A combination of 5-azacytidine and nivolumab is a potentially effective rescue therapy in relapsed/refractory AITL.

Introduction: Angioimmunoblastic T-cell lymphoma (AITL) is a peripheral T-cell lymphoma characterized by a T follicular helper cell phenotype expressing PD-1 (programmed cell death-1). AITL exhibits a poor response to conventional chemotherapy, with a median 5-year overall survival of 44% and a progression-free survival of 32%. Relapse is common, resulting in a median overall survival of 6 months. Recurrent mutations are detected in genes regulating DNA methylation, including TET2, DNMT3A, and IDH2 variants, along with the prevalent RHOA G17V mutation. In this context, patients treated with the hypomethylating agent 5-azacytidine achieved overall response and complete response rates of 75% and 41%, respectively. We hypothesized that targeted therapies combining anti-PD-1 checkpoint blockers with hypomethylating agents could be efficient in AITL patients and less toxic than standard chemotherapy. Methods: Here, we report the efficacy of a regimen combining 5-azacytidine and nivolumab in nine relapsed or refractory AITL patients. Results: This regimen was well-tolerated, especially in elderly patients. The overall response rate was 78%, including four partial responses (44%) and three complete responses (33%). Allogeneic hematopoietic stem cell transplantation was performed in two patients who reached complete response. Discussion: These preliminary favorable results may serve as a basis for further investigation in prospective studies.

Preclinical in vivo assessment of the activity of AZD7442 anti-SARS-CoV-2 monoclonal antibodies against Omicron sublineages.

Therapeutic monoclonal antibodies have been successful in protecting vulnerable populations against SARS-CoV-2. However, their effectiveness has been hampered by the emergence of new variants. To adapt the therapeutic landscape, health authorities have based their recommendations mostly on in vitro neutralization tests. However, these do not provide a reliable understanding of the changes in the dose-effect relationship and how they may translate into clinical efficacy. Taking the example of EvusheldTM (AZD7442), we aimed to investigate how in vivo data can provide critical quantitative results and project clinical effectiveness. We used the Golden Syrian hamster model to estimate 90 % effective concentrations (EC90) of AZD7442 in vivo against SARS-CoV-2 Omicron BA.1, BA.2 and BA.5 variants. While our in vivo results confirmed the partial loss of AZD7442 activity for BA.1 and BA.2, they showed a much greater loss of efficacy against BA.5 than that obtained in vitro. We analyzed in vivo EC90s in perspective with antibody levels measured in a cohort of immunocompromised patients who received 300 mg of AZD7442. We found that a substantial proportion of patients had serum levels of anti-SARS-CoV-2 spike protein IgG above the estimated in vivo EC90 for BA.1 and BA.2 (21 % and 92 % after 1 month, respectively), but not for BA.5. These findings suggest that AZD7442 is likely to retain clinical efficacy against BA.2 and BA.1, but not against BA.5. Overall, the present study illustrates the importance of complementing in vitro investigations by preclinical studies in animal models to help predict the efficacy of monoclonal antibodies in humans.

[Mobilization and conditioning protocols actualization for autologous stem cell transplantation for autoimmune diseases: Guidelines from MATHEC-SFGM-TC]. / Actualisation des protocoles de mobilisation et conditionnement pour la pratique des autogreffes de cellules souches hématopoïétiques chez les patients atteints de maladies auto-immunes : recommandations de la Société francophone de greffe de moelle et de thérapie cellulaire (MATHEC-SFGM-TC).

The Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) organized the 13th workshop on hematopoietic stem cell transplantation clinical practices harmonization procedures in September 2022 in Lille, France. The aim of this workshop is to update the mobilization and conditioning protocols for autologous hematopoietic stem cell transplantation for autoimmune diseases, and to specify contraindications for transplant, conditioning regimen selection, immunosuppressive treatment discontinuation before mobilization and disease-specific surveillance.

Coexistence of three hematological malignancies in association with a first time documented mutation: "One train can hide another"°, and even more!

Coexisting malignancies is not only an uncommon event but, it can also represent a medical challenge. Its complexity relies on the difficulty of management and the need for personalized and prioritized therapeutic approaches, on the one hand, and in the potential misdiagnosis of recurrence or even a de novo disease, on the other. Here, we present a case of a 69-year-old patient, who was initially diagnosed with a chronic myelomonocytic leukemia (CMML), followed by monoclonal gammopathy of uncertain significance (MGUS). Few years later, the patient developed Hodgkin's lymphoma (HL), and a new mutation, previously undocumented in the medical literature, was also detected. As a conclusion, we can say that the decision must be taken with caution and must be based on two major factors: 1- The rapid evolution of malignancies: give priority to treating the most rapid/life-threatening disease. 2- Prioritize the treatment of symptomatic disease and/or that which may most improve patients' quality of life.

[Vaccination before and after autologous hematopoietic cell transplantation for autoimmune diseases: Guidelines from the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (MATHEC-SFGM-TC)]. / Vaccinations avant et après greffe de cellules hématopoïétiques autologues chez les patients atteints de maladies auto-immunes : propositions du groupe Maladies Auto-immunes et Thérapie Cellulaire de la SFGM-TC.

The Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) organized the 12th workshop on hematopoietic stem cell transplantation clinical practices harmonization procedures on September 2021 in Lille, France. In the absence of specific national or international recommendation, the French working group for autologous stem Cell transplantation in Auto-immune Diseases (MATHEC) proposed guidances for vaccinations of patients undergoing autologous hematopoietic stem cell transplantation for autoimmune disease, including in the context of SARS-Cov-2 pandemic.

Changes on chest HRCT in systemic sclerosis-related interstitial lung disease after autologous haematopoietic stem cell transplantation.

OBJECTIVE: To evaluate extent of interstitial lung disease (ILD) and oesophageal involvement using high-resolution computed tomography (HRCT) in early diffuse SSc patients after autologous haematopoietic stem cell transplantation (aHSCT). METHODS: Overall chest HRCT, lung function and skin score changes were evaluated in 33 consecutive diffuse SSc patients before and after aHSCT during yearly routine follow-up visits between January 2000 and September 2016. Two independent radiologists blindly assessed the ILD extent using semi-quantitative Goh and Wells method, the widest oesophageal diameter (WOD) and the oesophageal volume (OV) on HRCT. Patients were retrospectively classified as radiological responders or non-responders, based on achieved stability or a decrease of 5% or more of HRCT-ILD at 24 months post-aHSCT. RESULTS: Using a linear mixed model, the regressions of the extent of ILD and of ground glass opacities were significant at 12 months (ILD P = 0.001; ground glass opacities P = 0.0001) and at 24 months (ILD P = 0.007; ground glass opacities P = 0.0008) after aHSCT, with 18 patients classified as radiological responders (probability of response 0.78 [95% CI 0.58, 0.90]). Meanwhile the WOD and the OV increased significantly at 12 months (WOD P = 0.03; OV P = 0.34) and at 24 months (WOD P = 0.002; OV P = 0.007). Kaplan-Meier analyses showed a trend towards better 5-year survival rates (100% vs 60%; hazard ratio 0.23 [95% CI 0.03, 1.62], P = 0.11) among radiological responders vs non-responders at 24 month follow-up after aHSCT. CONCLUSION: Real-world data analysis confirmed significant improvement in extent of HRCT SSc-ILD 24 months after aHSCT, although oesophageal dilatation worsened requiring specific attention.

Autologous hematopoietic cell transplantation as a part of a sequential multi-phase therapeutic approach (R-COPADM/CYVE/ASCT) as first-line treatment of high-grade B-cell lymphoma: results of a retrospective study with long-term follow-up.

Patients with high-risk lymphoma have a poor prognosis when treated with standard chemoimmunotherapy. This retrospective study included 23 high-risk lymphoma patients with a median age at diagnosis of 59 (range, 35-68) years. They received 2 cycles of R-COPADM and 2 cycles of CYVE, completed by ASCT for fit patients. With a median follow-up of 46 (range, 3-78) months, three (13%) patients in the cohort died. Nearly half of the patients had an ECOG performance status of 2 or 3. Most patients in the cohort (91%, n = 21) had Ann Arbor stage III-IV disease, and 88% (n = 20) had an IPI of 3 to 5. LDH levels were elevated in 83% (n = 19) of patients. Overall, 30% of patients were identified as having double-expressor lymphoma and 22% as having DHL, while two patients (9%) had THL. The origin of the lymphoma was GC B-cell-like in 15 patients (65%) and ABC-like in 8 patients (35%). Cumulative incidence of relapse at 46 months was 14% (95% CI, 5-37), while overall survival was 87% (95% CI, 64-95) and progression-free survival was 83% (95% CI, 60-93). These results showed the efficacy and an acceptable safety profile of the R-COPADM/CYVE/ASCT regimen in high-risk lymphoma, including patients with DHL.

A review of latest clinical practice guidelines for the management of cancer-associated thrombosis.

The management of cancer-associated thrombosis (CAT) poses unique challenges to healthcare professionals. While low-molecular weight heparins (LMWHs) have long been the gold standard for both the primary and secondary prevention of CAT, results from large randomized controlled trials assessing the benefit of direct oral anticoagulants (DOACs) in both settings have resulted in some paradigm shifts. Herein, we review and compare recommendations from the latest authoritative clinical practice guidelines (CPGs) for the management of CAT and summarize the most recent evidence on available treatment options. A rigorous methodology was used to select high quality CPGs and compare the recommendations across CPGs. Only CPGs focusing on the management of CAT developed by a multidisciplinary international working group and issued or endorsed by national or international scientific societies, or government organizations were eligible for inclusion. The quality of selected CPGs was assessed using the Appraisal of Guidelines, Research, and Evaluation II (AGREE II) tool. Four CPGs met the inclusion criteria, including the International Initiative on Thrombosis and Cancer (ITAC), the American Society of Clinical Oncology (ASCO), the American Society of Hematology (ASH), and the National Comprehensive Cancer Network (NCCN).

Non-Classical HLA Determinants of the Clinical Response after Autologous Stem Cell Transplantation for Systemic Sclerosis.

Systemic Sclerosis (SSc) is a chronic autoimmune disease with high morbidity and mortality. Autologous Hematopoietic Stem Cell Transplantation (AHSCT) is the best therapeutic option for rapidly progressive SSc, allowing increased survival with regression of skin and lung fibrosis. The immune determinants of the clinical response after AHSCT have yet to be well characterized. In particular, the pivotal role of the Human Leukocyte Antigen (HLA) system is not well understood, including the role of non-classical immuno-modulatory HLA-E and HLA-G molecules in developing tolerance and the role of Natural Killer cells (NK) in the immunomodulation processes. We retrospectively tested whether the genetic and/or circulating expression of the non-classical HLA-E and HLA-G loci, as well as the imputed classical HLA determinants of HLA-E expression, influence the observed clinical response to AHSCT at 12- and 24-month follow-up. In a phenotypically well-defined sample of 46 SSc patients classified as clinical responders or non-responders, we performed HLA genotyping using next-generation sequencing and circulating levels of HLA-G and quantified HLA-E soluble isoforms by ELISA. The -21HLA-B leader peptide dimorphism and the differential expression level of HLA-A and HLA-C alleles were imputed. We observed a strong trend towards better clinical response in HLA-E*01:03 or HLA-G 14bp Del allele carriers, which are known to be associated with high expression of the corresponding molecules. At 12-month post-AHSCT follow-up, higher circulating levels of soluble HLA-E were associated with higher values of modified Rodnan Skin Score (mRSS) (p = 0.0275), a proxy of disease severity. In the non-responder group, the majority of patients carried a double dose of the HLA-B Threonine leader peptide, suggesting a non-efficient inhibitory effect of the HLA-E molecules. We did not find any correlation between the soluble HLA-G levels and the observed clinical response after AHSCT. High imputed expression levels of HLA-C alleles, reflecting more efficient NK cell inhibition, correlated with low values of the mRSS 3 months after AHSCT (p = 0.0087). This first pilot analysis of HLA-E and HLA-G immuno-modulatory molecules suggests that efficient inhibition of NK cells contributes to clinical response after AHSCT for SSc. Further studies are warranted in larger patient cohorts to confirm our results.

The Ottawa Score Performs Poorly to Identify Cancer Patients at High Risk of Recurrent Venous Thromboembolism: Insights from the TROPIQUE Study and Updated Meta-Analysis.

The Ottawa score (OS) for predicting the risk of recurrent venous thromboembolism (VTE) in cancer patients with VTE may help to guide anticoagulant treatment decisions that will optimize benefit-risk ratios. However, data on its reliability are conflicting. We applied the OS to all cancer patients with VTE enrolled in the prospective multicenter TROPIQUE study who received low-molecular-weight heparin over a 6-month period. Of 409 patients, 171 (41.8%) had a high-risk OS. The 6-month cumulative incidence of recurrent VTE was 7.8% (95%CI 4.2-14.8) in the high-risk OS group versus 4.8% (95%CI 2.6-8.9) in the low-risk OS group (SHR 1.47; 95%CI 0.24-8.55). The Area Under the Receiver Operating Characteristic curve (AUROC) of the OS in identifying patients who developed recurrent VTE was 0.53 (95%CI 0.38-0.65), and its accuracy was 57.9%. Among individual variables included in the OS, only prior VTE was significantly associated with the 6-month risk of recurrent VTE (SHR 4.39; 95% CI 1.13-17.04). When pooling data from all studies evaluating this score for predicting VTE recurrence in cancer patients (7 studies, 3413 patients), the OS estimated pooled AUROC was 0.59 (95%CI 0.56-0.62), and its accuracy was 55.7%. The present findings do not support the use of the OS to assess the risk of recurrent VTE in cancer patients.

Diastolic Function Assessment of Left and Right Ventricles by MRI in Systemic Sclerosis Patients.

BACKGROUND: Heart involvement is frequent although often clinically silent in systemic sclerosis (SSc) patients. Early identification of cardiac involvement can be improved by noninvasive methods such as MRI, in addition to transthoracic echocardiography (TTE). PURPOSE: To assess the ability of phase-contrast (PC)-MRI to detect subclinical left (LV) and right (RV) ventricular diastolic dysfunction in SSc patients. STUDY TYPE: Prospective. POPULATION: Thirty-five consecutive SSc patients (49 ± 14 years) and 35 sex- and age-matched healthy controls (48.6 ± 13.5 years) who underwent TTE and MRI in the same week. FIELD STRENGTH/SEQUENCE: 5 T/PC-MRI using a breath-hold velocity-encoded gradient echo sequence. ASSESSMENT: LV TTE (E/E') and LV and RV PC-MRI indices of diastolic function (LV early and late transmitral [EM , EfM , AM , AfM ] and RV transtricuspid [ET , EfT , AT , AfT ] peak filling flow velocities and flow rates, as well as LV [ E M ' ] and RV [ E T ' ] peak longitudinal myocardial velocities during diastole) were measured. STATISTICAL TESTS: Two-tailed t-test, Wilcoxon test, or Fischer test for comparison of variables between SSc and healthy control groups; sensitivity, specificity, receiver-operating-characteristic (ROC) area under the curve (AUC) to assess discriminative ability of variables. A P-value <0.05 was considered statistically significant. RESULTS: TTE LV E/E' and MRI EM / E M ' and ET / E T ' were significantly higher in SSc patients than in controls (8.27 ± 1.25 vs. 6.70 ± 1.66; 9.43 ± 2.7 vs. 6.51 ± 1.50; 6.51 [4.70-10.40] vs. 4.13 [3.22-5.75], respectively) and separated SSc patients and healthy controls with good sensitivity (68%, 71%, and 80%), specificity (85%, 94%, and 62%), and AUC (0.787, 0.807, and 0.765). LV EfM was significantly higher in SSc patients than in controls (347.1 ± 113.7 vs. 284.7 ± 94.6) as RVAfT (277 [231-355] vs. 220 [154-253] mL/sec) with impaired relaxation pattern (EfT /AfT , 0.95 [0.87-1.21] vs. 1.12 [0.93-1.47]). DATA CONCLUSION: MRI was able to detect LV and RV diastolic dysfunction in SSc patients with good accuracy in the absence of LV systolic dysfunction at echocardiography. Use of MRI can allow to better assess the early impact of myocardial fibrosis related to SSc. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 2.