Extracellular vesicles in hematological malignancies: EV-dence for reshaping the tumoral microenvironment

Following their discovery at the end of the 20th century, extracellular vesicles (EVs) ranging from 50-1,000 nm have proven to be paramount in the progression of many cancers, including hematological malignancies. EVs are a heterogeneous group of cell-derived membranous structures that include small EVs (commonly called exosomes) and large EVs (microparticles). They have been demonstrated to participate in multiple physiological and pathological processes by allowing exchange of biological material (including among others proteins, DNA and RNA) between cells. They are therefore a crucial way of intercellular communication. In this context, malignant cells can release these extracellular vesicles that can influence their microenvironment, induce the formation of a tumorigenic niche, and prepare and establish distant niches facilitating metastasis by significantly impacting the phenotypes of surrounding cells and turning them toward supportive roles. In addition, EVs are also able to manipulate the immune response and to establish an immunosuppressive microenvironment. This in turn allows for ideal conditions for heightened chemoresistance and increased disease burden. Here, we review the latest findings and reports studying the effects and therapeutic potential of extracellular vesicles in various hematological malignancies. The study of extracellular vesicles remains in its infancy; however, rapid advances in the analysis of these vesicles in the context of disease allow us to envision prospects to improve the detection and treatment of hematological malignancies

Bone marrow graft versus peripheral blood graft in haploidentical hematopoietic stem cells transplantation: a retrospective analysis in1344 patients of SFGM-TC registry.

peer reviewedThe use of peripheral blood (PB) or bone marrow (BM) stem cells graft in haploidentical hematopoietic stem cell transplantation with post-transplant cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis remains controversial. Moreover, the value of adding anti-thymoglobulin (ATG) to PTCy is unknown. A total of 1344 adult patients received an unmanipulated haploidentical transplant at 37 centers from 2012 to 2019 for hematologic malignancy. We compared the outcomes of patients according to the type of graft, using a propensity score analysis. In total population, grade II-IV and III-IV acute GVHD (aGVHD) were lower with BM than with PB. Grade III-IV aGVHD was lower with BM than with PB + ATG. All outcomes were similar in PB and PB + ATG groups. Then, in total population, adding ATG does not benefit the procedure. In acute leukemia, myelodysplastic syndrome and myeloproliferative syndrome (AL-MDS-MPS) subgroup receiving non-myeloablative conditioning, risk of relapse was twice greater with BM than with PB (51 vs. 22%, respectively). Conversely, risk of aGVHD was greater with PB (38% for aGVHD II-IV; 16% for aGVHD III-IV) than with BM (28% for aGVHD II-IV; 8% for aGVHD III-IV). In this subgroup with intensified conditioning regimen, risk of relapse became similar with PB and BM but risk of aGVHD III-IV remained higher with PB than with BM graft (HR = 2.0; range [1.17-3.43], p = 0.012)

Les pièges des gammapathies monoclonales

Monoclonal gammopathy of undetermined significance (MGUS) is a frequent condition affecting at least 3 % of the general population over 50 years. Usually, the diagnosis of MGUS is made accidentally during a biological assessment for other conditions. Although MGUS is most frequently a benign and asymptomatic disorder, it has well been described that MGUS could be a premalignant status and that the risk of transformation into myeloma or other lymphoproliferative disorders is estimated at 1 % per year. MGUS can also be associated with other diseases than malignant disorders such as infections, autoimmune diseases. In some case it could reflect rare but severe disorders that will be crucial not to miss the diagnosis.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study

Background: Bortezomib, thalidomide, and dexamethasone (VTd) plus autologous stem-cell transplantation is standard treatment in Europe for transplant-eligible patients with newly diagnosed multiple myeloma. We evaluated whether the addition of daratumumab to VTd before and after autologous stem-cell transplantation would improve stringent complete response rate in patients with newly diagnosed multiple myeloma. Methods: In this two-part, randomised, open-label, phase 3 CASSIOPEIA trial, we recruited transplant-eligible patients with newly diagnosed multiple myeloma at 111 European sites. Patients were randomly assigned (1:1) to receive four pre-transplant induction and two post-transplant consolidation cycles of VTd alone (VTd group) or in combination with daratumumab (D-VTd group). The primary endpoint of part 1 was stringent complete response assessed 100 days after transplantation. Part 2 (maintenance) is ongoing. The trial is registered with ClinicalTrials.gov, number NCT02541383. Findings: Between Sept 22, 2015, and Aug 1, 2017, 1085 patients were enrolled at 111 European sites and were randomly assigned to the D-VTd group (n=543) or the VTd group (n=542). At day 100 after transplantation, 157 (29%) of 543 patients in the D-VTd group and 110 (20%) of 542 patients in the VTd group in the intention-to-treat population had achieved a stringent complete response (odds ratio 1·60, 95% CI 1·21–2·12, p=0·0010). 211 (39%) patients in the D-VTd group versus 141 (26%) in the VTd group achieved a complete response or better, and 346 (64%) of 543 versus 236 (44%) of 542 achieved minimal residual disease-negativity (10−5 sensitivity threshold, assessed by multiparametric flow cytometry; both p<0·0001). Median progression-free survival from first randomisation was not reached in either group (hazard ratio 0·47, 95% CI 0·33–0·67, p<0·0001). 46 deaths on study were observed (14 vs 32, 0·43, 95% CI 0·23–0·80). The most common grade 3 or 4 adverse events were neutropenia (28% vs 15%), lymphopenia (17% vs 10%), and stomatitis (13% vs 16%). Interpretation: D-VTd before and after autologous stem-cell transplantation improved depth of response and progression-free survival with acceptable safety. CASSIOPEIA is the first study showing the clinical benefit of daratumumab plus standard of care in transplant-eligible patients with newly diagnosed multiple myeloma. Funding: The Intergroupe Francophone du Myélome and Dutch-Belgian Cooperative Trial Group for Hematology Oncology.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Serum free light chains, not urine specimens, should be used to evaluate response in light-chain multiple myeloma

Guidelines for monitoring multiple myeloma (MM) patients expressing light chains only (light-chain MM [LCMM]) rely on measurements of monoclonal protein in urine. Alternatively, serum free light chain (sFLC) measurements have better sensitivity over urine methods, however, demonstration that improved sensitivity provides any clinical benefit is lacking. Here, we compared performance of serum and urine measurements in 113 (72κ, 41λ) newly diagnosed LCMM patients enrolled in the Intergroupe Francophone du Myélome (IFM) 2009 trial. All diagnostic samples (100%) had an abnormal κ:λ sFLC ratio, and involved (monoclonal) FLC (iFLC) expressed at levels deemed measurable for monitoring (≥100 mg/L). By contrast, only 64% patients had measurable levels of monoclonal protein (≥200 mg per 24 hours) in urine protein electrophoresis (UPEP). After 1 and 3 treatment cycles, iFLC remained elevated in 71% and 46% of patients, respectively, whereas UPEP reported a positive result in 37% and 18%; all of the patients with positive UPEP at cycle 3 also had elevated iFLC levels. Importantly, elevated iFLC or an abnormal κ:λ sFLC ratio after 3 treatment cycles associated with poorer progression-free survival (P = .006 and P < .0001, respectively), whereas positive UPEP or urine immunofixation electrophoresis (uIFE) did not. In addition, patients with an abnormal κ:λ sFLC ratio had poorer overall survival (P = .022). Finally, early normalization of κ:λ sFLC ratio but not negative uIFE predicted achieving negative minimal residual disease, as determined by flow cytometry, after consolidation therapy (100% positive predictive value). We conclude that improved sensitivity and prognostic value of serum over urine measurements provide a strong basis for recommending the former for monitoring LCMM patients.0SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Les gammapathies monoclonales de signification indéterminée: Quand et pourquoi les chercher?

Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic premalignant plasma cell disorder. MGUS is a common disorder and the diagnosis is often made accidentally when a protein electrophoresis is performed in a routine blood test or during a biological assessment for other conditions. In the absence of biological abnormalities or clinical symptoms suggesting a plasma or lymphoplasma-cell disorder, there is no indication for routine screening of the monoclonal protein. When MGUS is diagnosed, the risk of transformation into myeloma or other lymphoproliferative disorders is estimated at 1 % per year. MGUS can also be associated with diseases that are not malignant disorders and in some cases, the monoclonal gammopathy is the witness of another rare but severe disorder wich will be critical not to be missdiagnosed.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Biological basis of anemia.

Anemia is a frequent complication in cancer, occurring in more than 50% of patients with malignancies. Several factors can cause anemia in these patients, such as blood loss, hemolysis, bone marrow infiltration, hypersplenism, and nutrient deficiencies. However, in a considerable number of patients, no cause other than malignant disease itself can be implicated. This cancer-related anemia is similar to the anemia observed in other chronic diseases, such as rheumatoid arthritis and some chronic infections. The syndrome of anemia of chronic disease is characterized by a hyporegenerative, normocytic, normochromic anemia associated with reduced serum iron and transferrin saturation but elevated (or normal) ferritin levels. Cancer-related anemia results from activation of the immune and inflammatory systems, leading to increased release of tumor necrosis factor, interferon-gamma, and interleukin-1. The cytokine-mediated relative failure of erythropoiesis has been further investigated, and three different mechanisms of action are proposed: (1) impaired iron utilization; (2) suppression of erythroid progenitor cells differentiation; and (3) inadequate erythropoietin production. In addition, the life span of red blood cells is shortened in cancer-related anemia and production cannot compensate sufficiently for the shorter survival time. Administration of recombinant human erythropoietin (r-HuEPO, epoetin alfa) can not only correct inadequate endogenous erythropoietin production, but also can overcome the suppression of erythroid progenitor cells and impairment of iron mobilization.Journal ArticleReviewinfo:eu-repo/semantics/publishe

Waldenström Macroglobulinemia: new Classification and Therapeutic Options

info:eu-repo/semantics/publishe

Human marrow mesenchymal stem cell culture: Serum-free medium allows better expansion than classical alpha-minimal essential medium (MEM) [2]

SCOPUS: le.jFLWINinfo:eu-repo/semantics/publishe

Caspofungin salvage therapy in a neutropenic patient with probable invasive aspergillosis: a case report.

A 47-year-old man with acute lymphocytic leukemia was admitted in intensive care unit (ICU) because of respiratory failure. He had febrile neutropenia and probable invasive pulmonary aspergillosis (IA). Amphotericin B renal toxicity and clinical deterioration prompted a shift to caspofungin and resulted in a successful response.Case ReportsJournal ArticleSCOPUS: ar.jinfo:eu-repo/semantics/publishe