Humoral immune depression following autologous stem cell transplantation is a marker of prolonged response duration in patients with mantle cell lymphoma

Rituximab maintenance (RM) after autologous stem cell transplantation (ASCT) is standard-of-care for young patients with mantle cell lymphoma (MCL). RM may enhance post-transplantation immune depression and risk of infections. We compared infection incidence and immune consequences of RM versus observation in transplanted MCL patients. All randomized patients included in the LyMa trial were eligible. The following parameters were collected prospectively: occurrence of fever, infection, hospitalization, neutropenia, hypogammaglobulinemia, CD4 lymphopenia and γ globulin (Ig) substitution. The post-ASCT period was divided into four periods in order to assess the possible effects of RM or ASCT on immune status. Each arm included 120 patients. Concerning infection incidence and all biological parameters, there was no difference between the two arms during the first year post ASCT. After this period, RM patients were more exposed to fever (P=0.03), infections (P=0.001), hypogammaglobulinemia (P=0.0001) and Ig substitution (P<0.0001). Incidences of hospitalization, neutropenia and CD4 lymphopenia were not different between the two arms. The number of rituximab injections was correlated with infections and hypogammaglobulinemia, P<0.0001 and P=0.001; but was not correlated with neutropenia and CD4 lymphopenia. Ig substitution did not modify infection incidence. Patients who presented hypogammaglobulinemia <6 g/L or <4 g/L had longer 3-years progression-free survival (PFS), this applies to RM patients (P=0.012 and P=0.03) and to the global cohort (P=0.008 and P=0.003). Hypogammaglobulinemia did not influence overall survival. Occurrence of infectious event, neutropenia and CD4 lymphopenia did neither influence PFS nor overall survival. Post-ASCT RM in MCL patients causes sustained hypogammaglobulinemia, which is independently correlated with improved PFS

Complete Set of Elastic Moduli of a Spin-Crossover Solid: Spin-State Dependence and Mechanical Actuation

Molecular spin crossover complexes are promising candidates for mechanical actuation purposes. The relationships between their crystal structure and mechanical properties remain, however, not well understood. In this study, combining high pressure synchrotron Xray diffraction and nuclear inelastic scattering measurements, we assessed the effective macroscopic bulk modulus (11.5 ± 2.0 GPa), Young’s modulus (10.9 ± 1.0 GPa) and Poisson’s ratio (0.34 ± 0.04) of the spin crossover complex [FeII(HB(tz)3)2] (tz = 1,2,4-triazol-1-yl) in its low spin state. Crystal structure analysis revealed a pronounced anisotropy of the lattice compressibility, which was correlated with the difference in spacing between the molecules in different crystallographic directions. Switching the molecules from the low spin to the high spin state leads to a remarkable drop of the Young’s modulus to 7.1 ± 0.5 GPa, which was also assessed in thin film samples by means of micromechanical measurements. These results are in agreement with the high cooperativity of the spin crossover in this compound and highlight its application potential in terms of recoverable stress (21 ± 1 MPa) and work density (15 ± 6 mJ/cm3)

Etude de la faisabilité de l'allogreffe de cellules souches hématopoïétiques dans la myélofibrose primitive ou secondaire à un autre syndrome myéloprolifératif

L'objectif était d'étudier la faisabilité de l'allogreffe de cellules souches hématopoïétiques (CSH) à conditionnement myéloablatif ou d'intensité réduite dans le cas de la myélofibrose primitive ou secondaire à une polyglobulie ou à une thrombocytémie essentielles. 39 patients avec un âge médian de 49 ans (15-65) et allogreffés entre 1994 et 2008 ont été inclus dans notre étude rétrospective multicentrique. Le score de Dupriez était bas pour 9, intermédiaire pour 16 et élevé pour 14 patients, 10 étaient en phase acutisée. 15 patients ont reçu un conditionnement myéloablatif (CMA) et 24 un conditionnement d'intensité réduite (CIR). Le donneur était apparenté pour 25 patients et tous ont reçu un greffon HLA-matched (>= 9/10). La sortie d'aplasie a été effective chez tous les patients sauf un, avec une médiane de 15 jours [0-129] post greffe. Celle-ci a été plus rapide chez les patients splénectomisés ou ayant reçu un conditionnement de type CIR. 79% des patients ont développé une GVHD aigue de grade I à IV. Sur les 35 patients évaluables, 18 ont développé une GVHD chronique. La survie globale et la survie sans rechute à 3 ans étaient de 61 et 55% respectivement. La mortalité reliée au traitement (TRM) à 3 ans était de 28%. Il n'y avait aucune différence significative entre les groupes CMA et CIR en terme de survie globale ou TRM. Une thrombopénie < 100000/mm3 était associée à une survie globale inférieure (p=0.011). Notre étude confirme le potentiel curatif de l'allogreffe de CSH de type CMA ou CIR dans la myélofibrose, cependant au prix d'une TRM importante. Dans le groupe CIR, celle-ci était liée au délai trop important entre le diagnostic et la greffe qui va de paire avec un stade plus avancé de la maladie. Nous recommandons plutôt un conditionnement de type non myéloablatif pour les patients ayant un stade intermédiaire, quelque soit leur âge (jusqu'à 65 ans). Une splénectomie avant greffe ne doit pas être systématique. Les patients thrombopéniques (plaquettes < 100000/mm3) ne sont pas de bons candidats à l'allogreffe de CSH.CLERMONT FD-BCIU-Santé (631132104) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Faster clinical decisions in B‐cell acute lymphoblastic leukaemia: A single flow cytometric 12‐colour tube improves diagnosis and minimal residual disease follow‐up

International audienceSummary Assessing minimal residual disease (MRD) in B‐cell precursor acute lymphoblastic leukaemia (BCP‐ALL) is essential for adjusting therapeutic strategies and predicting relapse. Quantitative polymerase chain reaction (qPCR) is the gold standard for MRD. Alternatively, flow cytometry is a quicker and cost‐effective method that typically uses leukaemia‐associated immunophenotype (LAIP) or different‐from‐normal (DFN) approaches for MRD assessment. This study describes an optimized 12‐colour flow cytometry antibody panel designed for BCP‐ALL diagnosis and MRD monitoring in a single tube. This method robustly differentiated hematogones and BCP‐ALL cells using two specific markers: CD43 and CD81. These and other markers (e.g. CD73, CD66c and CD49f) enhanced the specificity of BCP‐ALL cell detection. This innovative approach, based on a dual DFN/LAIP strategy with a principal component analysis method, can be used for all patients and enables MRD analysis even in the absence of a diagnostic sample. The robustness of our method for MRD monitoring was confirmed by the strong correlation ( r = 0.87) with the qPCR results. Moreover, it simplifies and accelerates the preanalytical process through the use of a stain/lysis/wash method within a single tube (&lt;2 h). Our flow cytometry‐based methodology improves the BCP‐ALL diagnosis efficiency and MRD management, offering a complementary method with considerable benefits for clinical laboratories

Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) as a Curative Therapy in Primary and Secondary Myelofibrosis (MF): A 14-Year Period Oligocentric French Experience.

Abstract Background: MF patients (pts) with intermediate or high Lille score have a median survival from one to 2 years. After transformation into acute myeloid leukemia (AML), short-term survival is less than 5%. Until now, chemotherapy or other investigative drugs have not been reported to improve survival in pts with primary or secondary MF. Aim of the study: To describe the outcome of pts who underwent HSCT from 1994 to 2008 in 4 hematological French centers. Method: Thirty-nine pts with MF were identified. Overall survival (OS) and relapse free survival (RFS) were estimated by Kaplan-Meier method and cumulative incidence of non-relapse mortality (NRM) with relapse as a competing event, by Fine and Gray method (R Sofware). Patient and disease characteristics: Median age of pts at time of HSCT was 49 years (15–65). Twenty-seven pts had primary MF whereas 12 patients had MF secondary to polycythemia vera (PV) (n=7) or to essential thrombocythemia (ET) (n= 5). Among 25 pts with a cytogenetic analysis, 12 had clonal abnormalities. A JAK2 mutation was detected in 6 out of 22 tested patients (3/13 primitive MF, 1/2 MF secondary to TE and 2/3 MF secondary to PV). Treatment before transplantation mainly consisted of hydroxyurea or busulfan (26 pts). Before HSCT, 12 pts required platelet transfusions and 19 required blood transfusions. Twenty-three pts experienced a splenectomy in median 3 months before HSCT. Ten patients were transformed in AML before HSCT. Dupriez score was low in 9, intermediate in 16 and high in 14 pts at time of transplantation. Results: 25 pts received a HSCT from an HLA-identical sibling and all pts were transplanted with an HLA matched donor (3 9/10 HLA identities). Fifteen pts received a myeloablative conditioning regimen (MAC) and 24 received a fludarabine-based reduced intensity conditioning regimen (RIC). Graft-versus-Host disease (GVHD) prophylaxis consisted of cyclosporine plus mycophenolate in 21, cyclosporine plus methotrexate in 13 and cyclosporine alone in 5 pts. All but one pts engrafted in median 15 days (range:0–129) after transplantation. Median follow-up after HSCT was 729 days (79–1004). Thirty-one pts developed grade I-IV acute GVHD. Among 35 evaluable pts, 18 developed a chronic GVHD. Median time to discharge was shorter with RIC regimen (23 days) than with MAC regimen (46 days). Median OS was estimated at 4 years and 8 months. Three-year OS was 61% (95%Confidence Interval (CI): 47–80). 3-year RFS was 55% (41–75). 3-year NRM, was similar with RIC or MAC (32% (95%CI: 12–51) versus 20% (1–39). OS was not correlated to pre-transplantation Dupriez score (Low, OS: 57% (95%CI: 29–100)/Intermediate: 73% (95%CI: 53–99)/High: 56% (95%CI: 35–90)). Splenectomy, age, sex mismatch, CMV serology, conditioning regimen (RIC vs MAC) had no impact on outcome. Transformation into acute AML before HSCT was not a significant marker for poor OS (OS at 64%(95%CI: 48–85) versus 53% (95%CI: 18–28)). Patients who received platelet transfusions before HSCT had poorer OS: 25% (95%CI: 9–67) versus 78% (95%CI: 64–97), p &amp;lt; 0.0001). Conclusion: In these high risk MF pts, median OS after HSCT is much better than reported with alternative treatment. The main risk factor for poor outcome is thrombocytopenia requiring platelet transfusion before transplantation whereas other usual risk factors have no more impact after HSCT.</jats:p

Hypogammaglobulinemia during Rituximab Maintenance after Transplantation Is a Surrogate Marker for Disease Control in Patients with Mantle-Cell Lymphoma, an Analysis from the LyMa Trial

International audienceHypogammaglobulinemia during Rituximab Maintenance after Transplantation Is a Surrogate Marker for Disease Control in Patients with Mantle-Cell Lymphoma, an Analysis from the LyMa Tria

Humoral immune depression following autologous stem cell transplantation is a marker of prolonged response duration in patients with mantle cell lymphoma

Rituximab maintenance (RM) after autologous stem cell transplantation (ASCT) is standard-of-care for young patients with mantle cell lymphoma (MCL). RM may enhance post-transplantation immune depression and risk of infections. We compared infection incidence and immune consequences of RM versus observation in transplanted MCL patients. All randomized patients included in the LyMa trial were eligible. The following parameters were collected prospectively: occurrence of fever, infection, hospitalization, neutropenia, hypogammaglobulinemia, CD4 lymphopenia and γ globulin (Ig) substitution. The post-ASCT period was divided into four periods in order to assess the possible effects of RM or ASCT on immune status. Each arm included 120 patients. Concerning infection incidence and all biological parameters, there was no difference between the two arms during the first year post ASCT. After this period, RM patients were more exposed to fever (P=0.03), infections (P=0.001), hypogammaglobulinemia (P=0.0001) and Ig substitution (P&lt;0.0001). Incidences of hospitalization, neutropenia and CD4 lymphopenia were not different between the two arms. The number of rituximab injections was correlated with infections and hypogammaglobulinemia, P&lt;0.0001 and P=0.001; but was not correlated with neutropenia and CD4 lymphopenia. Ig substitution did not modify infection incidence. Patients who presented hypogammaglobulinemia &lt;6 g/L or &lt;4 g/L had longer 3-years progression-free survival (PFS), this applies to RM patients (P=0.012 and P=0.03) and to the global cohort (P=0.008 and P=0.003). Hypogammaglobulinemia did not influence overall survival. Occurrence of infectious event, neutropenia and CD4 lymphopenia did neither influence PFS nor overall survival. Post-ASCT RM in MCL patients causes sustained hypogammaglobulinemia, which is independently correlated with improved PFS.</jats:p