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

Large 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.

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.

Randomized Phase III Trial Evaluating Subcutaneous Rituximab for the First-Line Treatment of Low-Tumor Burden Follicular Lymphoma: Results of a LYSA Study.

PURPOSE: Rituximab improves progression-free survival (PFS) and time to next treatment (TTNT) when compared with the watch and wait strategy for patients with low-tumor burden follicular lymphoma (FL). Prolonged rituximab maintenance did not prolong TTNT, whereas it raises concerns about resources use and patient adhesion. Our aim was then to investigate the use of short rituximab maintenance using the subcutaneous (SC) route in patients with low-tumor burden FL. METHODS: Patients with histologically confirmed CD20+ low-tumor burden FL were randomly assigned to receive either rituximab, 375 mg/m2 once daily on D1, D8, D15, and D22, intravenous route (IV, control arm), or rituximab, 375 mg/m2, on day 1 (D1), IV followed by rituximab 1,400 mg total dose, SC once daily on D8, D15, and D22, with maintenance at months 3 (M3), M5, M7, and M9 (experimental arm). The primary end point was PFS. Secondary end points included safety, overall response rates, TTNT, and overall survival (OS). RESULTS: Two hundred two patients with low-tumor burden FL were randomly assigned to the experimental (n = 100) or control arm (n = 102). The primary end point was met: the 4-year PFS was 58.1% (95% CI, 47.5 to 67.4) and 41.2% (95% CI, 30.6 to 51.6) in experimental and control arms, respectively (hazard ratio, 0.585 [0.393 to 0.871]; P = .0076). Complete response (CR) rates were 59.0% (95% CI, 48.7 to 68.7) in the experimental arm and 36.3% (95% CI, 27.0 to 46.4) in the control arm (P = .001). TTNT and OS were not significantly different. CR was associated with longer PFS and TTNT. High rituximab exposure during the first three months was independently associated with higher CR, PFS, and TTNT. CONCLUSION: SC rituximab improves PFS for patients with low-tumor burden FL when used in induction followed by short maintenance. High rituximab exposure during the first 3 months after treatment initiation is, however, the only parameter influencing patient outcomes.

Premature Ovarian Insufficiency in CLPB Deficiency: Transcriptomic, Proteomic and Phenotypic Insights.

CONTEXT: Premature ovarian insufficiency (POI) is a common form of female infertility that usually presents as an isolated condition but can be part of various genetic syndromes. Early diagnosis and treatment of POI can minimize comorbidity and improve health outcomes. OBJECTIVE: We aimed to determine the genetic cause of syndromic POI, intellectual disability, neutropenia, and cataracts. METHODS: We performed whole-exome sequencing (WES) followed by functional validation via RT-PCR, RNAseq, and quantitative proteomics, as well as clinical update of previously reported patients with variants in the caseinolytic peptidase B (CLPB) gene. RESULTS: We identified causative variants in CLPB, encoding a mitochondrial disaggregase. Variants in this gene are known to cause an autosomal recessive syndrome involving 3-methylglutaconic aciduria, neurological dysfunction, cataracts, and neutropenia that is often fatal in childhood; however, there is likely a reporting bias toward severe cases. Using RNAseq and quantitative proteomics we validated causation and gained insight into genotype:phenotype correlation. Clinical follow-up of patients with CLPB deficiency who survived to adulthood identified POI and infertility as a common postpubertal ailment. CONCLUSION: A novel splicing variant is associated with CLPB deficiency in an individual who survived to adulthood. POI is a common feature of postpubertal female individuals with CLPB deficiency. Patients with CLPB deficiency should be referred to pediatric gynecologists/endocrinologists for prompt POI diagnosis and hormone replacement therapy to minimize associated comorbidities.

Functional characterization of PD1+TIM3+ tumor-infiltrating T cells in DLBCL and effects of PD1 or TIM3 blockade.

In diffuse large B-cell lymphoma (DLBCL), tumor-infiltrating T lymphocytes (TILs) are involved in therapeutic responses. However, tumor-specific TILs can be dysfunctional, with impaired effector functions. Various mechanisms are involved in this exhaustion, and the increased expression of programmed cell death receptor 1 (PD1) and TIM3 on dysfunctional cells suggests their involvement. However, conflicting data have been published regarding their expression or coexpression in DLBCL. We evaluated the presence and phenotype of CD4+ and CD8+ TILs in freshly collected tumor tissues in DLBCL and compared the results with those in follicular lymphoma, classical Hodgkin lymphoma, and nonmalignant reactive lymphadenopathy. We found that TILs expressing both PD1 and TIM3 were expanded in DLBCL, particularly in the activated B cell-like subgroup. Isolated PD1+TIM3+ TILs exhibited a transcriptomic signature related to T-cell exhaustion associated with a reduction in cytokine production, both compromising the antitumor immune response. However, these cells expressed high levels of cytotoxic molecules. In line with this, stimulated PD1+TIM3+ TILs from DLBCL patients exhibited reduced proliferation and impaired secretion of interferon-γ, but these functions were restored by the blockade of PD1 or TIM3. In summary, the PD1+TIM3+ TIL population is expanded and exhausted in DLBCL but can be reinvigorated with appropriate therapies.

Integrative Analysis of Cell Crosstalk within Follicular Lymphoma Cell Niche: Towards a Definition of the FL Supportive Synapse.

Follicular lymphoma (FL), the most frequent indolent non-Hodgkin's B cell lymphoma, is considered as a prototypical centrocyte-derived lymphoma, dependent on a specific microenvironment mimicking the normal germinal center (GC). In agreement, several FL genetic alterations affect the crosstalk between malignant B cells and surrounding cells, including stromal cells and follicular helper T cells (Tfh). In our study, we sought to deconvolute this complex FL supportive synapse by comparing the transcriptomic profiles of GC B cells, Tfh, and stromal cells, isolated from normal versus FL tissues, in order to identify tumor-specific pathways. In particular, we highlighted a high expression of IL-6 and IL-7 in FL B cells that could favor the activation of FL Tfh overexpressing IFNG, able in turn to stimulate FL B cells without triggering MHC (major histocompatibility) class II expression. Moreover, the glycoprotein clusterin was found up-regulated in FL stromal cells and could promote FL B cell adhesion. Finally, besides its expression on Tfh, CD200 was found overexpressed on tumor B cells and could contribute to the induction of the immunosuppressive enzyme indoleamine-2,3 dioxygenase by CD200R-expressing dendritic cells. Altogether our findings led us to outline the contribution of major signals provided by the FL microenvironment and their interactions with malignant FL B cells.

Prognostic factors in esophageal cancer treated with curative intent.

The overall prognosis of patients with esophageal cancer has improved in recent decades due to surgical and medical progress, but overall survival remains poor. Better patient selection and tailored treatment are needed. Different prognostic factors linked with the patient, tumoral characteristics and treatment with curative intent have been identified and are the purpose of this review. Tumor detection at an earlier stage, the advent of new molecules and therapeutic combinations, and the centralization of management in high-volume centers should help to improve the prognosis of esophageal cancer. Improved imaging techniques and a better prediction strategy should guide future treatments.

[Medico-economic benefits of subcutaneous formulations of trastuzumab and rituximab in day hospitalisation (SCuBA Study)]. / Bénéfices médicoéconomiques des formes sous-cutanées de trastuzumab et de rituximab en hospitalisation de jour (étude SCuBA).

INTRODUCTION: New pharmaceutical forms of trastuzumab and rituximab which can be administered by the subcutaneous route have been developed recently. For day hospitalisation units, these can be used in simpler treatment protocols than previous intravenous formulations. The objective of this study was to evaluate the medical and economic consequences of switching to subcutaneous formulations of trastuzumab and rituximab. METHODS: Thirty-six day care units in 30 hospitals or clinics participated in this observational study. Data were collected on the capacity of the units, the number of chemotherapy sessions implemented, the duration of occupation of a chair and the production capacity of the unit pharmacy. The number of additional sessions made possible by the use of subcutaneous forms in 2016 was determined and the associated gain in earnings calculated using national tariffs. RESULTS: Compared to the intravenous route, the mean duration of occupation of a chair was reduced by 56.1 % for a session of subcutaneous trastuzumab and by 73.8 % for a session of subcutaneous rituximab. The mean number of additional sessions made possible by the use of subcutaneous treatments was 242 [168-316] sessions by year by unit, corresponding to 2.7 % [1.9 %-3.4 %] of the total number of chemotherapy sessions in the unit. The corresponding gain in annual earnings was € 111 388. DISCUSSION: Switching the route of administration from the intravenous to the subcutaneous route is a useful strategy to address the increase in activity of day hospitalisation units. This allows an increase of 2.7 % in the total number of chemotherapy sessions in the unit. In most of the participating units, there was room for further optimization of activity, potentially to reach 4.2 % of the total number of sessions.