Search

Mycobacterial infections, both tuberculosis and nontuberculous, are more common in patients with haematological malignancies and haematopoietic stem cell transplant recipients than in the general population-although these infections remain rare. Mycobacterial infections pose both diagnostic and therapeutic challenges. The management of mycobacterial infections is particularly complicated for patients in haematology because of the many drug-drug interactions between antimycobacterial drugs and haematological and immunosuppressive treatments. The management of mycobacterial infections must also consider the effect of delaying haematological management. We surveyed the management practices for latent tuberculosis infection (LTBI) in haematology centres in Europe. We then conducted a meticulous review of the literature on the epidemiology, diagnosis, and management of LTBI, tuberculosis, and nontuberculous mycobacterial infections among patients in haematology, and we formulated clinical guidelines according to standardised European Conference on Infections in Leukaemia (ECIL) methods. In this Review, we summarise the available literature and the recommendations of ECIL 8 for managing mycobacterial infections in patients with haematological malignancies.

Although mutation profiling of defined genes is recommended for classification of acute myeloid leukemia (AML) patients, screening of targeted gene panels using next-generation sequencing (NGS) is not always routinely used as standard of care. The objective of this study was to prospectively assess whether extended molecular monitoring using NGS adds clinical value for risk assessment in real-world AML patients. We analyzed a cohort of 268 newly diagnosed AML patients. We compared the prognostic stratification of our study population according to the European LeukemiaNet recommendations, before and after the incorporation of the extended mutational profile information obtained by NGS. Without access to NGS data, 63 patients (23%) failed to be stratified into risk groups. After NGS data, only 27 patients (10%) failed risk stratification. Another 33 patients were re-classified as adverse-risk patients once the NGS data was incorporated. In total, access to NGS data refined risk assessment for 62 patients (23%). We further compared clinical outcomes with prognostic stratification, and observed unexpected outcomes associated with FLT3 mutations. In conclusion, this study demonstrates the prognostic utility of screening AML patients for multiple gene mutations by NGS and underscores the need for further studies to refine the current risk classification criteria. info:eu-repo/semantics/publishedVersion

Objectives: We present here data on Gram-negative rods bacteremia (GNRB) rates, risk factors and associated mortality. Methods: Data on GNRB episodes were prospectively collected in 65 allo-/67 auto-HSCT centers in 24 countries (Europe, Asia, Australia). In patients with and without GNRB, we compared: demography, underlying disease, HSCT-related data, center' fluoroquinolone prophylaxis (FQP) policy and accreditation status, and involvement of infection control team (ICT). Results: The GNRB cumulative incidence among 2818 allo-HSCT was: pre-engraftment (pre-eng-alloHSCT), 8.4 (95% CI 7-9%), post-engraftment (post-eng-allo-HSCT), 5.8% (95%CI: 5-7%); among 3152 auto-HSCT, pre-eng-auto-HSCT, 6.6% (95%CI: 6-7%), post-eng-auto-HSCT, 0.7% (95%CI: 0.4-1.1%). GNRB, especially MDR, was associated with increased mortality. Multivariate analysis revealed the following GNRB risk factors: (a) pre-eng-allo-HSCT: south-eastern Europe center location, underlying diseases not at complete remission, and cord blood source; (b) post-eng-allo-HSCT: center location not in northwestern Europe; underlying non-malignant disease, not providing FQP and never accredited. (c) pre-eng-auto-HSCT: older age, autoimmune and malignant (vs. plasma cell) disease, and ICT absence. Conclusions: Benefit of FQP should be explored in prospective studies. Increased GNRB risk in auto-HSCT patients transplanted for autoimmune diseases is worrying. Infection control and being accredited are possibly protective against bacteremia. GNRB are associated with increased mortality. (C) 2020 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

The purpose of this study was to analyze the results of second autologous hematopoietic stem cell transplantation (ASCT2) for patients with relapsed/refractory Hodgkin lymphoma (HL) after a first transplantation (ASCT1). Outcomes for 56 patients receiving an ASCT2 registered in the EBMT database were analyzed. The 4-year cumulative incidences of non-relapse mortality and disease relapse/progression were 5% and 67%, respectively. The 4-year overall survival (OS) and progression-free survival (PFS) were 62% and 28%. In univariate analysis, relapse of HL within 12 months of ASCT1 was associated with a worse OS (35% versus 76%

The Philadelphia chromosome (Ph; t(9;22)(q34;q11)) and the associated BCR-ABL1 gene are unique markers for chronic myeloid leukemia (CML). The chimeric gene is remarkably homogenous in CML, as nearly all patients express the P210BCRABL1 protein originated, in the majority of cases, by the e14a2 or

Introduction. Mutations in genes encoding the metabolic enzymes isocitrate dehydrogenase (IDH) 1 and 2 are found in 10-20% of patients with acute myeloid leukemia (AML). Recently, IDH inhibitors have shown good clinical response in patient's refractory to standard treatments, providing evidence for a new treatment paradigm. Comprehensive real-world studies are needed to explore genotype-to-phenotype correlations and prognosis of IDH mutated AML, which may influence targeted treatment strategies. Patients. From a retrospective, European, real-word population (ClinicalTrials.gov Identifier: NCT04369287) we studied 477 IDH mutated patients and 954 IDH wild type patients matched for age, sex and type of treatment with a 1:2 ratio. Results. Median age of IDH mutated patients was 67 years; IDH1 mutations were found in 202 patients (89% carried R132 mutation), while IDH2 mutations were found in 275 cases (51% and 28% carried R140 and R172 mutations, respectively). At diagnosis, IDH mutated patients had lower neutrophil and higher platelet count and higher percentage of marrow blasts (P Considering cytogenetic risk according to ELN criteria, the great majority of IDH1 and IDH2 mutated patients had an intermediate cytogenetic risk (84% and 86%, respectively, P We then analysed the most common co-mutational patterns in IDH mutated patients. A total of 53% of IDH1 mutated patients carried NPM1 mutations (without FLT3 mutations), while the majority of IDH2 mutated patients had wild type NPM1 gene (P Median overall survival from diagnosis (OS) was 14 months for IDH1 mutated patients, 23 for IDH2 mutated patients and 19 for IDH wild type patients (P IDH mutated patients receiving hypomethylating agents (n=211) had a lower response rate vs. wild type patients (56% vs. 36% of treatment failure, respectively, P=.04), while no significant different probability of response to intensive chemotherapy was noticed. In patients who received allogeneic transplantation (n=345), IDH1 mutated patients shower higher relapse rate vs. wild type and IDH2 mutated patients (53% vs. 34%, P Conclusion. In a real world context, AML patients with IDH1 and 2 mutations have high marrow blasts percentage, frequently present normal karyotype and show specific co-mutational patterns with respect to NPM1, FLT3 and ASXL1 genes. IDH1 mutations were an independent predictor of unfavorable outcome with high rate of disease recurrence under currently available treatment options, and could be considered as an additional marker to improve personalized prognostic assessment within ELN risk groups. Dissection of prognosis of IDH mutated AML may influence targeted treatment strategies in clinical practice. Disclosures Voso: Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Heibl:Takeda: Honoraria; AOP orphan: Consultancy, Honoraria, Research Funding; BMS/celgene: Consultancy, Honoraria, Research Funding; novartis: Consultancy, Honoraria. Metzeler:Astellas: Honoraria; Daiichi Sankyo: Honoraria; Otsuka Pharma: Consultancy; Pfizer: Consultancy; Jazz Pharmaceuticals: Consultancy; Novartis: Consultancy; Celgene: Consultancy, Honoraria, Research Funding. Thiede:AgenDix GmbH: Other: Co-owner and CEO. Fracchiolla:ABBVIE: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, expenses; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, expenses, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, expenses, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, expenses, Speakers Bureau. Todisco:Jannsen, Abbvie, Jazz: Membership on an entity's Board of Directors or advisory committees. Passamonti:Novartis: Speakers Bureau; BMS: Speakers Bureau; Roche: Other: Support of parent study and funding of editorial support.

Summary POEMS syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein and Skin changes) is a rare multisystemic disease. Clinical presentation is variable, the only mandatory criteria being polyneuropathy and monoclonal gammapathy in association with one major and one minor criterion. Primary adrenal insufficiency is rarely reported. We describe a case of a 33-year-old patient, in whom the presenting symptoms were mandibular mass, chronic sensory-motor peripheral polyneuropathy and adrenal insufficiency. The laboratory evaluation revealed thrombocytosis, severe hyperkalemia with normal renal function, normal protein electrophoresis and negative serum immunofixation for monoclonal protein. Endocrinologic laboratory work-up confirmed Addison’s disease and revealed subclinical primary hypothyroidism. Thoracic abdominal CT showed hepatosplenomegaly, multiple sclerotic lesions in thoracic vertebra and ribs. The histopathologic examination of the mandibular mass was nondiagnostic. Bone marrow biopsy revealed plasma cell dyscrasia and confirmed POEMS syndrome. Axillary lymphadenopathy biopsy: Castleman’s disease. Gluco-mineralocorticoid substitution and levothyroxine therapy were started with clinical improvement. Autologous hematopoietic cell transplantation (HCT) was planned, cyclophosphamide induction was started. Meanwhile the patient suffered two ischemic strokes which resulted in aphasia and hemiparesis. Cerebral angiography revealed vascular lesions compatible with vasculitis and stenosis of two cerebral arteries. The patient deceased 14 months after the diagnosis. The young age at presentation, multiplicity of manifestations and difficulties in investigation along with the absence of serum monoclonal protein made the diagnosis challenging. We report this case to highlight the need to consider POEMS syndrome in differential diagnosis of peripheral neuropathy in association with endocrine abnormalities even in young patients. Learning points: POEMS syndrome is considered a ‘low tumor burden disease’ and the monoclonal protein in 15% of cases is not found by immunofixation. Neuropathy is the dominant characteristic of POEMS syndrome and it is peripheral, ascending, symmetric and affecting both sensation and motor function. Endocrinopathies are a frequent feature of POEMS syndrome, but the cause is unknown. The most common endocrinopathies are hypogonadism, primary hypothyroidism and abnormalities in glucose metabolism. There is no standard therapy; however, patients with disseminated bone marrow involvement are treated with chemotherapy with or without HCT.

IntroductionCOVID-19 pandemic and the consequent containment measures have a negative impact on mental health. Simultaneously, the fear of infection can discourage patients from seeking necessary care.ObjectivesWe aim to compare sociodemographic and clinical characteristics of inpatients admitted during the COVID-19 confinement period in Portugal vs. inpatients admitted in the same period the previous year.MethodsRetrospective observational study of inpatients admitted between March 19th 2020 and May 1st 2020 and the analog period of 2019 in a psychiatry inpatient unit of a tertiary hospital. Descriptive analysis of the results was performed using the SPSS software, version 26.0.ResultsDuring the lockdown period, there were 30 admissions to the psychiatry inpatient unit, 55.2% less than the same period last year (n=67). The proportion of compulsory admissions and the average length of stay did not differ between the two periods. Regarding sociodemographic characteristics, in the confinement period inpatients were similar to the ones in the same period of 2019. In both periods, the majority of patients had previous psychiatric history (lockdown vs. same period last year: 95.5% and 90.0%) and a similar proportion of readmissions rate (previous year) was similar in the two groups (49.9% vs 47.6%). At discharge, the most frequent diagnostic groups were mood disorders (33.3% (n=10) and 34.3% (n=23)) and schizophrenia, schizotypal and delusional disorders (26,7% (n=8) and 31.3% (n=21)).ConclusionsAlthough there was an expressive reduction of admissions to the psychiatry inpatient unit during lockdown, the clinical characteristics of these patients were analogous to the same period in the previous year.

Introduction: Many older patients (pts) with AML respond to intensive induction chemotherapy (IC), but responses are often short-lived and overall survival (OS) is poor. The benefit of post-remission maintenance treatment (Tx) for pts with AML is unclear, as no therapy has shown to significantly improve OS. CC-486 is an oral hypomethylating agent that allows for prolonged drug exposure during each Tx cycle to sustain therapeutic activity. We hypothesized that prolonged Tx with CC-486 could be effective as post-remission maintenance in AML. Herein, we report the primary results of QUAZAR AML-001 (NCT01757535), a phase III international, randomized, double-blind, placebo (PBO)-controlled study evaluating CC-486 as maintenance therapy in pts aged ≥55 years with AML in first remission following IC. Methods: Eligible pts had de novo or secondary AML, intermediate- or poor-risk cytogenetics, and Eastern Cooperative Oncology Group performance status (ECOG PS) scores of ≤3; had achieved first complete remission (CR) or CR with incomplete count recovery (CRi) after IC, with or without consolidation chemotherapy; and were not candidates for hematopoietic stem-cell transplant (HSCT). Within 4 months of attaining CR/CRi, pts were randomized 1:1 to receive CC-486 300 mg or PBO once-daily on days 1-14 of repeated 28-day Tx cycles. A 21-day dosing schedule was permitted for pts who experienced AML relapse with 5-15% blasts in blood or bone marrow while on-study. Tx could continue indefinitely until the presence of >15% blasts, unacceptable toxicity, or HSCT. The primary endpoint was OS. Secondary endpoints included relapse-free survival (RFS), health-related quality of life (HRQoL), and safety. Samples were collected for exploratory translational endpoints, including measurable residual disease (MRD). Kaplan-Meier estimates of OS and RFS were compared for CC-486 vs. PBO by stratified log-rank test. Hazard ratios (HRs) and 95% confidence intervals (CIs) were generated using a stratified Cox proportional hazards model. Results: Between May 2013 and October 2017, 472 pts were randomized to receive CC-486 (n=238) or PBO (n=234). Baseline characteristics were balanced between Tx arms. Median age was 68 years (range 55-86), 91% of pts had de novo AML, and 86% and 14% of pts, respectively, had intermediate-risk or poor-risk cytogenetics. Following induction, 81% of pts achieved a CR and 19% achieved CRi; 80% of pts had received consolidation chemotherapy (45% received 1 consolidation cycle and 31% received 2 consolidation cycles). At a median follow-up of 41.2 months, OS was significantly improved with CC-486 vs. PBO: median OS was 24.7 months vs. 14.8 months from time of randomization, respectively (P=0.0009; HR 0.69 [95%CI 0.55, 0.86]) (FigureA). RFS was also significantly prolonged: median RFS was 10.2 months in the CC-486 arm, compared with 4.8 months in the PBO arm (P=0.0001; HR 0.65 [95%CI 0.52, 0.81]) (Figure B). OS and RFS benefits of CC-486 were demonstrated regardless of baseline cytogenetic risk, the number of prior consolidation cycles received, and CR/CRi status. CC-486 did not adversely impact overall HRQoL vs. PBO, as assessed by mean changes from baseline in HRQoL measures during Tx. CC-486 had a manageable safety profile generally consistent with that of injectable azacitidine. Median exposure to CC-486 was 12 cycles (range 1-80) and to PBO was 6 cycles (1-73). The most frequently reported adverse events (AEs) with CC-486 and PBO were grade 1 or 2 gastrointestinal (GI) events, including nausea (64% and 23%, respectively), vomiting (59% and 10%), and diarrhea (49% and 21%). The most common grade 3-4 AEs were neutropenia (CC-486, 41%; PBO, 24%), thrombocytopenia (23% and 22%), and anemia (14% and 13%). Serious AEs were infrequent, mainly infections, which occurred in 17% of pts in the CC-486 arm and 8% of pts in the PBO arm. Few AEs led to Tx discontinuation, most often GI events (CC-486, 5%; PBO, 0.4%). Conclusions: CC-486 is the first therapy used in the maintenance setting to provide statistically significant and clinically meaningful improvements in both OS and RFS in pts with AML in remission following induction chemotherapy, with or without consolidation. Oral CC-486 has a manageable safety profile and represents a new therapeutic standard for pts with AML in remission. Disclosures Wei: Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: AHW is a former employee of the Walter and Eliza Hall Institute and receives a fraction of its royalty stream related to venetoclax, Research Funding, Speakers Bureau; Macrogenics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Honoraria, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees. Döhner:AbbVie, Agios, Amgen, Astellas, Astex, Celator, Janssen, Jazz, Seattle Genetics: Consultancy, Honoraria; AROG, Bristol Myers Squibb, Pfizer: Research Funding; Celgene, Novartis, Sunesis: Honoraria, Research Funding. Montesinos:Abbvie: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research support, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research support, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: Research support; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Teva: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau. Ravandi:BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Orsenix: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Xencor: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Macrogenix: Membership on an entity's Board of Directors or advisory committees, Research Funding. Sayar:Celgene Corporation: Membership on an entity's Board of Directors or advisory committees. Porkka:Celgene: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Selleslag:Celyad: Consultancy; Novartis: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Astellas: Consultancy; Daichii Sankyo: Consultancy; Janssen-Cilag: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Astex Otsuka: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau. Sandhu:Takeda: Consultancy; Amgen: Consultancy; Novartis: Consultancy; Bioverativ: Consultancy; Celgene Corporation: Consultancy; Pfizer: Consultancy; Janssen: Consultancy. Giai:BMS: Honoraria; Pfizer: Honoraria; Novartis: Honoraria. Beltrami:Ospedale Policlinico San Martino: Employment. Ossenkoppele:Celgene Corporation: Consultancy, Honoraria, Research Funding. La Torre:Celgene Corporation: Employment, Equity Ownership. Skikne:Celgene Corporation: Employment, Equity Ownership. Kumar:Celgene Corporation: Employment, Equity Ownership. Dong:Celgene Corporation: Employment, Equity Ownership. Beach:Celgene Corporation: Employment, Equity Ownership. Roboz:AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Actinium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amphivena: Consultancy, Membership on an entity's Board of Directors or advisory committees; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astex: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: 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; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Eisai: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees; Otsuka: 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; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trovagene: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Introduction. The global increase in CPE infections is probably the strongest threat to the success of AL therapy nowadays. CP-K.pneumoniae (CP-Kp) BSI in particular have a high mortality in neutropenic pts, tend to reappear in subsequent courses and lead to delays in chemotherapy (CT). To make things worse, no effective decolonization is available, isolation measures are controversial, and optimal treatment is largely unknown. The widespread use and abuse of carbapenems perpetuate the problem. An outbreak of CP-Kp BSI began in our center in Nov/16, leading to profound changes in empirical and directed antibacterial protocols. This report analyzes the impact of these modifications on clinical outcomes. Methods. Until Feb/18, our empirical regimen for a first neutropenic fever was monotherapy with meropenem; for documented CP-Kp BSI a double or triple combination, including colistin, tigecycline, high-dose/prolonged infusion meropenem or an aminoglycoside, was selected according to MICs. Since Mar/18 empirical carbapenems were banned, and a new empirical strategy was implemented: pts who were not colonized (rectal swab screening at started Sept/17) received piperacillin-tazobactam; known colonized pts received colistin + tigecycline. This regimen was modified 48h later on the basis of blood culture results, with de-escalation (if no growth of CP-Kp) versus immediate prescription of ceftazidime-avibactam (CF-A) which was given even for colistin-susceptible strains, with the dual intention of reducing nephrotoxicity and delaying resistance to colistin. Univariate analysis was performed to identify factors related to mortality, using the χ2 test and Fisher's exact test. Results. From Nov/16 to Aug/18, 54 consecutive CP-Kp BSI were documented in 45 pts (9 pts surviving a first episode developed a new one in a later CT course). Of note, 3 of these 54 BSI occurred in 2016 (1% of all BSI and 4% of Kp BSI that year), 32 in 2017 (11% and 38%, respectively), and 19 in 2018 until August (13% and 32%). Median age of pts was 58 (17-85), 34 were male, and hospitalization was mainly intended for induction (74%) or consolidation (18%) cycles. Median duration of neutropenia < 500/μl at the onset of bacteremia was 7 days (0-74). A clinical source was identified in most pts: pneumonia in 26%, soft tissue infection in 22%, enterocolitis in 17%. Of the 30 episodes registered since screening began, 16 occurred in colonized patients (11 with KPC, 5 OXA-48). Septic shock developed in 41% of the episodes, and ICU admission was necessary in 30%. In 19 episodes (35%) empirical antibacterial treatment was (retrospectively) considered appropriate if it had included colistin and/or tigecycline. CF-A was prescribed as directed therapy in 28 cases (52%). Microbiological cure (negative blood cultures) was verified in 86% of 49 evaluable episodes. Attributable mortality (due to this infection) at day 14 of the onset of bacteremia was 22% (12 cases) and global mortality during hospitalization was 31% (17 cases). Fifteen of these 17 deaths occurred in the 40 episodes registered before protocol modification in Mar/18 and only 2 in the 14 episodes after that date (37% vs 14%). Adverse outcomes were significantly related to unresolved bacteremia, to occurrence of septic shock and to ICU admission (all p Conclusions. In this series of profoundly neutropenic pts under intensive CT, the mortality rate from CP-Kp BSI was very high. Unresolved neutropenia and severity of the infection itself (as measured by the presence of septic shock and/or ICU admission) had, as expected, a major impact on death. Two treatment-related factors (time to appropriate empirical coverage and directed use of CF-A) had a major influence on survival, both presumably through faster microbiological resolution. The strategy we implemented has two aims: allowing appropriate and timely empirical coverage in colonized patients while sparing carbapenems, and optimizing directed therapy while reducing colistin use and toxicity. Although the present data need confirmation in a larger series, we believe that the recent sharp decrease in mortality observed in our pts with CP-Kp bacteremia stems from these measures. Disclosures No relevant conflicts of interest to declare.

Acute myeloid leukemia (AML) is a hematopoietic malignancy characterized by clonal expansion of myeloid progenitor cells accounting for the majority of acute leukemia cases in adults, despite the h...

Gold nanoparticles functionalized with thiolated oligonucleotides (Au-nanoprobes) have been used in a range of applications for the detection of bioanalytes of interest, from ions to proteins and DNA targets. These detection strategies are based on the unique optical properties of gold nanoparticles, in particular, the intense color that is subject to modulation by modification of the medium dieletric. Au-nanoprobes have been applied for the detection and characterization of specific DNA sequences of interest, namely pathogens and disease biomarkers. Nevertheless, despite its relevance, only a few reports exist on the detection of RNA targets. Among these strategies, the colorimetric detection of DNA has been proven to work for several different targets in controlled samples but demonstration in real clinical bioanalysis has been elusive. Here, we used a colorimetric method based on Au-nanoprobes for the direct detection of the e14a2 BCR-ABL fusion transcript in myeloid leukemia patient samples without the need for retro-transcription. Au-nanoprobes directly assessed total RNA from 38 clinical samples, and results were validated against reverse transcription-nested polymerase chain reaction (RT-nested PCR) and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The colorimetric Au-nanoprobe assay is a simple yet reliable strategy to scrutinize myeloid leukemia patients at diagnosis and evaluate progression, with obvious advantages in terms of time and cost, particularly in low- to medium-income countries where molecular screening is not routinely feasible. Graphical abstract Gold nanoprobe for colorimetric detection of BCR-ABL1 fusion transcripts originating from the Philadelphia chromosome.

Background and objectives The role of the Janus kinase 2 V617F (JAK2(V617F)) mutation in the pathogenesis of the various BCR-ABL1-negative myeloproliferative neoplasms (MPNs) remains unclear. Its significance in leukemic transformation is a matter of even greater controversy. The aim of this study was to evaluate both the JAK2(V617F) mutational status of the rare cases in which blast crisis occurred in our institution and the response after intensive treatment. Materials and methods Between 1999 and 2009, 778 patients received diagnoses of BCR-ABL1-negative MPNs in our center (395 polycythemia vera, 329 essential thrombocythemia, and 45 primary myelofibrosis cases, as well as 9 MPN cases not otherwise classifiable). Of these patients, 7 developed leukemic transformation. The genotyping of the JAK2(V617F) mutation was performed by the amplification-refractory mutation system. Results Six of the 7 patients were tested for JAK2(V617F) in the chronic phase of their disease, and 3 of these patients were positive for JAK2(V617F). These patients, 2 with polycythemia vera and 1 with essential thrombocythemia, also harbored JAK2(V617F) in the heterozygous state during blast crisis and even after intensive treatment in one of these patients. The other cases that evolved to blast crisis did not harbor the JAK2(V617F) mutation before and after transformation. All 7 patients died despite conventional or supportive treatment. Conclusions The transformation of MPNs into acute leukemia is by itself a very rare phenomenon, and so is the persistence of the JAK2(V617F) mutation after blast crisis. In our series, all JAK2(V617F)-positive patients remained positive for this mutation after leukemic transformation, although in the heterozygous state, suggesting that JAK2(V617F) is not essential for transformation in these cases. The fact that all JAK2(V617F)-negative cases remained negative after blast crisis reinforces the theory that other molecular event(s) may play a role in the clonal heterogeneity of MPNs. Owing to the poor outcome of acute myeloid leukemia secondary to MPN, patients should be included in clinical trials of the novel JAK2 inhibitors.

In adults, non-Hodgkin’s lymphoma (NHL) is the second most common neoplasm found in the head and neck region after squamous cell carcinoma. Within this region, primary NHL of the nasopharynx is rare. We report the case of a 28-year-old male diagnosed with a B lymphoblastic lymphoma (CD20−; CD79a+; CD3−; CD10+; PAX5+, CyclinD1−; TdT+) of the nasopharynx extending to the deep and superficial structures of the right hemiface, to the skull base with an intracranial component and a small but detectable bone marrow involvement, who was started on chemotherapy with a complete response. To the best of our knowledge, this is the first case of a primary nasopharynx B-LBL in an adult patient with such aggressive regional spread to be reported in the literature.

Philadelphia chromosome (Ph1), which results from the reciprocal translocation t(9;22)(q34;q11), is the hallmark of almost all the cases of chronic myeloid leukemia (CML). Most patients express eit...

© 2014 Ferrata Storti Foundation. This is an open-access paper, Adult B-cell acute lymphoblastic leukemia remains a major therapeutic challenge, requiring a better characterization of the molecular determinants underlying disease progression and resistance to treatment. Here, using a phospho-flow cytometry approach we show that adult diagnostic B-cell acute lymphoblastic leukemia specimens display PI3K/Akt pathway hyperactivation, irrespective of their BCR-ABL status and despite paradoxically high basal expression of PTEN, the major negative regulator of the pathway. Protein kinase CK2 is known to phosphorylate PTEN thereby driving PTEN protein stabilization and concomitant PTEN functional inactivation. In agreement, we found that adult B-cell acute lymphoblastic leukemia samples show significantly higher CK2 kinase activity and lower PTEN lipid phosphatase activity than healthy controls. Moreover, the clinical-grade CK2 inhibitor CX-4945 (Silmitasertib) reversed PTEN levels in leukemia cells to those observed in healthy controls, and promoted leukemia cell death without significantly affecting normal bone marrow cells. Our studies indicate that CK2-mediated PTEN posttranslational inactivation, associated with PI3K/Akt pathway hyperactivation, are a common event in adult B-cell acute lymphoblastic leukemia and suggest that CK2 inhibition may constitute a valid, novel therapeutic tool in this malignancy., This study was supported by grant PTDC/IC/83023/2007, from Fundação para a Ciência e a Tecnologia (FCT). A.M.G. and V.P. received BI fellowships from FCT. L.R.M. and A.M. received a post-doctoral and a PhD fellowship, respectively, both from FCT.

Introduction: the shortage of some anticancer drugs has forced their substitution in established combination chemotherapy regimens, but the replacement may have critical effects on the results of treatment and need careful evaluation. Since 1996 we treat Hodgkin's lymphoma (HL) with the Stanford V (SV) regimen, which achieves the same results as the more widely employed ABVD regimen with the benefits of a shorter duration (12 weeks) and lower cumulative doses of bleomycin and doxorubicin. When mechlorethamine became unavailable in 2008, we substituted cyclophosphamide at a dose of 650 mg/m2 for mechlorethamine 6 mg/m2. In 2012 the Pediatric Hodgkin Lymphoma Consortium, which had adopted the same policy, suggested in a retrospective analysis that the modification could lead to an inferior event-free survival (EFS). To assess the impact of the substitution, we retrospectively compared our results with the original SV (SVo) and the modified SV (SVm). Methods: we evaluated the 265 patients consecutively treated in our center with SV between Nov/96 and Dec/14. We compared the pre-treatment characteristics, the complete remission (CR) rate, EFS and overall survival (OS) of the 184 patients who received SVo to those of the 81 patients treated with SVm. Radiotherapy indications and supportive measures were unchanged between the 2 periods. Results: median age of the 2 groups was identical: 31 (16-69) for SVo and 31 (15-72) for SVm. No differences were found in histologic subtypes (nodular sclerosis 76/74%), frequency of B symptoms (36/47%, p=0.09), proportion of advanced stages (32/33%) or International Prognostic Score (≥3 in 20/13%, p=0.22). The CR rate was 89% for SVo and 86% for SVm. With a median follow up of 9 years for the SVo group and 4.6 years for the SVm group, there were no significant differences in EFS (76/73%, p=0.66) and OS (89%/85%, p=0.63) at 5 years. Conclusion: the impact of forced substitutions in components of combination chemotherapy regimens due to drug shortage must be carefully scrutinized, notably in first line protocols for curable diseases. In the case of HL treated with the SV regimen, the present study is the first, to our knowledge, to evaluate the impact of replacing mechlorethamine by cyclophosphamide in adults. We found no difference in OS nor, unlike the pediatric study, in EFS. The substitution can be considered safe, since the modified version of SV achieves the same favorable results as the original SV. Disclosures No relevant conflicts of interest to declare.

The role of the Janus kinase 2 V617F (JAK2(V617F)) mutation in the pathogenesis of the various BCR-ABL1-negative myeloproliferative neoplasms (MPNs) remains unclear. Its significance in leukemic transformation is a matter of even greater controversy. The aim of this study was to evaluate both the JAK2(V617F) mutational status of the rare cases in which blast crisis occurred in our institution and the response after intensive treatment.Between 1999 and 2009, 778 patients received diagnoses of BCR-ABL1-negative MPNs in our center (395 polycythemia vera, 329 essential thrombocythemia, and 45 primary myelofibrosis cases, as well as 9 MPN cases not otherwise classifiable). Of these patients, 7 developed leukemic transformation. The genotyping of the JAK2(V617F) mutation was performed by the amplification-refractory mutation system.Six of the 7 patients were tested for JAK2(V617F) in the chronic phase of their disease, and 3 of these patients were positive for JAK2(V617F). These patients, 2 with polycythemia vera and 1 with essential thrombocythemia, also harbored JAK2(V617F) in the heterozygous state during blast crisis and even after intensive treatment in one of these patients. The other cases that evolved to blast crisis did not harbor the JAK2(V617F) mutation before and after transformation. All 7 patients died despite conventional or supportive treatment.The transformation of MPNs into acute leukemia is by itself a very rare phenomenon, and so is the persistence of the JAK2(V617F) mutation after blast crisis. In our series, all JAK2(V617F)-positive patients remained positive for this mutation after leukemic transformation, although in the heterozygous state, suggesting that JAK2(V617F) is not essential for transformation in these cases. The fact that all JAK2(V617F)-negative cases remained negative after blast crisis reinforces the theory that other molecular event(s) may play a role in the clonal heterogeneity of MPNs. Owing to the poor outcome of acute myeloid leukemia secondary to MPN, patients should be included in clinical trials of the novel JAK2 inhibitors.

INTRODUCTION: Invasive fungal infections (IFIs) are a life-threatening complication in patients with hematologic malignancies, mainly in acute leukemia patients, following chemotherapy. IFI incidence is increasing, and associated mortality remains high due to unreliable diagnosis. Antifungal drugs are often limited by inadequate antimicrobial spectrum and side effects. Thus, the detection of circulating fungal DNA has been advocated as a rapid, more sensitive diagnostic tool. PATIENTS AND METHODS: Between June 01 and January 03, weekly blood samples (1,311) were screened from 193 patients undergoing intensive myelosuppressive or immunosuppressive therapy. IFI cases were classified according to European Organization for Research and Treatment of Cancer/Mycoses Study Group criteria. Fungal DNA was extracted from whole blood and amplified using polymerase chain reaction (PCR) published primers that bind to the conserved regions of the fungal 18S rRNA gene sequence. In our study, two or more consecutive positive samples were always associated with fungal disease. RESULTS: PCR screening predicted the development of IFI to be 17 days (median). This test had a specificity of 91.1% and a sensitivity of 75%. IFI incidence was 7.8%. DISCUSSION: Therefore, our results confirm the potential usefulness of PCR serial screening and the clinical applicability in everyday routine. PCR screening offers a noninvasive repeatable aid to the diagnosis of IFI.

Fungal infections are an important cause of morbidity and mortality in patients with acute leukemia (AL). Candidemia, once rare, is now a common nosocomial infection because of the intensity of chemotherapy, prolonged neutropenia, administration of broad-spectrum antibiotics and use of central venous catheters (CVC). We retrospectively identified patients treated for AL from 6/86 to 6/95 who also had candidemia. We describe 28 patients (incidence 6.3%) with a median age of 39 years, 24 of whom were on remission induction and 4 on postremission chemotherapy. All patients had CVC and empiric antimicrobial therapy, 4 had been given prophylactic antifungal drugs, and 2 had parenteral nutrition. Neutropenia was profound (median leukocyte nadir 200/microliters, median duration 19 days). Candida was isolated in blood cultures 10 days (median) after the start of neutropenia. The clinical presentation included fever (100%), respiratory symptoms (71.4%), skin lesions (39.2%) and septic shock (17.8%). Amphotericin B was given to 17 patients and liposomal amphotericin to 5 patients. Infection resolved in 18 patients (64.2%). 10 of whom were in complete remission. Mortality from candidemia was 17.8% (5/28). In conclusion, fungal infections are responsible for death in a significant number of patients. In our series treatment success was related to its rapid onset and to the recovery of neutropenia.

Abstract 430 Introduction: 25–30% of patients with advanced stage classical Hodgkin lymphoma (cHL) develop progressive disease despite treatment with ABVD. While more intensive upfront treatments, such as BEACOPP, result in a higher failure free survival, this comes at the expense of increased toxicity and morbidity. 10–15% of patients with advanced stage cHL will ultimately succumb to the disease, with similar outcomes using different upfront regimens likely reflecting the planned use of second-line high dose therapy. The International Prognostic Factors Project Score, a prognostic tool developed using freedom from progression of disease as the outcome, has been used in clinical practice and has guided clinical trials. We hypothesized that biological factors, as measured by gene expression profiling in pretreatment formalin fixed paraffin embedded tissue (FFPET) samples, might provide a robust predictor of overall survival (OS). Method and Patients: NanoString technology was used to quantitate 261 mRNA species in diagnostic FFPET samples from patients in the Intergroup E2496 trial, which compares ABVD with Stanford V chemotherapy in locally advanced and advanced stage cHL. The 261 genes included individual genes and genes that represent cell and cellular process signatures that have been associated with outcome in cHL. Total RNA was extracted from whole section scrolls from the 309 FFPET blocks available. A penalized binary logistic regression model with leave-one-out cross validation was used to produce a parsimonious predictive model for OS. A threshold was selected that maximized the Chi square of the Log Rank (Mantel-Cox) test between the identified low and high risk groups. An independent cohort of patients with advanced stage cHL enriched for treatment failure, consisting of 59 patients from British Columbia treated with ABVD and 71 patients from Portugal treated with Stanford V, was used to test the generated model and threshold. Results: Gene expression of adequate quality was produced in 293 of the 309 samples (95%). At a median follow up of 5.3 years, 36 (12%) of the 293 patients had died. 51 genes were differentially expressed (t-test p < 0.05) with respect to OS, including genes that are part of macrophage, cytotoxic/NK cell and apoptosis signatures. A predictive model for OS was produced with an area under the curve (AUC) of the receiver operating characteristic (ROC) curve of 0.73. The predictor identified a high-risk group, comprising 39% of the cohort, with a 77% estimated 5-year OS compared with 96% in the low risk group (Figure 1A, log-rank p < 0.0001). The predictor was validated in the independent cohort giving an AUC of the ROC curve of 0.73 and an estimated 5-year OS of 71% in the high-risk group compared with 91% in the low risk group (Figure 1B, log-rank p = 0.006). Discussion: We have produced a parsimonious gene expression-based predictor of OS in cHL, developed in, and applicable to, widely available FFPET using NanoString technology. The predictor identifies, at diagnosis, a clinically meaningful proportion of patients at significantly higher risk of death when treated with ABVD or Stanford V. Further evaluation of the gene expression signature with alternative treatments, ideally in the context of clinical trials, is needed to understand the impact of more intensive cytotoxic therapies versus novel targeted approaches. Disclosures: Horning: Genentech: Employment, Equity Ownership. Connors:Seattle Genetics: Consultancy, Research Funding.

Administration of colony-stimulating factors (CSF) after autologous peripheral-blood progenitor cell transplantation is the current standard of care, and G-CSF is usually given from day +5 or +7 until engraftment. Recent preliminary data in a non-transplant setting suggest that 2 doses of G-CSF may be equivalent to the standard schedule. In this pilot study, we evaluated the safety and efficacy of giving only 2 doses of filgrastim post-transplant (days +7 and +9) in non-myeloma pts; exclusion criteria were re-transplants and clinical instability at day +7. From July 07 to June 08, 19 consecutive pts were included (16 lymphomas, 3 acute leukaemias) and their outcome was compared to a historical control group of 42 similar pts transplanted from Jan 06 to Jun 07, who received filgrastim from d+7 until 1000 neutrophils/ul (4–18 days, median 9). There were no significant differences in primary endpoints: median time to neutrophil engraftment (500/ul reached on day +12 vs +11) rate of documented infections (with bacteremia in 23% of transplants in the study group vs 36% in the control group) and median length of hospitalisation (both 22 days). Median duration of intravenous antibiotics (11 vs 12 days) median time to platelet engraftment (20,000/ul reached on day +13 vs +14) incidence of grade 3/4 mucositis and transfusion requirements were also similar. There were no deaths at day +30 in the study group. In 2 of the 19 pts a secondary prescription of filgrastim was made (for 2 and 4 days). In this pilot study, reducing filgrastim administration to 2 doses seems possible without undue risks. If confirmed in a randomized trial, these findings could have a significant impact on the cost of transplantation.

Meningeal infiltration is extremely rare in CLL. Moreover, part of the cases found in the literature occurred in fact in patients with prolymphocytic leukemia. In the few CLL cases, this complication was reported at late stages of the disease, in elderly patients. A previously healthy 30-year-old man was referred to the emergency department for evaluation of blurred vision and headache that developed 2 weeks earlier. Bilateral papilledema was observed, with no other neurological abnormality. CT and MRI of the head and orbits disclosed thickening of both optic nerves. Hemoglobin and platelet count were within normal limits. The WBC count was 41800/μl with 83% small lymphocytes, which were SmIg+ λ(weak) CD19+, CD5+, CD23+, CD20+, CD79b+, CD11c+, bcl2+, CD38+, ZAP70+ and CD10 negative. Moderately enlarged cervical lymph nodes were present. A diagnosis of Binet stage A, Rai stage I B-CLL was made. Bone marrow aspiration and biopsy showed 95% lymphocytes, with a diffuse pattern of infiltration. No metaphases were obtained for karyotyping. FISH disclosed a rearranged IgH, and was negative for trisomy 12 and for deletions of 11q, 13q and 17q. Abdominal CT showed retroperitoneal lymphadenopathy. Serology for HIV and EBV was negative. The cerebrospinal fluid (CSF) revealed >1000 lymphocytes/μl which were immunophenotypically identical to the peripheral blood cells. Systemic corticosteroids and intrathecal chemotherapy (methotrexate and dexamethasone) followed by cranial irradiation led to resolution of headache, but blurred vision persisted. Clearance of leukemic cells from the CSF was slow, a normal CSF being achieved only after 6 alternate day intrathecal injections. Systemic chemotherapy and stem cell transplantation are planned. To our knowledge this is the first reported case of CLL presenting as meningeal infiltration. Two possible reasons for the apparent rarity of CLL meningitis can be put forward: meningeal invasion would frequently be clinically silent, a hypothesis that is strengthened by autopsy findings; and it would usually occur in very advanced stages of CLL (with misinterpretation of neurological symptoms in erderly patients) making underdiagnosis easy.

The myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis, peripheral blood cytopenias, increased apoptosis and possible transformation into acute myeloblastic leukemia (AML). MDS are considered “clonal” stem cell disorders but the precise mechanism is yet unknown. Lately there has been some evidence implicating the extrinsic apoptosis pathway in the pathogenesis of these diseases. The present study included 30 cases (2001/03) classified according to WHO: 6 RA, 1 RARS, 7 RAEB type I, 3 RAEB type II, 2 RCMD, 2 MDS/MDP, and 2 aplastic anemias, 3 AML secondary to MDS and 4 control cases with normal histology. We assessed the expression of TNF-related-apoptosis-inducing ligand (TRAIL) and its receptors, of Fas, Fas-L, Fas-associated-death-domain (FADD), caspase-8, caspase-3 and DNA fragmentation factor (DFFP) by RT-PCR and by immunohistochemical staining. Results were correlated with the expression of CD34, HLA-DR15, CD15, CD20, CD68 and CD117. Patients were stratified according to the international prognostic scoring system (IPSS). Fas, Fas-L and FADD were overexpressed in low risk IPSS categories and in RA and RARS, but gradually lost their expression in more advanced stages and were not expressed in RAEB II and AML cases. This expression was inversely correlated with the expression of caspase-8 and DFFP. We observed that CD34+ and HLA-DR15+ samples were positively correlated with the expression of FADD, caspase-8 and DFFP. TRAIL was positive in normal histology and AML cases but its expression was diminished in all other samples. Our data suggest that the extrinsic apoptotic pathway may be implicated in MDS through Fas, Fas-L and FADD. RAEB II may be grouped with AML, as it shows a lesser degree of apoptosis than lower risk MDS categories. A better understanding of these diseases will allow for a better and more individualized management. This work was supported by a grant from the Terry-Fox Foundation.

The admission of neutropenic patients (pts) to intensive care units (ICU) is controversial, especially when mechanical ventilation is required. Knowledge of the relative prognostic impact of factors related to the underlying disease and to the severity of acute organ failures might help avoiding futile admissions. We retrospectively assessed predictors of 30-day mortality in neutropenic (500/ul). Pts who died were more likely to have non-M3 AL subtype vs M3 (p=0.037), to have ≥ 2 acute OSF vs < 2 (p=0.012) and a higher SAPS II score (p< 0.001). In multivariate analysis only the latter 2 variables remained significant. In conclusion, our data show that 27% of neutropenic pts admitted to ICUs are alive at 30 days; that selection for admission should not be based on the characteristics of the underlying malignancy; and that the 30-day mortality is highly predictable by initial acute illness severity scores.

The best strategy for the empirical treatment of fever in profoundly neutropenic patients (pts) remains unclear. We retrospectively compared the efficacy and safety of 2 antibacterial regimens consecutively used in our center for febrile neutropenia (FN) in pts undergoing intensive chemotherapy for acute leukemia or autologous stem cell transplantation. From 1/99 to 6/01, 374 episodes of FN in 179 pts were treated with piperacillin-tazobactam plus amikacin (PTA, 4.5 g q6h and 20 mg/kg q24h respectively), then from 7/01 to 12/03, 428 episodes in 223 pts were treated with cefepime (CEF, 2g q8h). Any modification of the initial regimen was evaluated as a failure. Pts were nursed in HEPA-filtered rooms and received prophylactic aciclovir (and ciprofloxacin until 12/99) with no antifungal primary prophylaxis. There were no significant differences between the PTA and CEF episodes regarding median age of the pts, median days with neutrophils