A French multicentric prospective prognostic cohort with epidemiological, clinical, biological and treatment information to improve knowledge on lymphoma patients: study protocol of the "REal world dAta in LYmphoma and survival in adults" (REALYSA) cohort.

BACKGROUND: 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. METHODS: 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. DISCUSSION: 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. TRIAL REGISTRATION: 2018-A01332-53, ClinicalTrials.gov identifier: NCT03869619

Efficacy of ruxolitinib in the treatment of relapsed/refractory large granular lymphocytic leukaemia

International audienceLarge granular lymphocytic (LGL) leukaemia is a rare chronic lymphoproliferative disorder characterized by an expansion of cytotoxic T or NK cells. Despite a usually indolent evolution, most patients will require a treatment over the course of the disease because of cytopenia or symptomatic associated autoimmune disorders. First-line treatment is based on immunosuppressive agents, namely cyclophosphamide, methotrexate and ciclosporin. However, relapses are frequent, and there is no consensus on the management of relapsed/refractory patients. The implication of the JAK/STAT pathway in the pathogenesis of this disease has prompted our group to propose treatment with ruxolitinib. A series of 21 patients who received this regimen is reported here. Ten patients (47.6%) were refractory to the three main immunosuppressive drugs at the time of ruxolitinib initiation. Ruxolitinib yielded an overall response rate of 86% (n = 18/21), including 3 complete responses and 15 partial responses. With a median follow-up of 9 months, the median response duration was 4 months. One-year event-free survival and 1-year overall survival were 57% and 83% respectively. Mild side effects were observed. Biological parameters, notably neutropenia and anaemia, improved significantly, and complete molecular responses were evidenced. This study supports ruxolitinib as a valid option for the treatment of relapsed/refractory LGL leukaemia

A French National Survey on Clotting Disorders in Mastocytosis.

Mastocytosis is characterized by a clonal mast cell proliferation with organ infiltration and uncontrolled degranulation. Although not characteristic and poorly explained, some patients develop clotting abnormalities. We retrospectively identified patients with established diagnosis of mastocytosis and related clotting abnormalities (clinical and/or biological) using the national French Reference Centre for Mastocytosis database. From our cohort of 14 adult patients with clotting abnormalities (median age 46 years [range 26-75]), 4 had a presentation suggestive of a primary hemostasis disorder alone (by their symptoms and/or abnormal clotting tests [PFA, von Willebrand's disease [vWD] screening]) and 10 had a laboratory impairment of secondary hemostasis. Among these, 7 had bleeds characteristic of a coagulation cascade disorder (severe/life-threatening in 5 and mild in 2 patients). Clotting abnormalities were of variable severity, typically related to intense crisis of degranulation, such as anaphylactic reactions, and/or to severe organ infiltration by mast cells. Importantly, classical hemostatic management with platelet transfusion, fresh frozen plasma, or vitamin K infusions was unsuccessful, as opposed to the use of agents inhibiting mast cell activity, particularly steroids. This illustrates the crucial role of mast cell mediators such as tryptase and heparin, which interfere both with primary (mainly via inhibition of von Willebrand factor) and secondary hemostasis. There was interestingly an unusually high number of aggressive mastocytosis (particularly mast cell leukemia) and increased mortality in the group with secondary hemostasis disorders (n = 5, 36% of the whole cohort). Mast cell degranulation and/or high tumoral burden induce both specific biologic antiaggregant and anticoagulant states with a wide clinical spectrum ranging from asymptomatic to life-threatening bleeds. Hemostatic control is achieved by mast cell inhibitors such as steroids

Obinutuzumab Versus Rituximab in Transplant Eligible Untreated MCL Patients, a Matching Comparison between the Lyma and Lyma-101 Trials

International audienceAim: Obinutuzumab (O) and Rituximab (R) have never been compared in a prospective randomized trial in mantle cell lymphoma (MCL). The LYMA-101 trial (NCT02896582) investigated the Obinutuzumab-DHAP (O-DHAP) regimen followed by autologous stem cell transplant (O-BEAM, ASCT) plus O maintenance (OM) in transplant eligible patients <66y with untreated MCL (Le Gouill et al, Lancet Hem 2020). The LYMA trial (NCT00921414) used the same regimen with Rituximab instead of Obinutuzumab (Le Gouill et al, NEJM 2017). Herein, we report the long-term outcome of patients enrolled in the LYMA-101 trial and used a propensity score matching (PSM) approach to allow a comparison with patients treated in the LYMA trial (i.e. O versus R group matched comparison). Method: LYMA (n=299 pts, of whom 120 received R Maintenance, RM) is a phase III prospective trial with a median follow-up of 7.5 years (7.4-7.7) from inclusion (Sarkozy et al, ASCO 2023) that randomized, after ASCT, 240 pts between observation and RM. LYMA-101 (n=86) is a prospective single arm phase 2 trial with a median FU of 5.1y (5-5.25) at the time of the present analysis. We first compared minimal residual disease (MRD) at end of induction (EOI), assessed in both trial with quantitative PCR of clonal immunoglobulin gene and used PSM based on clinical characteristics at inclusion (Sex, Ann Arbor stage, MIPI score, B symptoms, blastoid variant, bulky disease) to balance patients' discrepancies between LYMA-101 and LYMA. To compare PFS and OS from inclusion of patients treated with R versus O based regimen, half of the non-randomized LYMA patients (29 out of 58) were randomly reattributed to the RM arm to create an intention to treat RM (RM-ITT) arm including 149 pts (29 non-randomized and 120 randomized) subsequently matched with the 86 LYMA-101 pts. Balance between populations was checked using standardized mean differences (SMD). Results: Eighty-five LYMA-101 pts received the first course of O-DHAP (1 withdrew consent before treatment), 81 (95.3%) completed the 4 cycles and 73 (85.9%) underwent ASCT followed by OM in 69 (81.2%). The estimated 5y PFS and OS since inclusion were 83.4% (95%CI: 73.5-89.8%) and 86.9% (95%CI: 77.6-92.5%) respectively. At EOI, ORR were similar in both studies (89.6% versus 91.8% in LYMA versus LYMA-101 respectively), but within responders, pts treated in LYMA-101 (O-DHAP) had a more frequent MRD negativity than pts treated in LYMA (R-DHAP) both in bone marrow (BM, 82.1% versus 65.3% MRD negativity in O vs R group, Chi2 p=0.011) and blood (95.5% versus 79.2% of MRD negativity in O vs R group, Chi2 p=0.002). These results were confirmed using the propensity score matched populations, with a more frequent MRD negativity in the O versus R group in BM (82.1% vs 63.4%, Chi-2, p=0.01) and blood (95.5% vs 72.9%, Chi-2, p<0.001). To compare PFS and OS since induction, a PSM was performed using the 149 patients treated in the R-group with an RM-ITT and the 85 patients in the O group, resulting in 2 sets of 82 patients with comparable characteristics at inclusion. From treatment initiation, patients treated with O presented a prolonged PFS (p=0.029, figure 1A) and OS (p=0.039, figure 1B) compared to those treated with R, with an estimated 5-year PFS of 82.8% versus 66.6% (HR 1.99, IC95 1.05-3.76) and OS of 86.4% versus 71.4% (HR 2.08, IC95 1.01-4.16) with O and R based regimen respectively. Finally, 37/120 (30.8%) patients in LYMA and 23/69 (33.3%) in LYMA-101 prematurely stopped R and OM respectively (with a similar mean maintenance duration of 29 and 29.4m with R and OM respectively). Reason for maintenance discontinuation were adverse events in 15 cases in R group (12.5% of the population) versus 14 cases in O group (20% of the population), progression or death in 10 (8.3%) versus 3 (4.3%) cases in the R versus O group respectively. Causes of death were comparable in O and R groups, the most common being lymphoma (42% in O and 53% in R group). Infectious deaths in the O group (N=3) were all COVID related (3/12 deaths, 25%), whereas in the R group (LYMA being conducted before the pandemic), 8 deaths were related to infection (8/97 deaths, 8%, including 1 infectious death out of 22 deaths during RM, 5%). Conclusion: O-DHAP followed by OM post ASCT provide prolonged PFS and OS in young patients with MCL. O-based therapy in MCL induce deeper response with increased MRD negativity and seems to outperform R-based therapy in term of PFS and OS, without any significant excess of toxicity

Gastrointestinal manifestations in mastocytosis: A study of 83 patients.

International audienceBACKGROUND: Mastocytosis is a heterogeneous disease characterized by mast cell accumulation in 1 or more organs. Gastrointestinal manifestations of systemic mastocytosis have been previously studied in small cohorts of patients, and no specific histologic description is available. OBJECTIVE: We sought to assess the clinical and pathologic features of gastrointestinal manifestations in patients with mastocytosis. METHODS: Medical history and gastrointestinal symptoms of patients with mastocytosis (n = 83) were compared with those of matched healthy subjects (n = 83) by means of patient questionnaire. Data were analyzed for epidemiologic, clinical, biological, and genetic factors associated with gastrointestinal symptoms for patients with mastocytosis. A comparative analysis of gastrointestinal histology from patients with mastocytosis (n = 23), control subjects with inflammatory bowel disease (n = 17), and healthy subjects (n = 19) was performed. RESULTS: The following gastrointestinal symptoms occurred more frequently and were more severe in patients with mastocytosis than in healthy subjects: bloating (33% vs 7.2%, P < .0001), abdominal pain (27.3% vs 4.8%, P < .0001), nausea (23% vs 8.4%, P = .02), and diarrhea (33.85% vs 1.2%, P < .0001). Patients with mastocytosis had a significantly higher incidence of personal history of duodenal ulcer (P = .02). Wild-type (WT) c-Kit was associated with diarrhea (P = .03). Specific histologic lesions were present in patients with mastocytosis but were not correlated with clinical symptoms. CONCLUSION: Gastrointestinal manifestations in patients with mastocytosis are highly prevalent and often severe. Clinical symptoms do not correspond to histologic findings, are nonspecific, and can simulate irritable bowel syndrome

Masitinib for treatment of severely symptomatic indolent systemic mastocytosis: a randomised, placebo-controlled, phase 3 study

International audienceBACKGROUND:Indolent systemic mastocytosis, including the subvariant of smouldering systemic mastocytosis, is a lifelong condition associated with reduced quality of life. Masitinib inhibits KIT and LYN kinases that are involved in indolent systemic mastocytosis pathogenesis. We aimed to assess safety and efficacy of masitinib versus placebo in severely symptomatic patients who were unresponsive to optimal symptomatic treatments.METHODS:In this randomised, double-blind, placebo-controlled, phase 3 study, we enrolled adults (aged 18-75 years) with indolent or smouldering systemic mastocytosis, according to WHO classification or documented mastocytosis based on histological criteria, at 50 centres in 15 countries. We excluded patients with cutaneous or non-severe systemic mastocytosis after a protocol amendment. Patients were centrally randomised (1:1) to receive either oral masitinib (6 mg/kg per day over 24 weeks with possible extension) or matched placebo with minimisation according to severe symptoms. The primary endpoint was cumulative response (≥75% improvement from baseline within weeks 8-24) in at least one severe baseline symptom from the following: pruritus score of 9 or more, eight or more flushes per week, Hamilton Rating Scale for Depression of 19 or more, or Fatigue Impact Scale of 75 or more. We assessed treatment effect using repeated measures methodology for rare diseases via the generalised estimating equation model in a modified intention-to-treat population, including all participants assigned to treatment minus those who withdrew due to a non-treatment-related cause. We assessed safety in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT00814073.FINDINGS:Between Feb 19, 2009, and July 15, 2015, 135 patients were randomly assigned to masitinib (n=71) or placebo (n=64). By 24 weeks, masitinib was associated with a cumulative response of 18·7% in the primary endpoint (122·6 responses of 656·5 possible responses [weighted generalised estimating equation]) compared with 7·4% for placebo (48·9 of 656·5; difference 11·3%; odds ratio 3·6; 95% CI 1·2-10·8; p=0·0076). Frequent severe adverse events (>4% difference from placebo) were diarrhoea (eight [11%] of 70 in the masitinib group vs one [2%] of 63 in the placebo group), rash (four [6%] vs none), and asthenia (four [6%] vs one [2%]). The most frequent serious adverse events were diarrhoea (three patients [4%] vs one [2%]) and urticaria (two [3%] vs none), and no life-threatening toxicities occurred. One patient in the placebo group died (unrelated to study treatment).INTERPRETATION:These study findings indicate that masitinib is an effective and well tolerated agent for the treatment of severely symptomatic indolent or smouldering systemic mastocytosis

Cell-of-Origin (COO) Classification, BCL2 and MYC Expression Associated Outcome in Younger Patients Treated By RCHOP Front-Line Therapy Versus Intensive Regimen Followed By Autologous Transplant for De Novo Advanced Diffuse Large B Cell Lymphoma (DLBCL) : Results of the French Prospective Multicenter Randomized Trial Goelams-075

WOS:000368021800177International audienceThe prognostic value of COO classification by immunohistochemistry (IHC) for de novo untreated advanced DLBCL remains controversial after Rituximab-based frontline therapy. Other biomarkers such as BCL2 or MYC protein expression have been proposed to predict survival. IHCcharacteristics were investigated in a large multicenter randomized study