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Thrombocytopenia is defined by a platelet level below 150 G/l. However, the limit of 100 G/l seems more appropriate to determine which thrombocytopenia will require further investigation. Initially, a thorough medical history should be performed as well as screening for any signs of bleeding. After having excluded the presence of platelet aggregates, it should be determined whether thrombocytopenia is isolated or associated with other abnormalities (cytopenias, coagulation disorder, abnormal renal or liver tests). Causes of thrombocytopenia along with the biological tests to achieve diagnosis, will be detailed in this article. We will then determine the medical emergencies that will need to be addressed to a reference center : active bleeding, biological signs of disseminated intravascular coagulation, acute renal failure, platelet count30 G/l (or50 G/l if the patient is on anticoagulation or antiplatelet therapy), significant and/or brutal onset pancytopenia. Outside these situations where vital prognosis is engaged, the patient should be rapidly addressed in case of platelet count between 30 and 50 G/l without any concomitant anticoagulation or antiplatelet therapy. Platelet levels between 50 and 100 G/l will require investigation, without any urgency, in outpatient haematology clinic.La thrombopénie est définie par un taux de plaquettes inférieur à 150 G/l. Néanmoins, la limite de 100 G/l est plus appropriée pour déterminer les thrombopénies qui nécessitent une mise au point. Dans un premier temps, une anamnèse méticuleuse ainsi que la recherche de tout signe hémorragique devront être effectuées. Après avoir exclu la présence d’agrégats plaquettaires, il conviendra de déterminer si la thrombopénie est isolée ou associée à d’autres anomalies (cytopénies, troubles de la coagulation, altération des tests hépatiques ou de la fonction rénale). Les causes de thrombopénie, ainsi que les examens biologiques à réaliser afin de parvenir au diagnostic, seront détaillées dans notre article. Ensuite, nous déterminerons les situations d’urgences thérapeutiques, nécessitant d’adresser le patient en urgence dans un centre de référence: la présence de saignements actifs, de signes biologiques de coagulation intravasculaire disséminée, une insuffisance rénale aiguë, un taux de plaquettes30 G/l (ou50 G/l si le patient est traité par anticoagulant ou antiagrégant), une pancytopénie profonde et/ou d’apparition brutale. En dehors de ces situations à risque vital, il conviendra de référer rapidement le patient en cas de thrombopénie isolée entre 30 et 50 G/l, en dehors de tout traitement anticoagulant ou antiagrégant. Un taux de plaquettes entre 50 et 100 G/l nécessitera une mise au point sans urgence en consultation d’hématologie.

Summary The virological diagnosis of Parvovirus B19 (PvB19) infection is currently based on sero-diagnosis, molecular methods or both, yet without clear recommendations. We retrospectively identified patients with polymerase chain reaction-positive PvB19 and/or positive serological assay between 2007 and 2013. Eighty-two adults with at least one diagnostic criterion of recent PvB19 infection (IgM antibodies, viral DNA in blood and/or in marrow) were included and classified into three homogeneous groups: 30 patients had no underlying predisposing condition, 25 a hereditary haemolytic anaemia, 27 an underlying immunodeficiency. The classical PvB19related manifestations were less frequent in immunocompromised than in immunocompetent patients (arthromyalgia: 5 vs. 14; erythema: 4 vs. 17, respectively). Only 414% of patients with no underlying disease were anaemic. Bicytopenia and pancytopenia were observed mainly in immunocompromised patients. Classical pure red cell aplasia was observed in only 9 of the 27 marrow smears performed. Specific IgM were found in 93% of immunocompetent patients, whereas only 58% had detectable viral DNA in blood. IgM and DNA were present alone or together in all patients with hereditary haemolytic anaemia. In immunocompromised patients, the diagnosis was confirmed by marrow analysis in 91% of cases. We make some proposals based on this large series of PvB19-infected patients.

Emergence of new molecules has considerably reshaped the management of patients in onco-hematology. Cytotoxic chemotherapy has not been altered, and CHOP remains the reference treatment for lymphomas. However, the development of targeted therapies has allowed for a broader spectrum of treatments. Immunotherapy with monoclonal antibodies entered the market with rituximab in diffuse large B-cell lymphomas, in the 1990s and it is now developing as new-generation anti-CD20 antibodies (obinotuzumab and ofatumumab). Anti-CD30 antibodies have been proposed in the treatment of T lymphomas and Hodgkin lymphomas. More recently, anti-PD1 antibodies have brought new perspectives in several cancers and more specifically in Hodgkin's lymphoma. Finally the BTK inhibitor, ibrutinib developed in the LLC has established itself in the management of mantle cell lymphoma and Waldenström macroglobulinemia. How can we deal with all these new molecules? Should they be offered as monotherapy or in association? In first line or relapse? The objective of this review is to trace history of the latest advances, and to highlight the validated strategies representing the new standards of treatment of lymphomas in 2017.

International audience; Vancomycin is a widely prescribed antibiotic, but the exact nature of vancomycin-associated nephrotoxicity is unclear, in particular when considering the frequent coadministration of aminoglycosides. We describe here the initial case of a 56-year-old woman with normal renal function developing unexplained ARF without hypovolemia after administration of vancomycin without coadministration of aminoglycosides. Studying the patient’s renal biopsy specimen, we ascertained that obstructive tubular casts composed of noncrystal nanospheric vancomycin aggregates entangled with uromodulin explained the vancomycin-associated ARF. We developed in parallel a new immunohistologic staining technique to detect vancomycin in renal tissue and confirmed retrospectively that deleterious vancomycin-associated casts existed in eight additional patients with acute tubular necrosis in the absence of hypovolemia. Concomitant high vancomycin trough plasma levels had been observed in each patient. We also reproduced experimentally the toxic and obstructive nature of vancomycin-associated cast nephropathy in mice, which we detected using different in vivo imaging techniques. In conclusion, the interaction of uromodulin with nanospheric vancomycin aggregates represents a new mode of tubular cast formation, revealing the hitherto unsuspected mechanism of vancomycin-associated renal injury.

Viral respiratory infections (VRIs) are frequent after hematopoietic stem cell transplantation and constitute a potential cause of mortality. We analyzed the incidence, risk factors, and prognosis of VRIs in a cohort of transplanted patients. More frequent viruses were human coronavirus and human rhinovirus followed by flu-like viruses and adenovirus. Risk factors for death were lymphocytopenia and high steroid dosage.

By means of an unbiased, automated fluorescence microscopy-based screen, we identified the epidermal growth factor receptor (EGFR) inhibitors erlotinib and gefitinib as potent enhancers of the differentiation of HL-60 acute myeloid leukemia (AML) cells exposed to suboptimal concentrations of vitamin A (all-trans retinoic acid, ATRA) or vitamin D (1α,25-hydroxycholecalciferol, VD). Erlotinib and gefitinib alone did not promote differentiation, yet stimulated the acquisition of morphological and biochemical maturation markers (including the expression of CD11b and CD14 as well as increased NADPH oxidase activity) when combined with either ATRA or VD. Moreover, the combination of erlotinib and ATRA or VD synergistically induced all the processes that are normally linked to terminal hematopoietic differentiation, namely, a delayed proliferation arrest in the G0/G1 phase of the cell cycle, cellular senescence, and apoptosis. Erlotinib potently inhibited the (auto)phosphorylation of mitogen-activated protein kinase 14 (MAPK14, best known as p38(MAPK)) and SRC family kinases (SFKs). If combined with the administration of ATRA or VD, the inhibition of p38(MAPK) or SFKs with specific pharmacological agents mimicked the pro-differentiation activity of erlotinib. These data were obtained with 2 distinct AML cell lines (HL-60 and MOLM-13 cells) and could be confirmed on primary leukemic blasts isolated from the circulation of AML patients. Altogether, these findings point to a new regimen for the treatment of AML, in which naturally occurring pro-differentiation agents (ATRA or VD) may be combined with EGFR inhibitors.

The term myelodysplastic syndrome (MDS) identifies a heterogeneous group of clonal disorders originating from bone marrow stem cells that often progress to acute myeloid leukemia (AML). The reference treatments for MDS include the DNA methyltransferase inhibitors azacytidine and decitabine. Recently, the epidermal growth factor receptor (EGFR) inhibitor erlotinib has been shown to exert antileukemic activity in vitro and in vivo, independent of the EGFR. Thanks to this feature, erlotinib is currently being tested as an antileukemic drug in clinical trials. Here, we report that azacytidine and erlotinib mediate synergistic antineoplastic effects in several primary or secondary (post-MDS) AML cell lines. The combination of azacytidine and erlotinib blocked cell-cycle progression and induced caspase-dependent apoptosis more consistently than either of the two agents alone. These effects were not a consequence of cellular differentiation and could be discriminated from each other, as the former depended on caspases whereas the latter did not. The synergy between azacitidine and erlotinib, which involved the proteasomal degradation of the anti-apoptotic Bcl-2 family members MCL-1 and BCL2L10 and the upregulation of their pro-apoptotic counterpart PUMA, was abolished when azacytidine was replaced by decitabine but persisted when erlotinib was substituted with gefitinib, another EGFR inhibitor. Of note, the intracellular accumulation of azacytidine was exacerbated by both erlotinib and gefitinib, pointing to a pharmacokinetic mechanism of synergy. In approximately half of the cases studied, marrow and circulating blasts from MDS and AML patients, respectively, exhibited hyperadditive cytotoxic responses to the combination of azacytidine and erlotinib. These results strongly suggest that the combination of azacytidine and erlotinib may exert clinically relevant antileukemic effects.

Treatment of CMML remains a clinical challenge, with no drug demonstrating clear clinical benefit. Even if azacitidine is approved in the treatment of CMML, its role remains disputed. We report a cohort of 76 CMML patients (according to WHO classification) treated with azacitidine in 3 programs (French AZA compassionate program, Cleveland Clinic Foundation and H. Lee Moffitt Cancer Center). 45% had CMML2, and 55% had splenomegaly and/or WBC counts >13 G/L, which are known to be poor prognostic factors in CMML. All patients received AZA for at least one cycle, and the median number of cycles administered was 6. Thirty-three patients (43%) achieved a response according to IWG 2006 criteria, including 13 complete remissions (17%). Median survival was 29 months. Increased bone marrow blast percentage and proliferative features of the disease, including splenomegaly and high WBC counts, were significantly associated with shorter survival. By multivariate analysis, only marrow blasts >10% and palpable splenomegaly had prognostic impact on survival. Although promising, the efficacy of azacitidine in advanced CMML needs to be confirmed in a randomized prospective study.

A 28-year-old man, a native of Morocco, was hospitalized for acute renal failure associated with persistent vomiting. The patient first presented at age 16 with cyclical episodes of abdominal pain with vomiting, relieved transiently by compulsive hot baths. He had continuously smoked 15 cigarettes and 5 cannabis ‘joints’ a day since the age of 14 years. He denied consumption of medication and other illicit drugs or alcohol.