Allogeneic stem cell transplantation benefits for patients >= 60 years with acute myeloid leukemia and FLT3 internal tandem duplication : a study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation

Intermediate-risk cytogenetic acute myeloid leukemia with an internal tandem duplication of FLT3 (FLT3-ITD) is associated with a high risk of relapse, and is now a standard indication for allogeneic stem cell transplantation. Nevertheless, most studies supporting this strategy have been performed in young patients. To address the benefit of allogeneic transplantation in the elderly, we made a selection from the European Society for Blood and Marrow Transplantation registry of de novo intermediate-risk cytogenetic acute myeloid leukemia harboring FLT3-ITD in patients aged 60 or over and transplanted from a related or unrelated donor between January 2000 and December 2015. Two hundred and ninety-one patients were identified. Most patients received a reduced-intensity conditioning (82%), while donors consisted of an unrelated donor in 161 (55%) patients. Two hundred and twelve patients received their transplantation in first remission, 37 in second remission and 42 in a more advanced stage of the disease. The 2-year leukemia-free survival rate was 56% in patients in first remission, 22% in those in second remission and 10% in patients with active disease, respectively (P= 60 with FLT3-ITD acute myeloid leukemia in first remission, similarly to current treatment recommendations for younger patients.Peer reviewe

Impact of central nervous system involvement in adult patients with Philadelphia-negative acute lymphoblastic leukemia: a GRAALL-2005 study

Whereas the prognosis of adult patients with Philadelphia-negative acute lymphoblastic leukemia (ALL) has greatly improved since the advent of pediatric-inspired regimens, the impact of initial central nervous system (CNS) involvement has not been formerly re-evaluated. We report here the outcome of patients with initial CNS involvement included in the pediatric-inspired prospective randomized GRAALL-2005 study. Between 2006 and 2014, 784 adult patients (aged 18-59 years) with newly diagnosed Philadelphia-negative ALL were included, of whom 55 (7%) had CNS involvement. In CNSpositive patients, overall survival was shorter (median 1.9 years vs. not reached, HR=1.8 [1.3-2.6], P<0.001). While there was no statistical difference in cumulative incidence of relapse between CNS+ and CNS- patients (HR=1.5 [0.9-2.5], P=0.11), non-relapse mortality was significantly higher in those with initial CNS disease (HR=2.1 [1.2-3.5], P=0.01). This increase in toxicity was mostly observed in patients randomized to the high-dose cyclophosphamide arm and in those who received allogeneic stem cell transplantation. Exploratory landmark analyses did not show any association between either cranial irradiation or allogeneic stem cell transplantation and outcome. Despite improved outcome in young adult ALL patients with pediatric-inspired protocols, CNS involvement is associated with a worse outcome mainly due to excess toxicity, without improved outcome with allogeneic SCT

Absence de valeur diagnostique ou pronostique de l'expression du CD36, du nombre de plaquettes réticulées ou de microparticules plaquettaires évalués par cytométrie de flux au cours des thrombocytémies essentielles et des thrombocytoses réactionnelles

ANGERS-BU Médecine-Pharmacie (490072105) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Different Roles of Two Autotaxin Isoforms in Proliferation, Migration and Adhesion in the Non-Mutational Tyrosine Kinase Inhibitor Resistant Acute Lymphoblastic Leukemia Cell Line SupB15.

Abstract The Bcr-Abl oncogene is present in 30–40% of adult patients with acute lymphoblastic leukemia (ALL). The Abl kinase inhibitor imatinib-based therapy has become standard for this subset ALL. Acquired resistance to imatinib occurs frequently and is associated with mutations in the tyrosine kinase domain (TKD) approximately in about 80% of patients. In contrast, TKD mutations are uncommon in primary imatinib resistance which appears to be multifactorial, although the underlying mechanisms have been incompletely elucidated. We have established a Ph+ cell line for the analysis of non-mutational resistance mechanisms of imatinib resistance: SupB15RT, a Bcr-Abl expressing lymphoblastic cell line derived from SupB15WT cell line by gradually increasing the exposure to imatinib. SupB15RT shows cross-resistance to the second generation Abl kinase inhibitors Nilotinib and Dasatinib. We have shown that several commonly implicated mechanisms of imatinib resistance do not play a role in conferring the imatinib resistance in SupB15RT cells. By comparative gene expression analysis of SupB15WT vs. SupB15RT cells using Affymetrix- Microarrays, we identified 29 differentially regulated genes. Autotaxin (ATX) is one of the most highly up-regulated genes in imatinib resistant SupB15RT cells, and suggested a contribution to imatinib resistance. ATX is an exo-enzyme (pyrophosphophatase/phosphodiesterase). It plays a role in tumor progression and migration as a tumor cell autocrine motilty factor in various solid tumor cell types. ATX is involved in the synthesis of the signaling molecule, lysophosphatidic acid (LPA) which promotes survival and motility. It was the aim of this study to determine whereas ATX plays a functional role for imatinib resistance in Ph+ ALL. Using RT-PCR we demonstrated that 2 isoforms of ATX are expressed in SupB15RT cells: ATXshort and ATXlong. ATXlong (863 aa) contains highly basic insertion in the catalytic domain (52 residues). We retroviraly transfected BaF3 cells with p185 and/or ATXshort or ATXlong to analyze its influence on growth, adhesion and migration in mouse cell model. In comparison to wild type BaF3 cells the proliferation of BaF3 cells expressing ATXshort is enhanced (1,5-fold), whereas ATXlong expressing BaF3 cells showed no difference in proliferation in comparison to Mock infected cells. The proliferation of p185 expressing BaF3 cells co-expressing ATXshort or ATXlong is not inhibited by the treatment with 1μM imatinib after 3 days in contrast to p185 expressing BaF3 cells. In adhesion experiments, BaF3 cells expressing ATXshort showed a higher attachment independent of p185 expression. We also performed migration experiments using transwell assays. These assays showed more migration with cells co-expressing p185 and ATXlong compared to p185 alone. This is in agreement with our results for SupB15RT vs. SupB15WT with a 3-fold migration increase of SupB15RT. Application of 10% fetal calf serum (FCS) in migration experiments resulted in a 1,5-fold higher migration of the ATXlong expressing BaF3 cells compared to culture without FCS. One explanation for this finding may be that FCS contains lysophosphatidic choline (LPC) which is converted to LPA by ATX. Although expression of both 2 isoforms of ATX is important for the increased proliferation, it seems that the 2 isoforms have different cellular functions in Ph+ lymphoblastic cells. ATXshort seems to enhance adhesion whereas ATXlong plays an important role in motility. Taken together our results indicate a role for ATX in TK- inhibitor resistant SupB15RT cells through LPA signaling via LPA receptors. The ratio between ATXshort and ATXlong probably is important for the intracellular signaling and has to be explored.</jats:p

Lymphomatoid Granulomatosis and Tuberculosis, Coincidence or Cohabitation&mdash;A Case Report

Background: Lymphomatoid granulomatosis (LYG) is a rare and atypical EBV-induced B-cell lymphoproliferative disorder. Clinical manifestations are mainly respiratory, with nodular infiltrates, varying in number and size, being responsible for respiratory distress. Cutaneous, hepatic, or neurological involvement is also possible. Although pathogenesis is not clearly elucidated, quantitative or qualitative cellular immunodepression is thought to be a main factor. Here, we report a case of concomitant LYG and pulmonary tuberculosis. Case presentation: An 80-year-old female patient presented to the emergency unit for steadily increasing dyspnea, with workup revealing bilateral pulmonary nodules and mediastinal lymph node enlargement on chest imaging. Empiric antibiotic therapy was initially started with amoxicillin-clavulanate, which was later combined with azithromycin following respiratory deterioration. A CT-guided lung biopsy showed grade 2 LYG. Treatment with corticosteroids and weekly rituximab was initiated, leading to rapid improvement of respiratory symptoms. After the second dose of rituximab, sputum cultures that were initially collected were found to be positive for Mycobacterium tuberculosis. Rituximab was suspended, and antituberculous treatment was initiated. Rituximab was restarted once tuberculosis was controlled. Follow-up imaging later showed adequate control of both tuberculosis and LYG, with at least a partial remission of the latter. Conclusions: Our case highlights the importance of a complete diagnostic workup when a diagnosis of LYG is made, to avoid missing a concomitant pulmonary disease, such as tuberculosis, even when definite pathologic and clinical features of the former are present

Acquired Factor IX (fIX) Deficiency Associated with a Multiple Myeloma.

Abstract Multiple myeloma is associated with bleeding disorders in about 15 % of patients. The pathophysiology is multifactorial and may be related to the paraprotein level. The bleeding tendency has been reported to be caused by thrombocytopenia, paraprotein-induced qualitative platelet dysfunction, inhibition of polymerization of fibrin monomers, monoclonal thrombin inhibitor, factor X deficiency, acquired von Willebrand syndrome and local tissue fragility secondary to amyloidosis. Here, we report the first case of acquired fIX deficiency associated with a multiple myeloma (MM) in a 54 year-old Caucasian man. The patient presented with a Monoclonal Gammapathy of Undetermined Significance (MGUS) (IgA lambda 15 g/L). His laboratory evaluation then revealed an activated prothrombin time (aPTT) of 37 s (normal 29–36 seconds) without any bleeding disorder. Three years later, the MGUS evolved into a stage III multiple myeloma (IgA lambda 55 g/L) and the patient presented a hemorrhage after a bone marrow biopsy. At this time, the coagulation tests showed an aPTT of 54 s, a thrombin time of 27 s (normal 20–25 seconds), a normal platelet count without any other abnormalities. Clotting factors assay revealed a fIX deficiency of 10 %. No inhibitor was found using the Bethesda method and no fIX mutation was detected in the patient DNA as well as in his sister’s. After receiving chemotherapy (VAD-type chemotherapy and high-dose of Melphalan with autologous stem cells transplantation), the paraprotein concentration decreased to 9 g/L and the coagulation results returned to normal. Sixteen months later, the MM recurred (IgA lambda 78 g/L) and the patient presented hemorrhagic manifestations associated with an aPTT of 70 s and a fIX deficiency at 11 %. Factor IX deficiency and bleeding diathesis were detected in every MM relapses. He died during a severe bleeding event (epistaxis, hematuria and rectorrhagia) despite fIX concentrate treatments. The etiology of this acquired fIX deficiency is not clear. The simultaneous evolution of MM and fIX deficiency, and the absence of congenital hemophilia mutation confirm that it is an acquired deficiency. Nevertheless there is no fIX inhibitor. Until now no case of acquired fIX deficiency is described in the literature apart from Gaucher disease. Our hypothesis is that fIX can be adsorbed by the malignant plasma cells. We are currently performing immunostaining of fIX in the bone marrow of this patient to assess whether fIX is adsorbed by the medullar malignant cells.</jats:p

The conjunction of uncommon diagnoses: a case report of concomitant lymphomatoid granulomatosis and pulmonary tuberculosis

Abstract Background: Lymphomatoid granulomatosis (LYG) is a rare and atypical EBV induced B-cell lymphoproliferative disorder. Clinical manifestations are mainly respiratory, with nodular infiltrates, varying in number and size being responsible for respiratory distress. Cutaneous, hepatic, or neurological involvement is also possible with the disease. Lymphatic involvement is uncommon. Although pathogenesis is not clearly elucidated, quantitative or qualitative cellular immunodepression is thought to be a main factor. Here, we report a case of concomitant LYG and pulmonary tuberculosis in an elderly woman. Case presentation: An 80-year-old woman presented to the emergency unit for steadily increasing dyspnea, with a workup revealing bilateral nodules and mediastinal lymph node enlargement on chest imaging, associated with a mildly elevated C-reactive protein (CRP). She had no relevant prior medical history and no known immunodepression. Empiric antibiotic therapy was initially started with amoxicillin-clavulanate, which was later combined to azithromycin following respiratory deterioration. A CT-guided lung biopsy showed grade I lymphomatoid granulomatosis. Treatment with corticosteroids and weekly rituximab was initiated, leading to a rapid improvement of respiratory symptoms. After the second dose of rituximab, initially collected sputum cultures were found positive for Mycobacterium tuberculosis. Rituximab was suspended and antituberculous treatment was initiated. Rituximab was restarted once tuberculosis was controlled. Follow-up imaging later showed adequate control of both infectious and hematological diseases with at least a partial remission of the lymphomatoid granulomatosis. Conclusions: This case report highlights both diagnosis and therapeutic challenges in a rare but plausible situation. Lymph-node involvement in lymphomatoid granulomatosis should always be questioned in LYG as it is seldom seen in the disease. Finally, pathologic confirmation for LYG should not eliminate the need for a comprehensive workup to eliminate other differential diagnoses with management-changing potential.</jats:p

Severe Viral Hepatitis in a Patient with Chronic Lymphocytic Leukemia (CLL) Complicated with Autoimmune Haemolytic Anemia (AIAH), Treated with Steroids

International audienceInfectious complications are a major cause of morbidity and mortality in patients with chronic lymphocytic leukemia (CLL) due to impaired immunity secondary to the disease itself and to the immunosuppressive therapies administered to these patients. We report a 78-year-old woman with CLL who was treated with steroids for autoimmune hemolytic anemia (AIHA). A few weeks later, she was admitted for severe acute hepatitis with disseminated intravascular coagulation (DIC). Despite the symptomatic treatment of DIC, standard reanimation and probabilistic antibiotics, the patient died within 24h with severe hepatic failure. Autopsy was in favor of a disseminated viral infection with esophageal, hepatic and pulmonary cytopathologic lesions with acidophilic intranuclear inclusions suggestive of herpes virus, even though HSV 1 and 2, CMV and HHV6 PCRs were negative. This case of severe viral hepatitis with esophagitis occurring three weeks after the introduction of high-dose steroid treatment for AIHA in a CLL patient calls for anti-herpetic prophylaxis in such patients, immunodepressed by their diseases and the treatment they receive