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•Our study explores the interest of systematic screening of fungal markers for COVID-19- associated pulmonary aspergillosis in a medical ward.•Our study does not support systematic screening of fungal markers in COVID-19 patients hospitalized outside an ICU.•This approach should be explored in specific subgroups, such as immunocompromised COVID-19 patients.

The 9th web-based European Conference on Infections in Leukemia (ECIL-9), held September 16-17, 2021, reviewed the risk of infections and febrile neutropenia associated with more recently approved immunotherapeutic agents and molecular targeted drugs for the treatment of acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Novel antibody based treatment approaches (inotuzumab ozogamicin, gemtuzumab ozogamicin, flotetuzumab), isocitrate dehydrogenases inhibitors (ivosidenib, enasidenib, olutasidenib), FLT3 kinase inhibitors (gilteritinib, midostaurin, quizartinib), a hedgehog inhibitor (glasdegib) as well as a BCL2 inhibitor (venetoclax) were reviewed with respect to their mode of action, their immunosuppressive potential, their current approval and the infectious complications and febrile neutropenia reported from clinical studies. Evidence-based recommendations for prevention and management of infectious complications and specific alerts regarding the potential for drug-drug interactions were developed and discussed in a plenary session with the panel of experts until consensus was reached. The set of recommendations was posted on the ECIL website for a month for comments from members of EBMT, EORTC, ICHS and ELN before final approval by the panelists. While a majority of these agents are not associated with a significantly increased risk when used as monotherapy, caution is required with combination therapy such as venetoclax plus hypomethylating agents, gemtuzumab ozogamicin plus cytotoxic drugs or midostaurin added to conventional AML chemotherapy.

B-cell receptor (BCR) signaling is crucial for the pathophysiology of most mature B-cell lymphomas/leukemias and has emerged as a therapeutic target whose effectiveness remains limited by the occurrence of mutations. Therefore, deciphering the cellular program activated downstream this pathway has become of paramount importance for the development of innovative therapies. Using an original ex vivo model of BCR-induced proliferation of chronic lymphocytic leukemia cells, we generated 108 temporal transcriptional and proteomic profiles from 1 h up to 4 days after BCR activation. This dataset revealed a structured temporal response composed of 13,065 transcripts and 4027 proteins, comprising a leukemic proliferative signature consisting of 430 genes and 374 proteins. Mathematical modeling of this complex cellular response further highlighted a transcriptional network driven by 14 early genes linked to proteins involved in cell proliferation. This group includes expected genes (EGR1/2, NF-kB) and genes involved in NF-kB signaling modulation (TANK, ROHF) and immune evasion (KMO, IL4I1) that have not yet been associated with leukemic cells proliferation. Our study unveils the BCR-activated proliferative genetic program in primary leukemic cells. This approach combining temporal measurements with modeling allows identifying new putative targets for innovative therapy of lymphoid malignancies and also cancers dependent on ligand–receptor interactions.

Introduction: The frequency of invasive fungal diseases (IFDs) has increased in recent years. Within a context where both treatments and guidelines are fast evolving, we aim to shed new light on IFD management in hematologic departments in France. Methods: A multicenter cross-sectional observational study was prospectively conducted in 24 French centers in September and October 2013. Results: Four hundred ninety-four hospitalized children and adult patients suffering from hematologic malignancy were enrolled: 147 (30%) were allogeneic hematopoietic stem cell transplant (HSCT) recipients, 131 (27%) were patients with acute myeloblastic leukemia or myelodysplastic syndrome (MDS), 71 (14%) were patients with acute lymphoblastic leukemia who did not undergo allogeneic HSCT, and the 145 (29%) remaining patients did not belong to the three above groups. Two hundred forty-six patients (50%) received antifungal treatment, which was prophylactic in 187 (76%) treated patients. These rates were similar across all groups (63–80%). Patients received prophylaxis with an azole (79%), intravenous amphotericin B formulation (10%), echinocandin (9%), or two combination drugs (2%). Conclusion: Results indicate that prophylaxis is the leading antifungal strategy in French hematology units, regardless of the disease condition, representing 76% of prescriptions for antifungal therapy. Funding: Astellas Pharma France.

Invasive pulmonary aspergillosis (IPA) is a common complication of immunosuppression. Rapid diagnosis using molecular techniques is essential to improve patient survival. PCR techniques are promising in enhancing Aspergillusdetection in blood and respiratory samples. We evaluate for the first time the performances of two commercial real-time PCR kits, the A. fumigatusBio-Evolution and the MycoGENIE A. fumigatusfor the detection of A. fumigatusDNA in bronchoalveolar lavage (BAL) from patients with and without IPA. Seventy-three BAL samples were included. Thirty-one of them corresponded to patients with probable IPA, 11 to patients with possible IPA, and 31 to patients without aspergillosis, according to the 2008 European Organization for Research and Treatment of Cancer/Mycoses Study Group criteria. In the probable IPA group, A. fumigatusBio-Evolution and the MycoGENIE A. fumigatusreal-time PCR kits showed a specificity of 100% and a sensitivity of 81% and 71%, respectively. The A. fumigatusBio-Evolution detected AspergillusDNA in the 14 BAL samples with a positive Aspergillusculture result, whereas the MycoGENIE A. fumigatusPCR result was positive only for 12. In the possible IPA group, there were no positive real-time PCR or positive Aspergillusculture results. For the patients without aspergillosis, no positive result was observed for real-time PCR kit, despite the presence of various other non-Aspergilluspathogens in this group. Our study demonstrates an excellent specificity and a good sensitivity of A. fumigatusDNA detection in BAL samples with both kits.

Infection and malignancy represent two common complications after solid organ transplantation, which are often characterized by poorly specific clinical symptomatology. Herein, we have evaluated the role of 18F-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography/computed tomography (PET/CT) in this clinical setting. Fifty-eight consecutive patients who underwent FDG PET/CT after kidney, lung or heart transplantation were included in this retrospective analysis. Twelve patients underwent FDG PET/CT to strengthen or confirm a diagnostic suspicion of malignancies. The remaining 46 patients presented with unexplained inflammatory syndrome, fever of unknown origin (FUO), CMV or EBV seroconversion during post-transplant follow-up without conclusive conventional imaging. FDG PET/CT results were compared to histology or to the finding obtained during a clinical/imaging follow-up period of at least 6 months after PET/CT study. Positive FDG PET/CT results were obtained in 18 (31 %) patients. In the remaining 40 (69 %) cases, FDG PET/CT was negative, showing exclusively a physiological radiotracer distribution. On the basis of a patient-based analysis, FDG PET/CT’s sensitivity, specificity, PPV and NPV were respectively 78 %, 90 %, 78 % and 90 %, with a global accuracy of 86 %. FDG PET/CT was true positive in 14 patients with bacterial pneumonias (n = 4), pulmonary fungal infection (n = 1), histoplasmosis (n = 1), cutaneous abscess (n = 1), inflammatory disorder (sacroiliitis) (n = 1), lymphoma (n = 3) and NSCLC (n = 3). On the other hand, FDG PET/CT failed to detect lung bronchoalveolar adenocarcinoma, septicemia, endocarditis and graft-versus-host disease (GVHD), respectively, in four patients. FDG PET/CT contributed to adjusting the patient therapeutic strategy in 40 % of cases. FDG PET/CT emerges as a valuable technique to manage complications in the post-transplantation period. FDG PET/CT should be considered in patients with severe unexplained inflammatory syndrome or FUO and inconclusive conventional imaging or to discriminate active from silent lesions previously detected by conventional imaging particularly when malignancy is suspected.

Pulmonary mucormycosis (PM) is a life-threatening invasive mold infection. Diagnosis of mucormycosis is challenging and often delayed, resulting in higher mortality.

Little data is currently available in the literature on neutropenia and agranulocytosis in the elderly, and, to our knowledge, idiosyncratic drug-induced agranulocytosis is particularly poorly covered, or not at all. We herein describe the clinical picture and outcome of patients aged ≥75 years with established idiosyncratic drug-induced agranulocytosis. Data from 61 patients over 75 years old with idiosyncratic drug-induced agranulocytosis were retrospectively reviewed. All cases were extracted from a cohort study on agranulocytosis (n= 203) in the Strasbourg University Hospitals (Strasbourg, France), a referral center. The mean age was 84.9 years (range 75–95), the gender ratio (F/M) was 2.4. Underlying diseases were present in 74 %. The most frequent causative drugs were antibiotics (43.8 %), antithyroid drugs (15.8 %), neuroleptic and anti-epileptic agents (12.3 %), and antiaggregant platelet agents (10.5 %). The primary clinical features during hospitalization included isolated fever (27.6 %), septicemia or septic shock (24.1 %), and pneumonia (20.7 %). The mean neutrophil count at nadir was 0.15 × 109/L (range 0–0.4). All febrile patients were treated with broad-spectrum antibiotics and 36 with hematopoietic growth factors. Outcome was favorable in 85.3 % of patients; nine patients died. Two elderly patients (3.3 %) died of uncontrolled septic shock relating to the depth of the neutropenia. Comparison of mortality between <75- and ≥75-year-old patients revealed a statistical difference: 4.2 % versus 14.8 % (p= 0.023). Our study demonstrates that 30 % of idiosyncratic drug-induced agranulocytosis concerned elderly patients. Antibiotic, antithyroid, neuroleptic, anti-epileptic, and antiaggregant platelet agents are the primary causative drug classes. Idiosyncratic drug-induced agranulocytosis is typically serious in this frail population of elderly patients, with at least 50 % suffering from severe sepsis and with a mortality rate of approximately 15 %. Modern management of agranulocytosis may reduce the infection-related mortality (3.3 %).

Isavuconazole is a novel triazole with broad-spectrum antifungal activity. The SECURE trial assessed efficacy and safety of isavuconazole versus voriconazole in patients with invasive mould disease.

ABSTRACTThe monitoring and prediction of treatment responses to invasive aspergillosis (IA) are difficult. We determined whether serum galactomannan index (GMI) trends early in the course of disease may be useful in predicting eventual clinical outcomes. For the subjects recruited into the multicenter Global Aspergillosis Study, serial GMIs were measured at baseline and at weeks 1, 2, and 4 following antifungal treatment. Clinical response and survival at 12 weeks were the outcome measures. GMI trends were analyzed by using the generalized estimation equation approach. GMI cutoffs were evaluated by using receiver-operating curve analyses incorporating pre- and posttest probabilities. Of the 202 study patients diagnosed with IA, 71 (35.1%) had a baseline GMI of =0.5. Week 1 GMI was significantly lower for the eventual responders to treatment at week 12 than for the nonresponders (GMIs of 0.62 ± 0.12 and 1.15 ± 0.22, respectively; P= 0.035). A GMI reduction of >35% between baseline and week 1 predicted a probability of a satisfactory clinical response. For IA patients with pretreatment GMIs of <0.5 (n= 131; 64.9%), GMI ought to remain low during treatment, and a rising absolute GMI to >0.5 at week 2 despite antifungal treatment heralded a poor clinical outcome. Here, every 0.1-unit increase in the GMI between baseline and week 2 increased the likelihood of an unsatisfactory clinical response by 21.6% (P= 0.018). In summary, clinical outcomes may be anticipated by charting early GMI trends during the first 2 weeks of antifungal therapy. These findings have significant implications for the management of IA.

Chronic lymphocytic leukemia (CLL) is characterized by a highly variable clinical course with 2 extreme subsets: indolent, ZAP70−and mutated immunoglobulin heavy chain gene (M-CLL); and aggressive, ZAP70+and unmutated immunoglobulin heavy chain (UM-CLL). Given the long-term suspicion of antigenic stimulation as a primum movensin the disease, the role of the B-cell receptor has been extensively studied in various experimental settings; albeit scarcely in a comparative dynamic proteomic approach. Here we use a quantitative 2-dimensional fluorescence difference gel electrophoresis technology to compare 48 proteomic profiles of the 2 CLL subsets before and after anti-IgM ligation. Differentially expressed proteins were subsequently identified by mass spectrometry. We show that unstimulated M- and UM-CLL cells display distinct proteomic profiles. Furthermore, anti-IgM stimulation induces a specific proteomic response, more pronounced in the more aggressive CLL. Statistical analyses demonstrate several significant protein variations according to stimulation conditions. Finally, we identify an intermediate form of M-CLL cells, with an indolent profile (ZAP70−) but sharing aggressive proteomic profiles alike UM-CLL cells. Collectively, this first quantitative and dynamic proteome analysis of CLL further dissects the complex molecular pathway after B-cell receptor stimulation and depicts distinct proteomic profiles, which could lead to novel molecular stratification of the disease.

L’éducation thérapeutique du patient est un élément important de la prise en charge médicale. L’objectif de notre étude était d’estimer son impact clinique potentiel chez les patients traités par des médicaments anticancéreux. Pour cela, nous avons relié la survenue d’un effet indésirable ayant entraîné un appel au médecin, une consultation et/ou une hospitalisation, à un défaut de compliance des traitements de support, une automédication à risque d’interaction avec le traitement anticancéreux et/ou un comportement à risque (exposition aux UVs, absence de contraception, conduite de véhicules) potentiellement imputables à un défaut d’éducation thérapeutique. Cent-un patients adultes traités par chimiothérapie en hôpital de jour ont été inclus (âge moyen : 60 ans ; extrêmes : 24-88). Notre étude révèle que 21 % (14/67) des patients ayant un traitement de support à prendre lors du retour à domicile ne le prennent que partiellement ou pas du tout, 60 % (60/101) pratiquent l’automédication (une contre-indication absolue identifiée chez un patient) et 14 % (14/101) affirment n’avoir reçu aucun conseil sur les comportements à risque. La survenue d’un effet indésirable est évoquée par 83 % (83/101) des patients. Ainsi, 11 % (44/397) des effets indésirables, 12 % (4/33) des appels au médecin, 6 % (1/17) des consultations et 21 % (3/14) des hospitalisations suite à un effet indésirable ont pu être reliés à un défaut d’éducation thérapeutique. Ces données soulignent l’importance de l’éducation thérapeutique du patient en onco-hématologie.

ABSTRACTThe outcomes for 73 invasive fusariosis patients treated with voriconazole were investigated. Patients with proven (n= 67) or probable (n= 6) infections were identified from the voriconazole clinical database (n= 39) and the French National Reference Center for Mycoses and Antifungals database (n= 34). Investigator-determined success was a complete or partial response. Survival was determined from day 1 of voriconazole therapy to the last day known alive. Patients were 2 to 79 years old (median, 43 years), and 66% were male. Identified Fusariumspecies (62%) were F. solani, F. moniliforme, F. proliferatum, and F. oxysporum. Underlying conditions analyzed included hematopoietic stem cell transplant (HSCT; 18%), hematologic malignancy (HM; 60%), chronic immunosuppression (CI; 12%), or other condition (OC; 10%). Infection sites were brain (5%), disseminated excluding brain (67%), lungs/sinus (15%), and other (12%). Most patients (64%) were or had recently been neutropenic (<500 cells/mm3). Therapy duration was 1 to 480 days (median, 57 days), with a 47% success rate. Baseline neutropenia impacted success adversely (P≤ 0.03). Success varied by underlying condition (HSCT, 38%; HM, 45%; CI, 44%; OC, 71%) and infection site (brain, 0%; disseminated, 45%; other, 56%; lung/sinus, 64%) (P> 0.05). Combination therapy (13 patients) was no better than treatment with voriconazole alone. Overall, 59% of the patients died (49% died of fusariosis), and 90-day survival was 42%. Site of infection influenced survival (P= 0.02). Median survival (in days) by species was as follows: F. solani, 213; F. oxysporum, 112; Fusariumspp., 101; F. proliferatum, 84; F. moniliforme, 76. We conclude that voriconazole is a therapeutic option for invasive fusariosis.

Drug interactions occur frequently with triazole antifungal agents because of their properties as inhibitors of 1 or more phase 1 (cytochrome P450) biotransformation enzymes and, possibly, as inhibitors or substrates of a phase 2 biotransformation enzyme or transporter protein. Multimorbid patients, including those with hematologic malignancies or other cancers, hematopoietic stem cell or organ transplant recipients, patients infected with the human immunodeficiency virus, and those in the intensive care unit, are at increased risk for drug interactions because they typically require several concomitant medications. They may also be extremely vulnerable to the clinical signs and symptoms of drug interactions. This review describes clinically significant drug interactions most frequently seen in multimorbid patients who receive systemic therapy with triazole antifungals for the prophylaxis or treatment of invasive fungal infections; including interactions with corticosteroids, immunosuppressants, anti-infective drugs, benzodiazepines, opioid analgesics, statins, anticoagulants, anticonvulsants, and drugs affecting gastric pH. The review also describes recommendations concerning contraindications and dose-modification strategies. The azoles differ markedly in their pharmacokinetic and antifungal properties, safety and tolerability, and drug-interaction profiles. Many drug interactions can be prevented if clinicians are thoroughly familiar with the pharmacokinetic profiles of different azoles, follow contraindications and dose-modification recommendations, and switch azoles when possible to achieve the best combination of clinical efficacy and safety. Therapeutic drug monitoring can help optimize treatment and prevent underdosing or overdosing of drugs. Education of patients and their families about signs and symptoms of possible drug interactions is also beneficial.

Introduction: B-cell immunophenotype could be swiftly assessed by flow cytometry on blood samples or bone marrow aspirate specimens. It provides crucial information later refined with histologic, genetic and molecular features to assert accurate diagnosis of chronic B-cell lymphoproliferative disorders (B-CLPD). Besides Matutes score we identified additional useful markers, i.e. CD148 and CD180 to classify mantle cell lymphoma (MCL) and marginal zone lymphoma (MZL), respectively. Furthermore, CD200 is known to be highly expressed in chronic lymphoid leukemia (CLL) while absent in MCL.

[18F]fluoro-2-deoxy-D-glucose (FDG) positron emission tomography/computed tomography is a widely developed method that allows not only accurate staging of cancers but also prognostic information in order to lead antimitotic modalities. Among primitive uterine malignant tumors, non-Hodgkin lymphoma (NHL) is rare. Herein, we report the case of a 61-year-old woman with uterine NHL whose diagnostic and therapeutic approaches were essentially managed by [18F]FDG imaging. Because of a high sensitivity from major glucidic uptake in aggressive NHL lesions, [18F]FDG positron emission tomography/computed tomography easily showed the exact extension of disease and its metabolic status early after beginning chemotherapy.

The accurate diagnosis of the different forms of chronic mature B-cell lymphocytic malignancies is of primary importance to determine an appropriate and efficient treatment. Usually, the diagnosis is achieved by morphology and immunophenotyping. Nevertheless, the diagnostic tools available are not able to discriminate pathologies with variable evolution, or to classify some of them. To discover new biomarkers, we used peptide and protein profiling SELDI-TOF−MS, to analyze 39 chronic B-cell malignancies and 20 control serum samples. Markers of interest were subsequently identified and characterized. In the obtained SELDI−MS profiles, most of the differences were observed in three mass ranges (m/z 13 000; m/z 9000; m/z< 2000). Identification of these biomarkers was achieved either by direct enrichment on the ProteinChip arrays followed by on-chip-MS/MS or by chromatographic fractionation, 1D-gel followed by nanoLC−MS/MS analysis. An increase of a sulfite form of transthyretin (13 841 Da) was observed in the patient group. A second set of markers at 8.6 and 8.9 kDa was identified as complement related fragment proteins, the C3a and C4a anaphylatoxins. In the low mass range, several peptides originating from N-terminal and C-terminal processing of the C3 alpha and C4 alpha chains were specifically observed in 38% of the patient sera, but in none of the control sera. This study emphasizes the usefulness of mass spectrometry studies in such malignancies.

Les formulations lipidiques de l’amphotéricine B sont au nombre de trois : l’amphotéricine B en dispersion colloïdale, l’amphotéricine B en complexe lipidique et l’amphotéricine B liposomale. Ces trois formulations diffèrent par leur composition en lipides et, en conséquence, par leurs caractéristiques physiques et pharmacocinétiques, leur efficacité et leur tolérance. Les études cliniques ont montré de façon générale une amélioration de la tolérance comparativement à l’amphotéricine B désoxycholate, en particulier sur le plan rénal. Cependant si la néphrotoxicité est moindre elle n’est pas nulle. Peu d’études randomisées ont été réalisées avec ces formulations lipidiques. Aucune d’entre elles ne démontre de façon convaincante la supériorité en terme efficacité d’une des formulations lipidiques par rapport à l’amphotéricine B désoxycholate. Récemment une étude en double aveugle, comparant dose standard d’amphotéricine B liposomale (3 mg/kg/j) et dose de charge (10 mg/kg/j pendant 14 jours) relayée par la dose standard, a démontré sans ambiguïté un taux de réponse de 50 % en fin de traitement randomisé et une survie de 72 % à trois mois dans le traitement de première ligne des infections à champignons filamenteux, principalement aspergillaires. Les résultats étaient numériquement inférieurs dans le bras à 10 mg/kg mais la différence n’est pas significative. L’absence de bénéfice d’une haute dose d’amphotéricine B liposomale dans les aspergilloses ne peut cependant pas être extrapolée aux autres infections à champignons filamenteux. La néphrotoxicité de la dose de charge était notablement plus marquée et contre-indique son utilisation en pratique clinique.

B-cell posttransplantation lymphoproliferative disorder (B-PTLD) is a rare but severe complication of transplantation, with no consensus on best treatment practice. This prospective trial, the first to test a treatment for PTLD, was designed to evaluate the efficacy and safety of rituximab in patients with B-PTLD after solid organ transplantation (SOT). Fortysix patients were included and 43 patients were analyzed. Patients were eligible if they had untreated B-PTLD that was not responding to tapering of immunosuppression. Treatment consisted of 4 weekly injections of rituximab at 375 mg/m2. At day (d) 80, 37 (86%) patients were alive, and the response rate was 44.2%, including 12 complete response/unconfirmed complete response (CR/CRu). The only factor predictive of a response at d80 was a normal lactate dehydrogenase level (P = .007, odds ratio [OR] = 6.9). At d360, responses were maintained in 68% of patients, and 56% of patients were alive. The overall survival rate at 1 year was 67%. We conclude that rituximab is effective and safe in PTLD, with stable responses at 1 year. The response rate and overall survival might be improved by combining rituximab with other treatments.

ABSTRACTWe assessed the activity and safety of liposomal nystatin, a broad-spectrum antifungal agent, for invasive aspergillosis in patients refractory to or intolerant of amphotericin B. Thirty-three patients were enrolled, received at least one dose of the study drug, and were evaluable for safety. Twenty-six patients had confirmed probable or definite aspergillosis and were fully eligible. Most patients had a hematological malignancy (53.8%) or hematopoietic stem cell transplantation (23.0%), were neutropenic (61.5%), and were refractory to previous amphotericin B (92.3%). The median duration of previous amphotericin B treatment was 16.5 days (range, 5 to 64 days). Aspergillosis was definite in 3 cases and probable in 23 cases. Liposomal nystatin was initiated at a dose of 4 mg/kg of body weight/day. Twenty-five patients were evaluable for response: a complete response was achieved for one patient, and a partial response was achieved for six. Thus, the overall response rate is 7 of 25 (28%; 95% confidence interval, 12 to 49%). Seventeen (68.0%) of the 25 evaluable patients died during therapy or within 1 month after the end of therapy. The primary cause of death was invasive aspergillosis for nine patients and underlying malignancy for eight patients. The most frequent side effects included chills, shivering, and fever, leading to discontinuation of therapy for two patients. Grade 1 decline in renal function was seen for 10 (30.3%) patients, and hypokalemia was seen for 13 (39.4%). We conclude that liposomal nystatin can be effective for salvage therapy of invasive aspergillosis. Infusion-related adverse events have been observed frequently.

The new triazole antifungal, voriconazole (Vfend®, Pfizer Ltd), was developed for the treatment of life-threatening fungal infections in immunocompromised patients. The drug, which is available for both oral and intravenous administration, has broad-spectrum activity against pathogenic yeasts, dimorphic fungi and opportunistic moulds. Unlike fluconazole (Diflucan®, Pfizer Ltd), voriconazole has potent in vitro activity against Aspergillus spp., Fusarium spp. and Scedosporium apiospermum. In Phase II/III trials, voriconazole was well-tolerated and had excellent clinical efficacy in patients with fluconazole-sensitive and -resistant candida infection, aspergillosis, and various refractory fungal infections. The US Food and Drug Administration approved voriconazole in May 2002 for the treatment of invasive aspergillosis, and serious infections caused by Fusarium and S. apiospermum in patients who are intolerant of, or refractory to, other antifungal agents. In Europe, voriconazole is approved by the European Medicines Agency for the treatment of invasive aspergillosis, serious infections caused by Fusarium and S. apiospermum, and fluconazole-resistant serious invasive candida infections (including C. krusei).

Invasive pulmonary aspergillosis (IPA) is the most common fungal pulmonary infection in severely immunocompromised patients. Aspergillus species are commonly isolated from the soil, plant debris, and the indoor environment, including the hospital. Phagocytosis is the main host defense against Aspergillus conidia and hyphae. The diagnosis of IPA is based on clinical, radiological, and mycological data. Clinical signs have a low specificity. The most typical computed tomographic (CT) findings are nodules with or without the halo sign or the air crescent sign. Sensitivity of microscopy and culture of noninvasive collected samples is low. Galactomannan and nucleic acid detection in serum or in bronchoalveolar lavage (BAL) fluid help to confirm the diagnosis. Crude mortality is high and strongly correlated with the underlying condition, stage of the underlying disease, and extension of the aspergillosis. Optimal therapeutic strategies include the prevention of contamination in patients at high risk, early initiation of antifungal therapy, surgery in some instances, and, importantly, treatment of the underlying condition to restore whenever possible a certain degree of immunocompetence. Voriconazole has demonstrated better efficacy and safety than amphotericin B deoxycholate. The improved survival observed with voriconazole makes it a new reference for the first-line therapy of IA. Lipid formulations of amphotericin B, caspofungin, micafungin, and posaconazole are other therapeutic options in the event of failure of or contraindication to voriconazole. The main indication for surgery is prevention of severe hemoptysis when the lesion is adjacent to a large vessel.

We conducted a randomized trial to compare the intensive conventional chemotherapy regimen ACVBP (doxorubicin, cyclophosphamide, vindesine, bleomycin, prednisone) with standard CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) in previously untreated patients with poor-risk aggressive lymphoma. Patients aged 61 to 69 years who had aggressive non-Hodgkin lymphoma with at least one prognostic factor of the age-adjusted international prognostic index (IPI) were included. ACVBP consisted of an induction phase of intensified chemotherapy and central nervous system (CNS) prophylaxis followed by a sequential consolidation phase. Of the 708 patients registered for the study, 635 were eligible. The rate of complete response was 58% in the ACVBP group and 56% in the CHOP group (P = .5). Treatment-related death occurred in 13% of the ACVBP group and 7% of the CHOP group (P = .014). At 5 years, the event-free survival was 39% in the ACVBP group and 29% in the CHOP group (P = .005). The overall survival was significantly longer for patients treated with ACVBP, at 5 years it was 46% compared with 38% for patients treated with CHOP (P = .036). CNS progressions or relapses were more frequent in the CHOP group (P = .004). Despite higher toxicity, the ACVBP regimen, used as first-line treatment for patients with poor-risk aggressive lymphoma, is superior to standard CHOP with regard to both event-free survival and overall survival. (Blood. 2003;102:4284-4289)

Amphotericin B spectrum covers most of the fungal pathogens involved in human diseases. Its use is limited by infusion-related effects and nephrotoxicity. As a result of strong lipophilic properties, encapsulation in liposomes or binding to lipid complexes led to the development of lipid formulations in an attempt to increase both efficacy and safety. Three lipid formulations of amphotericin B are commercially available: a liposomal preparation, a lipid complex and a colloidal dispersion. They differ in their lipid composition, shape, pharmacokinetic behaviour and clinical effects. The nephrotoxicity of these formulations is significantly decreased compared to their parent compound. Infusion-related events are lowest with liposomal amphotericin B. Increased efficacy of the lipid formulations over conventional amphotericin B, however, still has to be demonstrated. These formulations are mainly indicated for the treatment of documented fungal infections in patients failing conventional amphotericin B or with renal impairment. Liposomal amphotericin B is also indicated for empirical therapy of suspected fungal infections in febrile neutropenic patients giving this compound an advantage over the two other formulations. Lipid formulations of amphotericin B are extremely expensive. Whether the increase in cost translates into a long-term benefit for the patient is still unknown.

Twenty three patients with relapsing (n = 11) or refractory (n = 12) non-Hodgkin's lymphoma (NHL) to one or two prior anthracycline based combination chemotherapy regimens were treated as second or third line regimen with 3 induction cycles of Idarubicin (IDA) (7 mg/m2/d IV dl-d3) and high dose cytarabine (HD Ara-C) (1 g/m2/12 h IV dl-d3), each cycle was repeated every 3 weeks. Responding patients received a maintenance therapy with monthly cycles of IDA : 15 mg/m2dl-d3, Etoposide 100 mg/m2dl-d3, both by oral route. Twenty two patients are evaluable and we observed 13 CR and 1 PR with an overall response rate of 61 % (14/23; 95% Cl = 38.5% 80.3%). The median time to progression was 32 months (6.5 - 63 + m.). The response rate to IDA-HD Ara C was not different for patients with (n = 14) or without (n = 9) objective response to the last prior therapy. The main toxicity was hematological: all patients experienced grade 4 neutropenia and 22 patients had grade 4 thrombopenia, but there were no toxic deaths. IDA and HD-Ara-C combination is highly effective in refractory or relapsed NHL. As hematological toxicity was the limiting factor for further escalation of dose-intensity, further studies might include hematopoietic growth factors support in the therapeutic scheme.

The purpose of this study was to, assess the efficacy of glycosylated recombinant human granulocyte colony-stimulating factor (lenograstim) in the prevention of neutropenia and infection in patients receiving dose-intensive chemotherapy for non-Hodgkin's lymphoma (NHL). A second objective was to determine clinical predicators of delay to cytotoxic chemotherapy administration. One hundred-sixty two patients with intermediate- or high-grade NHL and at least one poor prognostic factor received a total of 4 cycles of the LNH-84 regimen every 2 weeks, with an open randomization to treatment with anthracyclines. Patients were randomized to receive subcutaneous lenograstim 5 μg/kg/day (n = 82) or placebo (n = 80) from day 6 to day 13 of each cycle.The incidence of severe neutropenia (absolute neutrophil count (ANC) < 0.5 × 109/L) was reduced in the lenograstim group compared with placebo (52% vs 75%). A significant reduction (p < 0.001) in the median duration of ANC < 0.5 × 109/L was also observed in patients treated with lenograstim during each cycle of chemotherapy (0-1 day vs 2-4 days in placebo recipients). Fever occurred in 66 patients in each treatment group. Thirty-four percent of placebo recipients had documented infections during ANC < 1.0 × 109/L compared with 18.5% of lenograstim-treated patients (p < 0.05). Infections of ≥grade 2 severity were significantly less frequent (p = 0.001) among lenograstim recipients compared with placebo (25 vs 49). The most common adverse events among lenograstim recipients were headache, mild bone pain and injection site reactions. Although lenograstim significantly increased (p = 0.0001) relative dose intensity compared with placebo (93% vs 80%), no difference in CR rate (67% vs 71%) or 3-year survival (63% vs 55%) was observed.The results of this study suggest that patients treated with a chemotherapy regimen that induces severe neutropenia can benefit from treatment with lenograstim. Furthermore, lenograstim permits treatment to be delivered at full dose intensity at 2 week intervals, even in patients with bone marrow involvement, and may permit further dose escalation of the chemotherapeutic regimen used.

ABSTRACTTrichosporon mycotoxinivoransis a novel pathogen recently found in cystic fibrosis patients. We report the first case of a disseminated fatal infection with T. mycotoxinivoransassociated with invasive Aspergillus fumigatusand Scedosporium apiospermuminfection after lung and liver transplantation in a cystic fibrosis patient.

No relevant conflicts of interest to declare.

ABSTRACTWe report the first case of proven disseminated infection due to Fusarium dimerumassociated with a favorable outcome in a patient with acute leukemia and prolonged neutropenia. The patient presented persistent fever, multiple necrotic skin lesions, and bilateral pneumopathy. F. dimerumwas first isolated from three blood cultures and then from a skin biopsy and a mouth wash. Microscopy of positive blood cultures showed hyphae with phialides and few curved unicellular and some rare bicellular phialoconidia, permitting immediate presumptive identification of the genus Fusarium. The patient failed to respond to conventional amphotericin B but recovered after treatment was switched to amphotericin B-lipid complex and neutrophil recovery.

ABSTRACTWe report the first case of fungemia due to Candida catenulata, a contaminant of dairy products. C. catenulatawas isolated from three blood cultures of a patient with gastric cancer. The patient failed to respond to fluconazole but recovered after treatment was switched to amphotericin B. In vitro,C. catenulatawas susceptible to amphotericin B and itraconazole and was also susceptible to fluconazole in dose-dependent manner. The likely portal of entry was the digestive tract, as the patient often ate cheese and had multiple gastric ulcerations.

A mass spectrometry (MS) method that detects a serum disaccharide (DS) (MS-DS) was recently described for the diagnosis of invasive fungal infections (IFI). We carried out a European collaborative study to evaluate this assay.

No relevant conflicts of interest to declare.

Les infections par le flavivirus de la méningo-encéphalite à tiques (Tick-Borne encephalitis [TBE]), provoquent habituellement une atteinte isolée du système nerveux central. Nous rapportons un cas de neuronopathie motrice associée.

Introduction

Introduction:

Shi: Mayo Clinic: Employment. Flowers:Millenium/Takeda: Research Funding; TG Therapeutics: Research Funding; Pharmacyclics, LLC, an AbbVie Company: Research Funding; Gilead: Consultancy, Research Funding; NIH: Research Funding; Mayo Clinic: Research Funding; ECOG: Research Funding; Acerta: Research Funding; Infinity: Research Funding; AbbVie: Research Funding; Roche: Consultancy, Research Funding; Genentech: Consultancy, Research Funding. Ou:Mayo Clinic: Employment. Cunningham:Merrimack: Research Funding; Celgene: Research Funding; Bayer: Research Funding; Astra-Zeneca: Research Funding; Amgen: Research Funding; Medimmune: Research Funding. Pfreundschuh:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Spectrum: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Seymour:AbbVie Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Jaeger:Roche: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Haioun:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sandoz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Ghesquieres:Mundipharma: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche France: Research Funding. Merli:Teva Pharmaceuticals Industries: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Herbrecht:Cell Therapeutics, Inc: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees. Flament:Celgene: Employment, Equity Ownership. Fu:Celgene: Employment, Equity Ownership. Coiffier:MorphoSys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Sargent:Celgene: Research Funding.

Shi: Mayo Clinic: Employment. Cunningham:Amgen: Research Funding; Astra-Zeneca: Research Funding; Bayer: Research Funding; Celgene: Research Funding; Merrimack: Research Funding; Medimmune: Research Funding. Seymour:AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Jaeger:Roche: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Haioun:Sandoz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Ghesquieres:Mundipharma: Consultancy; Roche France: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Merli:Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Teva Pharmaceuticals Industries: Membership on an entity's Board of Directors or advisory committees. Herbrecht:Servier: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Cell Therapeutics, Inc: Membership on an entity's Board of Directors or advisory committees. Flament:Celgene: Employment, Equity Ownership. Fu:Celgene: Employment, Equity Ownership. Flowers:Gilead: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Acerta: Research Funding; ECOG: Research Funding; Mayo Clinic: Research Funding; Pharmacyclics, LLC, an AbbVie Company: Research Funding; Millenium/Takeda: Research Funding; Infinity: Research Funding; TG Therapeutics: Research Funding; Genentech: Consultancy, Research Funding; NIH: Research Funding; AbbVie: Research Funding. Ou:Mayo Clinic: Employment. Sargent:Celgene: Research Funding. Coiffier:MorphoSys: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees.

No relevant conflicts of interest to declare.

No relevant conflicts of interest to declare.

Acquired auto-immune TTP due to ADAMTS13 deficiency is a rare microangiopathy (∼ 4 /106 persons/yr). Untreated, mortality is > 90%, but with therapeutic plasma exchange (TPE) remission rates are ∼ 80%, and mortality is < 20%. TPE requires large volumes of fresh frozen plasma (FFP) with risk of transfusion-transmitted infection (TTI). Pathogen inactivation (PI) of plasma with Amotosalen-UVA (INTERCEPT Blood System™ for Plasma (IFFP)1, Cerus, Concord, CA) may mitigate TTI risk. Universal implementation of IFFP by the Établissement Français du Sang Alsace (EFS-Alsace) in 9/2007 to replace quarantine plasma (QFFP) provided an expanded experience of routine use with IFFP for TPE of TTP. Aims: The objective was to compare the efficacy and safety of IFFP to QFFP for acquired immune TTP. Methods: A retrospective, 2-period cohort study was conducted. EFS Alsace is the sole provider of FFP to regional TTP treatment centers, and administers an active hemovigilance program to assess patient outcomes. All patients with suspected TTP with pre-treatment ADAMTS13 data from 1/1998 to 3/2013 were reviewed, and patients with the following pre-treatment diagnostic criteria were included: platelet count < 100 x 109/L, microangiopathic hemolytic anemia, serum creatinine < 354 µmol/L, ADAMTS13 activity < 10% without non-immune TTP. Primary care medical records, including all available ECG recordings, and TPE records were reviewed for data extraction. ECG recordings were interpreted by an external cardiology consultant without knowledge of type of plasma administered. The primary efficacy outcome was the % of patients in remission 30 days after initiation of TPE. Secondary measures included the % in remission at day 60, days to remission (d), number of TPEs, volume of plasma used, and frequency of relapse. The primary safety measure was the % of patients with treatment related serious adverse events (SAE) in the Cardiac System Organ Class (SOC). Secondary safety outcomes were: proportion of days with Grade 3 or 4 hypokalemia and mortality. Median values were presented for continuous variables. Results: 49 patients were screened and 31 qualified for review (Cohort 1: QFFP=13; Cohort 2: IFFP=18). Baseline demographics and disease severity between cohorts were comparable. More IFFP patients (72.2%) than QFFP patients (38.5%) had paired pre- and post-TPE electrocardiograms (ECGs). The proportions of patients with abnormal ECGs prior to treatment were substantial (IFFP = 55.6%, QFFP = 53.8%). Frequencies of ECG abnormalities in descending order were: non-specific T wave changes, sinus tachycardia, short PR, ST depression, and atrial fibrillation. Greater than 90% of patients received steroid therapy and some received rituximab (IFFP = 38.9%, QFFP = 23.1%). IFFP was comparable to QFFP for efficacy outcomes, but median days (d) to remission were significantly shorter for IFFP (Table 1). After initiation of TPE, substantial proportions of patients in each cohort exhibited abnormal ECGs (IFFP = 66.7%, QFFP=46.2%). Frequencies of treatment emergent ECG abnormalities in descending order were: non-specific T wave changes, sinus tachycardia, flat T wave, QT interval changes, and short PR. The frequencies of cardiac adverse events, hypokalemia, and mortality were not different between the cohorts (Table 2). Conclusions: In patients with auto-immune TTP, ECG abnormalities were frequent prior to TPE, and during therapy in both cohorts. In this retrospective cohort study over 15 years, IFFP demonstrated comparable efficacy and safety to QFFP for TPE of acquired auto-immune TTP. 1Not approved in U.S.Herbrecht: Cerus Corporation: Research Funding. Ojeda-Uribe:Cerus Corporation: Research Funding. Remy:Cerus Corporation: Research Funding. Ernst:Cerus Corporation: Employment, Equity Ownership. Corash:Cerus Corporation: Employment, Equity Ownership. Cazenave:Cerus Corporation: Research Funding.

Patients with mantle cell lymphoma (MCL) typically respond to initial therapy and almost inevitably relapse with frequent chemoresistance over time and poor outcome. Multiple phase II studies have established the efficacy and safety of lenalidomide, an immunomodulatory agent with tumoricidal and antiproliferative properties, in relapsed/refractory MCL. The prospective phase II multicenter MCL-001 “EMERGE” study led to FDA approval of lenalidomide for patients with relapsed/refractory MCL after 2 prior treatments, that included bortezomib. The activity of lenalidomide was seen regardless of MIPI, number of prior therapies, prior high dose therapy, bulky disease or high tumor burden. One of the most established prognostic factors in MCL is the proliferation index Ki67 (MIB1), now confirmed both in standard and dose-intensive high-dose therapy strategies. We present here longer follow-up of efficacy and safety from the MCL-001 study in patients relapsed/refractory to bortezomib and the potential relationship between Ki-67 and efficacy outcomes.Patients with heavily pretreated MCL, that included prior bortezomib, received lenalidomide 25 mg/day PO, days 1-21 in 28-day cycles until disease progression or intolerability. Primary study endpoints were overall response rate (ORR) and duration of response (DOR); secondary endpoints included complete response (CR), time to response (TTR), progression-free survival (PFS), overall survival (OS), and safety. Response rates and time-to-event data were analyzed by independent central reviewers per modified IWG criteria and Kaplan-Meier estimates respectively (data cut-off March 20, 2013). Ki-67 was examined as an exploratory endpoint by immunohistochemistry for 81/134 patients (60%) either performed on biopsy samples for 24 patients, or based on the Ki-67 scores reported in local pathology reports for 57 patients.Median age for the enrolled intent-to-treat patient population (N=134) was 67 years (range, 43-83; 63% ≥65 years). The median number of previous therapies was 4 (range, 2-10; 78% received ≥3), 93% stage III/IV, and 72% were <6 months from last prior treatment. At a median follow-up of 13.2 months, the ORR was 28% (CR/CRu 8%), with a median DOR of 16.6 months (95% CI, 9.2-26.7; median not reached in patients with CR/CRu) by central review. Median TTR was 2.3 months (95% CI, 1.7-13.1), with a median time to CR/CRu of 4.1 months (95% CI, 1.9-13.2). Median PFS was 4.0 months (95% CI, 3.6-6.9), and median OS was 20.9 months (95% CI, 13.7-24.4). The average dose intensity of lenalidomide was 20 mg/day, for a median duration of 94.5 days (range, 1-1,256). Dose reductions or interruptions due to adverse events (AEs) occurred in 40% and 58% of patients, respectively. Neutropenia (44%), thrombocytopenia (28%), and anemia (11%) were the most common treatment-related grade 3/4 AEs. Ki-67 results were available in 81/134 patients, and efficacy data were categorized using 30% and 50% cut-off thresholds for Ki-67 expression (Table 1). Although patient numbers were limited, the ORR was similar in both lower and higher Ki-67 group, but those with lower Ki-67 levels demonstrated better CR rates, DOR and survival outcomes compared with patients with elevated Ki-67.Single-agent lenalidomide in heavily pretreated patients with relapsed/refractory MCL post-bortezomib showed durable long-term efficacy with a consistent safety profile. Consistent with what is reported in the literature, high Ki-67 is associated with poor outcome in our cohort with shorter OS. Though based on retrospective evaluation and subsets of patients, the ORR to lenalidomide was similar in both low and high Ki-67 groups, suggesting lenalidomide can be active in patients expressing high levels of Ki67. Prospective studies are needed to confirm these findings.Goy: Celgene: Consultancy, Research Funding, Speakers Bureau. Off Label Use: This is a phase 2 clinical study of safety and efficacy for lenalidomide in patients with MCL. Williams:Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Drach:Celgene: Honoraria. Ramchandren:Celgene: Research Funding. Zhang:Celgene: Employment. Cicero:Celgene: Employment. Fu:Celgene: Employment. Heise:Celgene: Employment, Equity Ownership. Witzig:Celgene: Research Funding.