive and EBV-negative tumours showed that EBV infection increased gene expression of Tr1-related markers (ITGA2, ITGB2, LAG3) and associated-immunosuppressive cytokines (IL10). This up-regulation was associated with an over-expression of several chemokine markers known to attract T-helper type 2 (Th2) and regulatory T cells thus contributing to immune suppression. This Tr1 cells recruitment in EBV-positive HL was confirmed by immunohistochemical analysis of frozen nodes biopsies and by flow cytometric analysis of peripheral blood mononuclear cells of EBV-positive patients. Additionally, we showed that IL10 production was significantly enhanced in tumours and blood of EBV-positive HL patients. Our results propose a new model in which EBV can recruit Tr1 cells to the nodes' microenvironment, suggesting that the expression of EBV proteins in tumour cells could enable the escape of EBV-infected tumour cells from the virus-specific CTL response.

[Indications of G-CSF administration in hematologic disorders]. / Indications des facteurs de croissance granulocytaires en hématologie.

Granulocyte colony stimulating factors (G-CSF) are largely used in the treatment of hematologic disorders to improve both the myelosuppression which might directly result from the disease or indirectly induced by the numerous chemotherapy regimen. G-CSF reduces the depth and duration of neutropenia in lymphoma patients and thus allows the design of more dose intense chemotherapy regimen which were shown to improve outcome particularly in patients with diffuse large B-cell and Hodgkin's lymphoma. G-CSF has been studied in patients with acute leukemias (ALL and AML) both concomitantly to induction chemotherapy to sensitize leukemic cells and after chemotherapy to reduce the duration of neutropenia and incidence of severe infection but it's benefit in these settings is still controversial. Myelodysplastic syndromes (MDS) can benefit from G-CSF in association with erythropoietin, particularly for patients with relative good prognosis according to the IPSS score at diagnosis. Still, an improvement of Quality of life needs to be demonstrated in the vue of the cost of these strategies. In aplastic anemia (AA), G-CSF has been used as a support during infection or in association with immunosuppressive treatments but caution is needed regarding the risk of clonal evolution in AA. The benefit of low dose G-CSF in chronic severe neutropenia is well established but the long term consequences of continuous G-CSF support are not known. Finally, G-CSF given alone or after chemotherapy as become one of the key components of hematopoietic stem cell mobilization allowing the use of high dose therapies with autologous or allogeneic stem cell support.

Hydroxyurea-induced apoptosis in an EBV-immortalized lymphoblastoid cell line.

Hydroxyurea (HU) is an inhibitor of nucleotide synthesis extensively used to control the chronic phase of myeloid leukemia. This antimetabolite has been employed in the clinic for several decades but in recent years the leukemogenic potential of HU has been suspected. In the present study, a B-lymphoblastoid cell line transformed by the Epstein-Barr virus was used to investigate the apoptotic effects of HU and delineate some of the molecular pathways implicated in the cytotoxic action. The cell line, characterized by immunophenotyping, cytogenetic and fluorescence in situ hybridization (FISH) studies, showed no chromosomal abnormalities, even after a prolonged exposure to HU. Different flow cytometry assays were used to measure HU-induced impairment of the cell cycle, inhibition of DNA synthesis, and the occurrence of apoptosis. The treatment with HU leads to the appearance of a hypo-diploid DNA content peak (sub-G1) characteristic of the apoptotic cell population. The drug also induces a cell block in S phase as measured by 5-bromo-2'-deoxyuridine (BrdU) incorporation. Inhibition of DNA synthesis precedes induction of apoptosis by HU. A drug-induced loss of plasma membrane asymmetry was characterized by flow cytometry using annexin V-FITC to stain phosphatidylserine residues. The implication of the antiapoptotic protein Bcl-2 and the tumor suppressor p53 in the development of HU-mediated apoptosis was also evidenced. The drug appears to promote cell death by regulating the expression levels of these two proteins. Different criteria define the apoptotic response of the lymphoblastoid cells to the treatment with HU. However, the extent of drug-induced cell death is limited, and no DNA fragmentation and no activation of the caspase cascade was observed in this model. Beyond the specific interest in HU-induced apoptosis, the work reported here illustrates the utility of the EBV immortalization process to investigate the pharmacological activity of specific drugs from clinical samples.

Three new cases of non-Hodgkin lymphoma with t(9;14)(p13;q32).

The majority of non-Hodgkin lymphomas of B-cell type (B-NHL) exhibit chromosomal abnormalities including many types of reciprocal translocations closely related to specific histopathologic entities. The t(9;14)(p13;q32) has been recognized as a primary genetic event directly involved in the development of lymphoplasmacytic lymphoma. In the 14 published cases, the t(9;14)(p13;32) seems to delineate a variety of low-grade B-cell disorders characterized by a common clinical history and immunopathologic similarities. We report here three new cases presenting a t(9;14)(p13;q32) with other chromosomal abnormalities which have been referred to as B-cell low-grade or high-grade malignant lymphoproliferative disorders. Two of these cases showed diffuse large B cell lymphoma morphology and two patients had a favorable clinical outcome. These data suggest that t(9;14)(p13;q32) is not restricted to low-grade lymphoma.

TPA stimulation culture for improved detection of t(11;14)(q13;q32) in mantle cell lymphoma.

Cytogenetic analysis of mantle cell lymphoma (MCL), characterized by the presence of t(11;14)(q13;q32) translocation, is often difficult because of the low proliferating rate of MCL cells and the presence of normal cells in bone marrow which may interfere with growth of MCL cells. We describe herein a TPA (12-O-tetradecanoylphorbol 13-acetate) stimulated culture to improve detection of t(11;14)(q13;q32) in 20 MCL patients regardless of the samples used.

Recurrent 14q32 translocations determine the prognosis of multiple myeloma, especially in patients receiving intensive chemotherapy.

Recently, we have described the biological correlations associated with the main translocations involving the 14q32 chromosomal region, that is, t(14q32), in patients with multiple myeloma (MM). We have now extended the analysis to the prognostic value of these chromosomal rearrangements in 168 consecutive patients with newly diagnosed MM receiving intensive chemotherapy within clinical trials of the Intergroupe Francophone du Myelome (IFM). Patients with t(4;14) displayed a poor outcome (short event-free survival and short overall survival), whereas those with t(11;14) displayed long survival. On the other hand, patients with neither t(4;14) nor t(11;14) presented an intermediate outcome. Importantly, chromosome 13 abnormalities (C13As) significantly influence the prognosis of this latter group. In contrast, C13As affected the outcome of the other patients to a much lesser extent, either because of an almost constant association (in the t(4;14) group) or because of a lack of any significant prognostic impact (in the t(11;14) group; only one event occurred in the 10 patients with t(11;14) and C13As). Considering that t(4;14) and t(11;14) (1) are the only (so far recognized) true, recurrent t(14q32)'s, (2) are linked to specific immunoglobulin isotypes, and (3) display specific outcomes, they represent distinct entities corresponding to a specific oncogenesis and prognosis. These data emphasized the interest in analyzing these two translocations by fluorescence in situ hybridization in prospective therapeutic trials in order to consider these translocations as distinct entities.