Search

BACKGROUND Mirasol pathogen reduction technology (PRT) treatment inactivates bacteria, viruses, and parasites in plasma products and platelets (PLTs) suspended in plasma and PLT additive solutions (PAS). Few clinical studies exist documenting transfusions with PAS. This study objective was to evaluate the count increments of PRT-treated PAS-C and PAS-E buffy coat (BC) PLTs in routine use observational settings. STUDY DESIGN AND METHODS PLT pools of five or six BCs were collected, processed, and suspended in PAS-C or PAS-E, respectively. Products were exposed to ultraviolet light in the presence of riboflavin and then transfused into 19 patients with hematologic diseases. Patients were monitored for PLT corrected count increment (CCI) at 1 and 24 hours and for any adverse events in the 72 hours after transfusion. Sterility monitoring was performed with a microbial detection system (BacT/ALERT, bioMerieux). RESULTS The PAS-E products had significantly higher PLT concentrations and counts than the PAS-C products. The mean CCIs of per-protocol (PP) units at 1 and 24 hours were 11,900 (n = 27) and 5500 (n = 30), respectively. Seventy-eight percent of PP transfusions classify as successful with CCIs at 1 hour of higher than 7500, and 63% higher than 4500 at 24 hours. One patient was excluded from all analyses as she was refractory to Mirasol-treated PLT transfusions and follow-up untreated transfusion products. No adverse events were observed and no contaminated products were detected by BacT/ALERT. CONCLUSION PRT-treated BC PLTs in PAS-C or PAS-E demonstrate PLT transfusion success rates in hematology patients with thrombocytopenia that are comparable to previous studies examining PLTs stored in plasma.

We report an 80-year-old man suffering from ulcerative colitis and a prostate adenocarcinoma. Due to melena, colon biopsies were taken. Diffuse bleeding and a cardiac infarction complicated this procedure. Laboratory studies showed a normal platelet count and a prolongation of the activated partial thromboplastin time (aPTT). Von Willebrand factor (VWF) antigen level and ristocetin cofactor activity were low. Several disorders are known to be associated with acquired von Willebrand disease (AVWD), the commonest being hematoproliferative and cardiovascular disorders. Non-hematologic neoplasms causing AVWD are rarely documented. The underlying mechanisms differ among these disorders or may overlap. These include development of autoantibodies and mechanical destruction of VWF under high shear stress. Absorption of VWF on or inside malignant cells is believed to be the main mechanism in non-hematologic malignancies. In this report, we give a concise overview of the underlying disorders and the mechanisms that we encountered in this complex case. J Hematol. 2016;5(3):110-112 doi: http://dx.doi.org/10.14740/jh284w

Introduction Since no curative options for Waldenstrom's Macroglobulinemia (WM) are available, novel safe and effective treatments are needed. Several new agents, including BTK inhibitors and proteasome inhibitors (PIs) have shown considerable efficacy. PIs have shown synergy with rituximab in newly diagnosed and relapsed patients, with bortezomib being most extensively used. However, WM patients often have disease-related polyneuropathy (PNP) and there is a considerable risk of bortezomib induced PNP or worsening of existing PNP. Additionally, it requires parenteral administration. In the current study, we aimed to investigate the efficacy and toxicity of the oral and less neurotoxic proteasome inhibitor ixazomib citrate in patients with relapsed WM. Given the fact that WM patients have a tendency to develop rituximab intolerance, we explored the use of subcutaneous rituximab. Methods We conducted a multicenter phase I/II trial of the Ixazomib, Rituximab, Dexamethasone (IRD) combination in patients with relapsed WM. The phase I part of the trial was performed according to a standard '3+3' design with a primary endpoint of dose limiting toxicity, aiming to establish the recommended phase II dose level (RP2D). For the phase II part the primary endpoint was overall response rate (ORR, at least minimal response (MR)) after 8 induction cycles. Treatment consisted of a total of 8 induction cycles q28 days with ixazomib citrate, 4 mg orally on day 1,8,15 and dexamethasone, 20 mg orally on day 1,8,15,22. In cycle 3 rituximab 375 mg/m2 iv on day 1 was added and in cycle 4-8 rituximab was given sc (1400 mg flat dose day 1). Subsequently, patients with at least a PR received 2 years of rituximab maintenance treatment (1400 mg sc q 3 months). Results With 60 patients, enrolment is complete. One patient was ineligible (rituximab refractory). Dose level 1 (ixazomib citrate 4 mg) was feasible and was taken forward as the phase II dose. Of the first 50 eligible patients included in the pre-final analysis and treated at the RP2D, the median age was 69 years (range 46-83) and 72% were male. The median number of prior treatments was 2 (range 1 to 7); 70% had an intermediate or high WM IPSS score. The median hemoglobin level was 10.2 g/dl (range 7.0-15.0) and the median IgM level was 3.4 g/dl (range 1.33-9.1 g/dl). 39/50 patients completed 8 cycles of induction therapy with a median relative dose intensity of 1.0 for all three drugs. Eleven patients went off protocol early (5 progression, 3 toxicity, 2 intercurrent death, 1 insufficient clinical benefit). 74% of patients achieved the primary endpoint (16%≥VGPR, 52%≥PR, 74%≥MR), and best ORR on protocol was 88% (2% CR, 22% VGPR, 44% PR, 20% MR). With a median follow-up of 19.5 months (range 7-49), the median duration of response and median progression free survival were not reached. A rapid and statistically significant decrease in IgM levels was seen already after cycle 2 (before the introduction of rituximab; IgM 3.93 to 2.37 g/dl, p Grade 3/4 toxicity was seen in 28% and 10% of patients respectively. 21 SAEs were reported in 15 patients, mostly infections. 6 patients died while on the trial (2 progressive disease, 1 progressive multifocal leukencephalopathy (symptoms present already at entry), 2 deaths considered unrelated in elderly patients (>80 years) with multiple pre-existing comorbidities, 1 graft versus host disease after progression and subsequent allogeneic stem cell transplantation. Conclusions Treatment with the combination of ixazomib citrate, sc rituximab and dexamethasone is feasible, easy to administer and shows promising efficacy with manageable toxicity in patients with relapsed or progressive WM. The final analysis for the primary endpoint for all 60 patients will be shown at the conference. Role of the funding source: the study was financially supported by grants from Takeda Oncology, Roche and the Dutch Cancer Society. Acknowledgments: the authors wish to acknowledge the trial coordinators and central datamanagers of HOVON data center and all patients and contributing centers for participation in the trial Figure IgM (A) and Hemoglobin (B) levels during treatment Disclosures Kersten: Gilead: Honoraria; Novartis: Honoraria; Roche: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Takeda Oncology: Research Funding; Kite Pharma: Honoraria, Research Funding; Miltenyi: Honoraria; Mundipharma: Honoraria, Research Funding. Minnema:Jansen Cilag: Honoraria; Celgene Corporation: Honoraria, Research Funding; Gilead: Honoraria; Amgen: Honoraria; Servier: Honoraria. Vos:Celgene: Honoraria. Kastritis:Genesis: Honoraria; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria; Pfizer: Honoraria; Prothena: Honoraria. Chamuleau:Genmab: Research Funding. Deeren:Alexion, Amgen, Janssen, Roche, Sunesis, Takeda, Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Doorduijn:Roche: Honoraria, Research Funding. Dimopoulos:Sanofi Oncology: Research Funding. OffLabel Disclosure: Ixazomib in Waldenstrom's Macroglobulinemia

Authors 1 -3: Contributed equally to this work Authors 8-9: Shared last author Background Genetic material from aggressive B-cell lymphoma is typified by recurrent multiple somatic alterations. Given some of the disease's most profound characteristics-large tumor cell turnovers and its evident physical relation to the cardiovascular system-it presents itself as an excellent candidate for cell-free DNA (cfDNA) based research through liquid biopsies. Recent studies on cfDNA mainly focus on targeted sequencing for single nucleotide variation and translocation detection. This technique remains expensive, requires targeted panels and is yet to be clinically standardized. In contrast, the much cheaper shallow whole genome sequencing (sWGS) for copy number variation (CNV) detection, is operative at most hospitals that offer noninvasive prenatal testing (NIPT). Despite these benefits, the potential of this approach for lymphoma remains insufficiently explored. Methods Between May 2016 and June 2019, 129 patients (pts; median age of 59; Ann Arbor stage I (4%), II (21%), III (20%) and IV (55%)) with confirmed lymphoma (86 diffuse large B-cell lymphoma (DLBCL), 39 Hodgkin lymphoma (HL) and 4 grey zone lymphoma (GZL)) were recruited. Ultimately, 236 samples were collected, including liquid biopsies at initial diagnosis; follow-up liquid biopsies at relapse or surveillance (25 pts); and paired formalin-fixed paraffin-embedded (FFPE) tissue samples (35 pts). Follow- up samples were collected during the following evaluations: DLBCL pts were evaluated by Lugano 2014 criteria after 4 cycles of R- CHOP and at the end of treatment. HL pts were subject to an early interim evaluation after only 2 cycles of ABVD. cfDNA was analyzed by sWGS (0.5x coverage), where resulting reads were mapped to both human and viral reference genomes, aiming at identifying nuclear CNVs and viral fragments, respectively. Additionally, the cohort was extended with 60 NIPT (liquid negative control) and 9 benign FFPE (tissue negative control) samples in order to statistically determine cancerous copy number profiles and abnormal viral titers. Results At staging, 36/44 (82%) of HL and 67/96 (70%) of DLBCL liquid biopsies had detectable CNVs. The remainder possibly had no structural aberrations, or, more likely, had an insufficient fraction of cell-free tumor DNA. Notably, no CNVs could be detected in 87% of HL FFPE samples, suggesting HL tumor DNA is more abundant in plasma. For DLBCL however, liquid copy number profiles were well-represented by their solid equivalent, indicated by an average Pearson correlation of 0.82. In order to quantify copy number abnormality, we developed a statistic that increases with rising deviance from the overall healthy diploid state. This score, named the copy number profile abnormality (CPA) score, positively and significantly correlates with Ann Arbor stage (p=0.044), the International Prognostic Index (IPI; p=0.038) and metabolic tumor volume (MTV; p=0.0004), derived from PET/CT scans. In 15 HL (34%), 18 DLBCL (19%) and 2 GZL (50%) samples, a statistically (q Detected CNVs at staging were often highly indicative for histological subtype. Leave-one-out cross-validation in combination with established modeling techniques shows that, eg, distinguishing HL from DLBCL, is characterized by an area under the curve of 0.9 during receiver operating characteristic analysis. Amongst 129 pts, 12 did not go in sustained CR. Sequential samples of these pts were compared to 13 similar cases with surveillance samples in CR. In the latter, all CNVs disappeared, whilst this was not the case for the remaining bad responders (Fig1). In this group, longitudinal analysis revealed that relapse is essentially not associated with a change in CNV pattern. Conclusion Both CNVs and viral DNA fragments can be detected frequently and accurately in liquid biopsies of lymphoma pts. In two longitudinal cases, a rise in CNV parameters predicted relapse. Disclosures Deeren: Alexion, Amgen, Janssen, Roche, Sunesis, Takeda, Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Background Allogeneic hematopoietic stem cell transplantation (alloHSCT) has been established as a powerful treatment modality for patients with hematological malignancies. The graft-versus-leukemia effect, however, is strongly associated with the occurrence of graft-versus-host disease (GVHD) and subsequent transplant-related mortality. The current standard Dutch regimen for prevention of GVHD in T-cell replete (TCR) alloHSCT following reduced intensity conditioning (RIC) consists of mycophenolic acid (MA) and cyclosporine A (CyA) for three and six months post-transplant, respectively. However, as approximately 30% of patients will never develop GVHD, immunosuppressive overtreatment is of concern and might impair outcome. Aims In the present prospective randomized, multicenter, phase III trial we set out to compare time-restricted immunosuppression versus a standard immunosuppressive regimen. The primary objective was to increase the proportion of patients with non-severe GVHD (either acute GVHD grades I-II without gut involvement or chronic GVHD not requiring systemic treatment) within 180 days after transplantation and to reduce the relapse rate, without increasing severe GVHD. Secondary endpoints included time to acute and chronic GVHD, progression-free survival (PFS), GVHD-free/relapse-free survival (GRFS), overall survival (OS), and adverse events. Methods Hematological patients planned to undergo TCR alloHSCT with a related or unrelated 8/8 HLA matched donor were included. The trial randomized patients between three treatment arms. The current analysis includes all patients randomized between arms A and B. Immunosuppression consisted of CyA twice daily aiming for serum trough levels of 250-350 µg/L and MA 16 mg/kg twice daily with a maximum dose of 2160 mg a day. The standard regimen (arm A) prescribed to discontinue MA at day 84 post-transplant and CyA was continued until day +120 followed by tapering until day +180. In those randomized for the time-restricted regimen (arm B) MA was discontinued at day 28 post-transplant and CyA was continued until day +84 followed by tapering. Results A total of 389 patients were randomized 1:1 between arms A and B, of whom 95% (184 in arm A versus 185 in arm B) proceeded to transplant. The median age was 55 (range: 18-71), 57% were male. Fifty-one patients received myeloablative conditioning and 318 (86%) patients RIC. Donors were matched siblings for 135 patients and matched unrelated donor (MUD) for 233 patients. The majority of patients received peripheral blood stem cells, consisting of median 6.46x106/kg CD34+ cells/kg (range: 0.94-26.3) and median 230x106/kg CD3+ T cells (range: 0-936). Baseline patient and transplantation characteristics were equally distributed between the treatment arms. The proportion of patients developing non-severe GVHD within 180 days post-alloHSCT was 24% in both treatment arms, with an odds ratio (OR) of 1.01 (95% confidence interval 0.61-1.67, p 0.98). The cumulative incidence (CI) of grade II-IV and grade III-IV acute GVHD at 6 months post-alloHSCT was not significantly different between the two arms (47% and 15% versus 52% and 18%), nor was the maximum grade or organ involvement of acute GVHD. In addition, no difference was seen in the two-year CI of chronic extensive GVHD between the two treatment arms (51% versus 49%). The three-year estimate of PFS was 51% (44-59%) versus 52% (44-59%), respectively. The three-year CI of progression/relapse was 28% in arm A versus 27% in arm B. OS at three years was 59% (0.51-0.66%) versus 57% (0.50-0.64%). The one-year estimate of the composite endpoint GRFS was 14% (9-19%) in arm A, and 17% (12-22%) in arm B. Incidences and nature of adverse events were comparable in both arms. Conclusion A time-restricted combination of MA and CyA did not increase the proportion of patients with non-severe GVHD within 180 days after transplantation and resulted in similar outcome as compared to standard immunosuppression following alloHSCT using sibling and well-matched unrelated donors. Given the observed high CI of acute grade II-IV and chronic extensive GVHD and low GRFS for both the time-restricted and standard regimen, recipients of TCR RIC alloHSCT should be considered for more intensive immunosuppression. Figure Disclosures Nur: Novartis: Consultancy. Deeren:Alexion, Amgen, Janssen, Roche, Sunesis, Takeda, Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

We report on a 36-year-old man who presented to the emergency department with haemoptysis. Computed tomography (CT) of the thorax showed a pulmonary mass paramediastinal in the right upper lobe, with the density of a haematoma. Laboratory data demonstrated an absolute lymphocytosis of 5.900 x 10(9)/l (normal range, 1.150-3.250 x 10(9)/l) and a prolonged activated partial thromboplastin time (APTT) of 47.7 s (normal range, 28.0-39.0 s). A de novo diagnosis of lymphoplasmacytic lymphoma (Waldenstrom macroglobulinaemia) was made, complicated by an acquired von Willebrand syndrome (aVWS) as demonstrated by further laboratory investigations. In this case report, we present a case of aVWS with markedly prolonged APTT and haemoptysis that revealed an underlying Waldenstrom macroglobulinaemia.

Objectives: Surface CD56 expression on leukemic cells in acute promyelocytic leukemia (APML) is considered an indicator of poorer outcome even in patients receiving conventional treatment. Methods: In the present case, at initial diagnosis, the hallmark phenotype of APML was found (strong CD33 and cytoplasmic MPO expression, absence of HLA-DR expression). Results: Both CD34 and CD56 antigen expression was considered negative. The patient relapsed 3 years after reaching complete remission, and the hallmark surface antigen combination for APML was again found. In contrast, the leukemic cells now clearly coexpressed CD34 and CD56. Retrospective analysis revealed the presence of small CD34+ and CD56+ populations at initial diagnosis ( Conclusions: This case report suggests that the presence of a clone with minimal coexpression of CD34/CD56 in APML at initial diagnosis should not be neglected since it may be associated with earlier relapse.

Objectives: We evaluated azacitidine (Vidaza (R)) safety and efficacy in patients with myelodysplastic syndrome (MDS), acute myeloid leukaemia (AML), and chronic myelomonocytic leukaemia (CMML), in a real-life setting. Treatment response, dose, and schedule were assessed. Methods: This non-interventional, post-marketing survey included 49/50 patients receiving azacitidine at 14 Belgian haematology centres from 2010-2012. Treatment-emergent adverse events (TEAEs), including treatment-related TEAEs, and serious TEAEs (TESAEs) were recorded throughout the study. Treatment response [complete response (CR), partial response (PR), haematological improvement (HI), stable disease (SD), treatment failure (TF)) and transfusion-independence (TI) were evaluated at completion of a 1-year observation period (1YOP) or at treatment discontinuation, and overall survival (OS), at study conclusion. Results: The median age of patients was 74.7 (range: 43.9-87.8) years; 69.4% had MDS, 26.5% had primary or secondary AML, and 4.1% had CMML. Treatment-related TEAEs, grade 3-4 TEAEs, and TESAEs were reported in 67.3%, 28.6%, and 18.4% of patients, respectively. During 1YOP, patients received a median of 7 (1-12) treatment cycles. Treatment response was assessed for 38/49 patients. Among MDS and CMML patients (n=29), 41.4% had CR, PR, or HI, 41.4% had SD, and 17.2% had TF. Among AML patients (n=9), 44.4% had CR or PR, 33.3% had SD, and 22.2% had TF. TI was observed in 14/32 (43.8%) patients who were transfusion-dependent at baseline. Median (95% confidence interval) OS was 490 (326-555) days; 1-year OS estimate was 0.571 (0.422-0.696). Conclusions: Our data support previous findings that azacitidine has a clinically acceptable safety profile and shows efficacy.

Early treatment of invasive mold infections improves the outcome. Therapy is often delayed, however, because available diagnostic tools such as culture, microscopy and conventional radiology lack sensitivity; consequently, empirical initiation of antifungal therapy has been advocated, particularly for patients with prolonged unexplained neutropenic fever.Much recent progress has been made in the development and evaluation of nonculture-based assays, including the detection of the fungal antigens galactomannan and beta-D-glucan and the detection of fungal DNA by polymerase chain reaction techniques. These new tools should aid the rapid, early diagnosis of invasive fungal disease, especially when used as screening tools in conjunction with sensitive imaging techniques.The review will consider these recent developments with the purpose of introducing the concept of preemptive antifungal therapy.

Rapidly fatal pulmonary tumour embolism is a rare complication of malignancy, and often presents as progressive dyspnea without obvious cause. We describe two cases presenting with a dramatic clinical picture of lactic acidosis and cardiopulmonary arrest soon after admission on ICU. The first patient was a 29-year old woman with a breast cancer seeming in remission who was admitted with rapidly increasing dyspnea since two weeks. The second patient was a 46-year old woman with HIV and no history of malignancy, who developed dyspnea and lactic acidosis over the course of a few days while she was investigated for an occipital brain lesion. Both patients died soon after admission and massive tumour emboli were found on autopsy. Breast cancer was the origin of the emboli in both cases. Symptoms were out of proportion to the initial physical cardiopulmonary findings and radiographic features. Clinical signs of pulmonary tumour embolism are non-specific and subacute. Prognosis is poor and definite diagnosis is usually made post-mortem. Solid malignancies such as breast cancer account for most of the cases. Pulmonary tumour embolism should be considered in critically ill patients with unexplained hypoxemia and lactic acidosis, mild or no radiological abnormalities and fast clinical deterioration. It may occur in young patients and in patients without history of malignancy.

The timely diagnosis of invasive aspergillosis (IA) remains difficult. In recent years, increased experience has been gained with the Platelia™ Aspergillus enzyme immunoassay. However, the excellent sensitivity and high positive predictive value that has been reported in earlier studies cannot consistently be reproduced in some of the more recent studies. As expected, this stems from major methodological and clinical heterogeneities between studies. This article reviews these between-study heterogeneities and concludes that the detection of serum galactomannan can be used to define a case of IA in a well-defined population of at-risk patients.

PURPOSE OF THE REVIEW: There has been an exponentially increasing interest in intra-abdominal hypertension (IAH). Comparison of the published data however is difficult due to the lack of consensus definitions. This review will focus on the available literature from the last 2 years. A Medline and PubMed search was performed using 'intra-abdominal pressure' (IAP), 'intra-abdominal hypertension' (IAH), and 'abdominal compartment syndrome' (ACS) as search items. The aim was to find an answer to the question 'Isn't it time to pay attention to intra-abdominal pressure in the critically ill?' RECENT FINDINGS: Although the number of studies published on this topic is steadily increasing and confirms the pathophysiologic implications of IAH on end-organ function within and outside the abdominal cavity it remains difficult to compare the literature data because the measurement methods and definitions used are not uniform. Provocative data have been published regarding the interactions between the abdominal and thoracic compartments especially in patients with capillary leak and fluid overload; most of this data raises even more questions than it gives answers and may therefore strengthen the nonbelievers who consider IAP, IAH and ACS as epiphenomena in critically ill patients. Unless the international scientific community does not come forward with clear-cut definitions we will keep comparing 'apples with oranges.' SUMMARY: It is time to pay attention to intra-abdominal pressure in the critically ill. It is also time for standardized IAP measurement methods, good consensus definitions and randomized interventional studies.

The study purpose was to report the first case of granulocyte colony-stimulating factor (G-CSF)-induced capillary leak syndrome (CLS) in which serial extravascular lung water (EVLW) measurements were performed and to compare this case with previously reported cases. To identify previously reported cases, we performed a literature search, using PubMed with the following search terms: CLS, EVLW, G-CSF, granulocyte-macrophage colony-stimulating factor (GM-CSF) and stem cell transplantation and the references in the bibliographies of the papers retrieved. To obtain additional information about these cases, we contacted the authors by e-mail. We describe the case of a 68-year-old woman who developed severe CLS during G-CSF treatment after autologous haematological stem cell transplantation. CLS is caused by damage to the endothelial cells, resulting in extravasation of plasma proteins and fluid from the capillaries into the extravascular space. This is illustrated by high values of EVLW and pulmonary vascular permeability, necessitating mechanical ventilation. We found five other case reports in the literature. The white blood cell count at the onset of the CLS varied from very low (zero) to very high (90,500/mul). The symptoms began on day 5-9 of the G-CSF treatment. All patients had fever. Three patients were mechanically ventilated and four received renal replacement therapy. Two patients died. Treatment with G-CSF can induce fatal CLS. Monitoring of EVLW in patients with severe CLS may be useful to guide fluid therapy and improve oxygenation.

Here, we report the case of a 57-year-old man, who was diagnosed with B-cell acute lymphoblastic leukemia (B-ALL). His diagnostic workup identified a translocation t(3;9)(p13;p13). This is the fifth case reported to date that involved the forkhead box P1 gene (FOXP1) and paired box gene 5 (PAX5). The PAX5-FOXP1 translocation is a nonrandom aberration, which is recurrent in both childhood and in adult B-ALL, and may contribute to leukemogenesis by blocking differentiation of hematopoietic cells into mature B-cells.

Mirasol pathogen reduction technology (PRT) treatment inactivates bacteria, viruses, and parasites in plasma products and platelets (PLTs) suspended in plasma and PLT additive solutions (PAS). Few clinical studies exist documenting transfusions with PAS. This study objective was to evaluate the count increments of PRT-treated PAS-C and PAS-E buffy coat (BC) PLTs in routine use observational settings.PLT pools of five or six BCs were collected, processed, and suspended in PAS-C or PAS-E, respectively. Products were exposed to ultraviolet light in the presence of riboflavin and then transfused into 19 patients with hematologic diseases. Patients were monitored for PLT corrected count increment (CCI) at 1 and 24 hours and for any adverse events in the 72 hours after transfusion. Sterility monitoring was performed with a microbial detection system (BacT/ALERT, bioMérieux).The PAS-E products had significantly higher PLT concentrations and counts than the PAS-C products. The mean CCIs of per-protocol (PP) units at 1 and 24 hours were 11,900 (n=27) and 5500 (n=30), respectively. Seventy-eight percent of PP transfusions classify as successful with CCIs at 1 hour of higher than 7500, and 63% higher than 4500 at 24 hours. One patient was excluded from all analyses as she was refractory to Mirasol-treated PLT transfusions and follow-up untreated transfusion products. No adverse events were observed and no contaminated products were detected by BacT/ALERT.PRT-treated BC PLTs in PAS-C or PAS-E demonstrate PLT transfusion success rates in hematology patients with thrombocytopenia that are comparable to previous studies examining PLTs stored in plasma.

Anaplastic lymphoma kinase (ALK)-positive lymphomas respond to chemotherapy, but relapses, which bear a poor prognosis, occur. Crizotinib inhibits ALK in vitro and in vivo and was administered as monotherapy to 11 ALK+ lymphoma patients who were resistant/refractory to cytotoxic therapy. The overall response rate was 10 of 11 (90.9%; 95% confidence interval [CI] = 58.7% to 99.8%). Disease status at the latest follow-up is as follows: four patients are in complete response (CR) (months >21, >30, >35, >40) under continuous crizotinib administration; 4 patients had progression of disease (months 1, 2, 2, 2); 1 patient obtained CR on crizotinib, received an allogeneic bone marrow transplant, and is in CR; 2 patients (treated before and/or after allogeneic bone marrow transplant) obtained and are still in CR but they have stopped crizotinib. Overall and progression-free survival rates at 2 years are 72.7% (95% CI = 39.1% to 94.0%) and 63.7% (95% CI = 30.8% to 89.1%), respectively. ALK mutations conferring resistance to crizotinib in vitro could be identified in relapsed patients. Crizotinib exerted a potent antitumor activity with durable responses in advanced, heavily pretreated ALK+ lymphoma patients, with a benign safety profile.

Background: Most patients with myelodysplastic syndromes (MDS) require transfusions at the risk of iron overload and associated organ damage, and death. Emerging evidence indicates that iron chelation therapy (ICT) could reduce mortality and improve survival in transfusion-dependent MDS patients, especially those classified as International Prognostic Scoring System (IPSS) Low or Intermediate-1 (Low/Int-1). Methods: Follow-up of a retrospective study. Sample included 127 Low/Int-1 MDS patients from 28 centers in Belgium. Statistical analysis stratified by duration (>= 6 versus < 6 months) and quality of chelation (adequate versus weak). Results: Crude chelation rate was 63% but 88% among patients with serum ferritin >= 1000 mu g/L. Of the 80 chelated patients, 70% were chelated adequately mainly with deferasirox (26%) or deferasirox following deferoxamine (39%). Mortality was 70% among non-chelated, 40% among chelated, 32% among patients chelated >= 6 m, and 30% among patients chelated adequately; with a trend toward reduced cardiac mortality in chelated patients. Overall, median overall survival (OS) was 10.2 years for chelated and 3.1 years for non-chelated patients (p < 0.001). For patients chelated >= 6 m or patients classified as adequately chelated, median OS was 10.5 years. Mortality increased as a function of average monthly transfusion intensity (HR = 1.08, p = 0.04) but was lower in patients receiving adequate chelation or chelation = 6 m( HR = 0.24, p < 0.001). Conclusion: Six or more months of adequate ICT is associated with markedly better overall survival. This suggests a possible survival benefit of ICT in transfusion-dependent patients with lower-risk MDS. (C) 2014 Elsevier Ltd. All rights reserved.

Background Little is known about the effects of renal replacement therapy (RRT) with fluid removal on intra-abdominal pressure (IAP). The global end-diastolic volume index (GEDVI) and extravascular lung water index (EVLWI) can easily be measured bedside by transpulmonary thermodilution (TPTD). The aim of this study is to evaluate the changes in IAP, GEDVI and EVLWI in critically ill patients receiving slow extended daily dialysis (SLEDD) or continuous venovenous haemofiltration (CVVH) with the intention of net fluid removal. Methods We performed a retrospective cohort study in ICU patients who were treated with SLEDD or CVVH and in whom IAP was also measured, and RRT sessions were excluded when the dose of vasoactive medication needed to be changed between the pre- and post-dialysis TPTD measurements and when net fluid loss did not exceed 500 ml. The TPTD measurements were performed within 2 h before and after SLEDD; in case of CVVH, before and after an interval of 12 h. Results We studied 25 consecutive dialysis sessions in nine patients with acute renal failure and cardiogenic or non-cardiogenic pulmonary oedema. The GEDVI and EVLWI values before dialysis were 877 ml/m² and 14 ml/kg, respectively. Average net ultrafiltration per session was 3.6 l, with a net fluid loss 1.9 l. The GEDVI decreased significantly during dialysis, but not more than 47.8 ml/m² (p = 0.008), as also did the EVLWI with 1 ml/kg (p = 0.03). The IAP decreased significantly from 12 to 10.5 mmHg (p < 0.0001). Conclusions Net fluid removal by SLEDD or CVVH in the range observed in this study decreased IAP, GEDVI and EVLWI in critically ill patients although EVLWI reduction was modest.

Bronchiolitis Obliterans Organizing Pneumonia (BOOP) can complicate allogeneic haematopoietic stem cell transplantation. It is associated with prior graft-versus-host disease (GVHD) and the case fatality is 21%. In 22%, diagnosis is preceded by tapering the corticosteroids given as a treatment for GVHD. We report a fatal case of BOOP after tapering the corticosteroids that the patient received for a Pneumocystis jirovecii pneumonia after stem cell transplantation.

Background C-reactive protein (CRP) is a widely used inflammatory marker. Yet, the clinical significance and outcome of extremely elevated CRP levels are poorly characterized. Methods We collected all patients seen at a university hospital in 2004 with at least one CRP level above 500 mg/l and retrospectively analyzed their electronic files, focusing on patient characteristics, clinical diagnosis, microbiology and vital outcome. Results CRP was above 500 mg/l in 130 patients with a median age of 62 years. Patient characteristics, settings, etiologies of inflammation, comorbidities and microbiology varied widely. Infections, mainly bacterial, accounted for 88% of episodes. Outcome was fatal in 36% of all patients and in 61% of patients with active malignancies. Conclusion A wide variety of infections, especially bacterial, that are generally readily identified account for the majority of instances of extreme CRP elevation. Mortality is high, certainly in oncological patients.

During therapy with amiodarone, widespread deposition of amiodarone and its major metabolite desethylamiodarone occurs, predominantly in adipose tissue, liver and lung (1, 2). The concentration of amiodarone at these extravascular sites is markedly higher than in plasma. We report the case of a 68-year-old man who was admitted to the intensive care unit (ICU) because of bilateral pneumonia with acute hypoxic respiratory insuffi ciency. Two years prior to this admission, he suffered from a myocardial infarction and four months prior to admission, he underwent coronary artery bypass grafting and amiodarone was started because of atrial fi brillation. On ICU admission, amiodarone was stopped. On the second ICU day, total atrioventricular block with hypotension developed, and a temporary pacing catheter was introduced. He needed high doses of dobutamine, norepinephrine and epinephrine, and was treated with continuous venovenous haemofi ltration because of acute anuric renal failure. The following hours, he regained sinus rythm and improved haemodynamically. However, thirty hours later, new episodes of atrioventricular block started to occur. These were refractory to atropine and isoproterenol but responded to epinephrine. The laboratory fi ndings of a massive rise in alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) levels and a moderate rise in bilirubin and alkaline phosphatase levels pointed to the diagnosis of ischaemic hepatitis (Figure). Unfortunately, on the sixth ICU day, the pacemaker failed to capture, a rapidly progressive cardiogenic shock with frequent episodes of total atrioventricular block followed and the patient died. Retrospectively, we measured the plasma amiodarone level (using high-performance liquid chromatography) in six blood specimens, collected during the previous month, and noted a dramatic rise after the laboratory fi ndings of ischaemic hepatitis had appeared (Figure). Ischaemic hepatitis refers to diffuse hepatic injury that results from hypoperfusion. Its histologic hallmark is necrosis in zone three (perivenular region) (3). Our results suggest that amiodarone leaked from necrotic hepatocytes, causing a rise in plasma and tissue amiodarone levels resulting in or potentiating the occurrence of atrioventricular block and hypotension. To a lesser extent, hypoperfusion in other organs may also have increased the amiodarone level.

A substantial number of cases of polyarteritis nodosa (PAN) are related to hepatitis B virus (HBV) infection. Different treatment strategies are reported in the literature. The aim of this study was to review 15 years of literature (1988-2002) to determine the optimal treatment for HBV-related PAN at present, and to discuss the indications and mechanism of action of corticosteroids in HBV-related PAN, as many physicians are reluctant to use these in the presence of HBV infection. The first patient stopped his initial treatment, relapsed and died of cerebral infarction. The second case illustrates the favorable outcome with the standard treatment: corticosteroids, lamivudine and plasma exchanges. If adequate follow-up is possible, antiviral agents as well as corticosteroids are indicated in HBV-related PAN. Corticosteroids diminish inflammation and corticosteroid withdrawal induces an alanine aminotransferase (ALT) rebound in patients with a low baseline ALT level. Antiviral agents are essential, as they reduce the production of HBV antigens and help to achieve hepatitis B early antigen (HBeAg) seroconversion. Plasma exchanges reduce the level of circulating immune complexes and are included in the treatment protocol of all recent studies. However, their effect has not been evaluated in controlled trials. We concluded that if adequate follow-up is possible, antiviral agents as well as corticosteroids are indicated in HBV-related PAN.

In hematological disorders ALK expression is present in >50% of Anaplastic Large Cell Lymphomas (ALCL) as a result of a t(2;5)(p23;q35) translocation that causes the ALK gene on chromosome 2 to fuse with the NPM gene on chromosome 5. ALK + ALCL respond to cytotoxic drugs, but relapses occur and bear a poor prognosis(Stein, Foss et al. Blood 96 3681-95 2000; Ferreri, Govi et al. Crit Rev Oncol Hematol 83 293-302 2012). ALK-positive large B-cell lymphoma (ALK+ LBCL) is a rare lymphoma with a most frequent t(2;17)(p23;q23) translocation responsible for Clathrin-ALK fusion protein(Swerdlow, Campo et al. 2 2008). Crizotinib is the first ALK inhibitor which entered clinical practice: it is an orally bioavailable small-molecule inhibitor active on the ALK and MET receptor tyrosine kinases. While the activity of crizotinib in ALK+ lung cancer is documented (Kwak, Bang et al. N Engl J Med 363 1693-703 2010)no report on long term effects of crizotinib in ALK+ lymphomas exists; impressive short-term therapeutic activity was reported in two patients (Gambacorti-Passerini, Messa et al. N Engl J Med 364 775-6 2011), but no long-term data are available. In the present study, crizotinib was administered (250 mg BID) as monotherapy to 11 ALK+ lymphoma patients, diagnosed with ALK+ Non-Hodgkin lymphoma (NHL) by immunohistochemistry and FISH. Nine patients had a ALCL histology while the remaining 2 were DLBCL Patients had a refractory or relapsed disease after at least one prior chemotherapy regimen and measurable disease. All had involvement at multiple sites (nodal and extranodal) as well as B symptoms and an ECOG performance score of 1-4. Response to therapy was assessed according to RECIST criteria (Therasse, Arbuck et al. J Natl Cancer Inst 92 205-16 2000) The Overall Response Rate (ORR) was 10/11 (91%, 95% CI: 60-99%) and included 9 CR (82%, 95% CI: 51-96%) and 1 PR. Evidence of response by PET/CAT scan was present as early as 12 days. B symptoms disappeared promptly and LDH levels normalized within 30 days after the start of crizotinib. Disease status at the latest follow-up (June 2013) is as follows: 4 patients are in CR under continuous crizotinib treatment; they also test negative by RT-PCR for NPM/ALK (Mussolin, Damm-Welk et al. Leukemia 27 416-22 2012). Three patients (2 with LBCL and 1 with ALCL) died due to disease progression; 1 patient obtained CR, relapsed after 2 months of treatment and is now in CR on continued brentuximab treatment (month 29); 1 patient obtained CR on crizotinib and after 2 months stopped treatment, received an alloBMT and is still in CR; 2 patients treated for relapses post alloBMT obtained CR and are still in CR but they stopped crizotinib after 8-10 months. The two patients with ALK+ LBCL died within 3 months; in those with ALCL the CR rate was 9/9 (100%, 95% CI, 74-100%) with a median duration of 10 months (range 2-37). The 3 years PFS and OS rates are 62% (95% CI, 35-85%) and 73% (95% CI, 40-93%) respectively, with a plateau in the curve after the initial 6 months. In two relapsed patients the kinase domain of NPM-ALK could be amplified from peripheral blood samples obtained at the time of relapse (month 5 and 2). Deep sequencing of these products revealed the presence of different mutations: Q1064R at high prevalence (95%,) in patient (pt) #2 and I1171N (33%) plus M1328I (14%) in pt #6. All these mutations were not present in samples obtained before crizotinib treatment. I1171N was already discovered in an in-vitro screening (Ceccon, Mologni et al. Mol Cancer Res 11 122-32 2012): it commands an intermediate level of resistance to crizotinib (RI: 5.8) which however is cross resistant with other anti-ALK TKI such as AP26113 and NVP-TAE684. The other two mutations were not previously described: they present a RI to crizotinib of 2.4 (M1328I) and 8.5 (Q1064R). Since these residues do not form direct contacts with crizotinib, they probably interact with different structures within the catalytic domain such as the hydrophobic R-spine (I1171N) (Ceccon, Mologni et al. Mol Cancer Res 11 122-32 2012), the activation loop (M1328I), or yet unidentified regions (Q1064R). In conclusion, these positive results extend our initial observation on two patients (Gambacorti-Passerini, Messa et al. N Engl J Med 364 775-6 2011) and provide long-term follow up data. Crizotinib exerted a potent antitumor activity in advanced ALK+ lymphoma and produced durable responses in this population of heavily pre-treated patients, with a benign safety profile. Disclosures: Gambacorti-Passerini: Pfizer: Consultancy, Research Funding; BMS: Consultancy.

A 74-year-old man was admitted to the cardiology ward because of heart failure. Echocardiography showed concentric hypertrophy, dense myocardium, and global hypocontractility. Endomyocardial biopsy showed deposition of eosinophilic substance, positive for lambda and negative for kappa, amyloid A, and transthyretin. The bone marrow was invaded with 20% plasma cells with lambda light chain restriction; these cells were responsible for the immunoglobin G lambda paraprotein in the blood. Several vessel walls on the bone marrow biopsy showed amyloid deposition. The patient had amyloidosis that seemed to be the result of myeloma. For the previous 12 months, the patient had noticed ecchymoses on both sides of the neck; these were more pronounced in the morning (Fig 1). There was no history of preceding trauma, and the patient was not receiving anticoagulant or antiplatelet medication. All coagulation tests were normal; factor X activity was 83%. The ecchymoses seemed to be caused by amyloid-induced capillary fragility, which resulted in subcutaneous bleeding even after minor stress, such as lying down to sleep. This phenomenon is known to cause periorbital ecchymosis (so-called raccoon eyes), but in this patient, the skin of the neck was the affected site. Early recognition of amyloidosis-induced ecchymosis may prevent additional myocardial damage.

epd.2011.0438 Auteur(s) : Dries Deeren DDeeren@hhr.be, Lien Deleu Department of Hematology, H.-Hartziekenhuis Roeselare-Menen vzw, Roeselare, Belgium To the editor We refer to the paper of Oghlakian et al. on levetiracetam-induced thrombocytopenia (2010). As has been demonstrated by others previously, levetiracetam was shown in this study to cause thrombocytopenia, most likely regulated by the immune system (Meschede et al., 2008; Peer Mohamed and Prabhakar, 2009). Piracetam has primarily been used [...]

Dear Editor, In the March 2008 issue of Annals of Hematology, Niscola and colleagues reported a case of B-lymphoblastic leukaemia 9 months after the diagnosis of autoimmune haemolytic anaemia (AIHA) [1]. The preceding AIHA was in remission and its treatment was stopped, so nor the preceding AIHA nor its treatment influenced the leukaemia treatment. However, when Blymphoblastic leukaemia presents immediately as AIHA, treatment should be directed against both leukaemia and haemolysis, and toxicity should be limited. Recently, a 61-year-old man was admitted to the emergency department because of dyspnoea. The Hb count was 6.7 g/dl, WBC count 1.2·10/l, 5.8% blasts, neutrophil count 0.3·10/l, platelet count 84·10/l. Despite a normal reticulocyte count, there was evidence of relevant haemolysis suggested by increased lactate dehydrogenase and indirect bilirubin, and decreased haptoglobin. The peripheral blood smear showed no schistocytes. The direct antiglobulin (Coombs’) test was positive (3+) with polyvalent antibodies and anti-C3d, and negative with anti-IgG. Testing for cold agglutinins was negative. Bone marrow examination showed a common acute lymphoblastic leukaemia (ALL) with 97.5% marrow blasts and a normal karyotype. Because he had a history of myocardial ischemia, packed cells were transfused. This caused a very modest Hb increase. Because of neutropenia and the expectation of several more weeks of neutropenia and mucositis, we wanted to reduce the amount of corticosteroids. We chose to start preinduction treatment for ALL with cytarabine, etoposide and methotrexate. After 1 month, the Coombs’ test was only slightly positive, and laboratory evidence of haemolysis had disappeared. Induction therapy for ALL was started, this time with corticosteroids (dexamethasone), vincristine and adriamycin. One month later, the Coombs’ test was negative. After the induction courses, the Hb started to increase. A complete remission of ALL was achieved. After consolidation with cytarabine and asparaginase, the patient was admitted for allogeneic stem cell transplantation. Cases of ALL with a positive Coombs’ test at the time of diagnosis have been reported [2]. All had a positive Coombs’ with anti-Cd3 but not with anti-IgG, and cold agglutinins could not be found. In these patients, the Coombs’ test became negative when complete remission was achieved. Even though cytostatic drug are immunosuppressive, corticosteroids are most often used as first-line therapy for haemolytic anaemia caused by warm antibodies. Our results suggest that corticosteroids may not be necessary in the initial treatment of AIHA caused by ALL, as long as effective treatment directed against ALL is started.

Introduction Correct bedside measurement of intra-abdominal pressure (IAP) is important. The bladder method is considered as the gold standard for indirect IAP measurement, but the instillation volumes reported in the literature vary substantially. The aim of this study was to evaluate the effect of instillation volume on intra-bladder pressure (IBP) as an estimation for IAP in critically ill patients.

Indocyaninegreen (ICG) clearance can be measured with the LiMON® device (Pulsion, Germany) and is expressed by the plasma disappearance rate (PDR) for ICG (normal value 18–25%) and the residual ICG after 15 min (R15, normal value 0–10%). In this study we investigated the correlation between PDR/R15 and IAP, SOFA score, and classic liver function tests in mixed ICU patients.

Volumetric monitoring with right ventricular end-diastolic volume indexed (RVEDVi) and global end-diastolic volume indexed (GEDVi) is increasingly being suggested as a better preload indicator than traditional intracardiac filling pressures (central venous pressure [CVP] and pulmonary artery occlusion pressure [PAOP]). Static volumetric monitoring, however, has not consistently been shown to correlate with the cardiac index (CI). This study aims (1) to evaluate the influence of ejection fraction (EF) on RVEDVi and GEDVi, (2) to study the effect of RVEDVi and GEDVi changes (Δ) corrected for right ventricle ejection fraction (RVEF) and global ejection fraction (GEF), respectively, on ΔCI, and (3) to identify optimal resuscitation target volumes.

Definitions for intra-abdominal hypertension (IAH) and abdominal compartment syndrome (ACS) stand or fall with the reproducibility and accuracy of the IAP measurement. The aim of this study is to validate a novel fully-automated continuous technique to measure IAP via a balloon-tipped catheter connected to an IAP monitor (Spiegelberg, Hamburg, Germany) versus a novel bladder FoleyManometer (Holtech Medical, Copenhagen, Denmark), and to look for the COVA (SD divided by mean) for IAP and APP during different 24 hour monitoring periods.