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Hematology, or Haematology

... was a major interest for our lab, during many years in the context of the GEIL still thriving, then EGIL, then European Leukemia Net.

 

Gilbert C FAURE's insight:

Hospital choices did not allow to pursue the efforts locally...

but to stay informed and allow others to surf the information wave....

 

Much information is available in the cloud, focusing on immunophenotyping of leukemias, and also on other haematology topics.


Blood cells being also immunocompetent cells, other topics curated should be of interest

http://www.scoop.it/t/immunology

http://www.scoop.it/t/from-flow-cytometry-to-cytomics

http://www.scoop.it/t/immunology-and-biotherapies

 

 

 

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A brief, but comprehensive, guide to clonal evolution in aplastic anemia. - PubMed - NCBI

A brief, but comprehensive, guide to clonal evolution in aplastic anemia. - PubMed - NCBI | Hematology | Scoop.it
Hematology Am Soc Hematol Educ Program. 2018 Nov 30;2018(1):457-466. doi: 10.1182/asheducation-2018.1.457.Review...
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The evaluation of monoclonal gammopathy of renal significance: a consensus report of the International Kidney and Monoclonal Gammopathy Research Group

The evaluation of monoclonal gammopathy of renal significance: a consensus report of the International Kidney and Monoclonal Gammopathy Research Group | Hematology | Scoop.it
This Expert Consensus Document from the International Kidney and Monoclonal Gammopathy Research Group includes an updated definition of monoclonal gammopathy of renal significance (MGRS) and recommendations for the use of kidney biopsy and other modalities for evaluating suspected MGRS
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GPIIb/IIIa autoantibody predicts better rituximab response in ITP - Feng - 2018 - British Journal of Haematology - Wiley Online Library

Primary immune thrombocytopenia (ITP) is an acquired bleeding disorder in which autoantibodies play a critical role in platelet destruction. Previous studies indicated that ITP patients with anti‐glycoprotein (GP)Ib/IX antibodies were less responsive to intravenous immunoglobulin G (IVIG) therapy (Peng et al, 2014) and showed a relatively lower response rate to glucocorticoid therapy (Zeng et al, 2012). Rituximab has been used as second‐line treatment in ITP for a decade, but there is still no clinically useful test to predict its efficacy. We retrospectively analysed the relationship between antibody specificities and the efficacy of rituximab in ITP, and found that patients with anti‐GPIIb/IIIa autoantibodies were more responsive to rituximab treatment. The present study included 86 corticosteroid‐resistant or relapsed adult ITP patients hospitalized between January 2011 and January 2016 at the Department of Haematology, Qilu Hospital. All included patients met the International Working Group diagnostic criteria for ITP (Rodeghiero et al, 2009). Rituximab was given intravenously at 100 mg weekly for 4 weeks (55 cases), or a single dose of 375 mg/m2 (31 cases). Response was defined as a platelet count increase to ≥30 × 109/l and doubling the baseline platelet count, and no haemorrhagic manifestations. The response rates were calculated at least 3 months after the initiation of rituximab treatment. Autoantibody specificity was determined prior to rituximab treatment by modified monoclonal antibody specific immobilization of platelet antigen (MAIPA) assay as previously described (Peng et al, 2014). Statistical analyses were conducted using t tests for quantitative variables and χ2 tests for categorical variables. Logistic regression analysis was used to quantify the effect of variables on rituximab response. A P value of <0·05 indicated statistical significance, Bonferroni correction was used for multi‐group comparisons. All tests were performed by SPSS (SPSS Inc., Chicago, IL, USA). Among the 86 patients, 22·1% (19/86) presented only anti‐GPIIb/IIIa antibodies, 16·3% (14/86) presented only anti‐GPIb/IX antibodies, 19·8% (17/86) presented both anti‐GPIIb/IIIa and anti‐GPIb/IX antibodies (double positive) and 41·9% (36/86) had neither anti‐GPIIb/IIIa nor anti‐GPIb/IX antibodies (double negative) (Table ). The response rates for different doses of rituximab are listed in Tables SI and SII. There were no statistical differences in gender (χ2 = 0·085, P = 0·994), age (F = 0·275, P = 0·843), baseline platelet counts (F = 0·639, P = 0·592), patients treated with different rituximab dose (χ2 = 1·024, P = 0·795) or duration of response (F = 0·362, P = 0·780) among the four groups. Cases of patients 86 Gender (female/male) 54/32 Median (range) age, years 36 (20‐77) Median (range) disease duration, months 11 (7‐55) Median (range) platelet count, ×109/l 12 (1‐28) Median (range) duration of response, weeks 30 (4‐not reached) Platelet autoantibodies GPIIb/IIIa (+), GPIb/IX (−) (female/male) 12/7 GPIIb/IIIa (−), GPIb/IX (+) (female/male) 9/5 GPIIb/IIIa (+), GPIb/IX (+) (female/male) 11/6 GPIIb/IIIa (−), GPIb/IX (−) (female/male) 22/14 GP, glycoprotein; ITP, immune thrombocytopenia. Patients who presented antibodies against GPIIb/IIIa (27/36 = 75·0%) achieved a higher response rate than patients without anti‐GPIIb/IIIa antibodies (23/50 = 46·0%) (χ2 = 7·233, P = 0·007; Table SIII, Fig ). No significant difference emerged between the groups with or without anti‐GPIb/IX antibodies (17/31 = 54·8% vs. 33/55 = 60%, χ2 = 0·217, P = 0·641). Further comparisons showed that the response rate was not significantly different between anti‐GPIIb/IIIa positive patients with (12/17 = 70·6%) or without (15/19 = 78·9%) (χ2 = 0·334, P = 0·563) anti‐GPIb/IX antibodies. Likewise, no statistical difference was observed in anti‐GPIIb/IIIa negative patients with (5/14 = 35·7%) or without (18/36 = 50%) (χ2 = 0·828, P = 0·363) the presence of anti‐GPIb/IX antibodies. Moreover, we also found that patients with single anti‐GPIIb/IIIa antibodies were more sensitive to rituximab treatment than those with single anti‐GPIb/IX antibodies (χ2 = 6·310, P = 0·012) and double negative cases (χ2 = 4·342, P = 0·037), but neither achieved significance (P > 0·05/6 ≈ 0·008, respectively). The response rate was not significantly different in patients with anti‐GPIb/IX antibodies, with or without the presence of anti‐GPIIb/IIIa antibodies (χ2 = 3·770, P = 0·052). Multivariate logistic regression analysis showed that age, gender, pre‐treatment platelet count, or rituximab dose were not associated with patients’ response (Table SIV). Only anti‐GPIIb/IIIa antibody remained related to rituximab response (the estimated odds ratio [OR] of response for patients with anti‐GPIIb/IIIa antibodies relative to patients without anti‐GPIIb/IIIa antibodies was 3·806 [P = 0·008]). The analysis did not show any association between the response rate and the existence of anti‐GPIb/IX autoantibody (OR 0·578, 95% confidence interval 0·216–1·546). Primary ITP is a disorder caused by increased platelet destruction and impaired platelet production. Corticosteroids are recommended as the first‐line treatment with relatively high response rates. Second‐line therapies for corticosteroid‐resistant or relapsed patients include splenectomy and rituximab. As splenectomy is an invasive procedure, very few patients opt to receive it in China. Rituximab is a monoclonal anti‐CD20 antibody that provides an initial response rate of almost 60% in ITP at the standard dosage at 375 mg/m2 weekly for 4 weeks (Patel et al, 2012). Recent studies demonstrated that two low‐dose rituximab regimens, 100 mg weekly for 4 weeks (Zaja et al, 2010) or a single dose of 375 mg/m2 (Taube et al, 2005), possessed similar therapeutic efficacy as the standard dose (Taube et al, 2005; Zaja et al, 2010), and these dosing schedules are currently recommended. We found that ITP patients with anti‐GPIIb/IIIa antibodies were more responsive to rituximab treatment. The precise reason for this phenomenon remains unknown. It has been reported that anti‐GPIb antibodies were associated with a lower platelet count and inadequate responses to corticosteroids (Zeng et al, 2012) and IVIG (Peng et al, 2014), although they were less prevalent than anti‐GPIIb/IIIa antibodies in ITP patients. By contrast, Nishimoto et al (2013) developed a murine ITP model by complete Treg depletion, and found that antiplatelet autoantibodies preferentially targeted GPIb/IX over GPIIb/IIIa. Similarly, it is reasonable to speculate that the immunological situation in ITP patients with anti‐GPIIb/IIIa antibodies might be different from those with anti‐GPIb/IX antibodies. Anti‐GPIIb/IIIa antibodies induce platelet destruction by Fc‐dependent phagocytosis, while the action of anti‐GPIb/IX antibodies is Fc‐independent (Nieswandt et al, 2000). Rituximab would deplete B‐lymphocytes, reducing autoantibody levels and anti‐GPIIb/IIIa‐mediated platelet destruction, which could barely interfere with the anti‐GPIb/IX antibody pathway (Stasi et al, 2008). Moreover, our recently published data showed that cytotoxic t‐lymphocytes could induce platelet GPIb desialylation, subsequently leading to platelet clearance in the liver via hepatocyte asialoglycoprotein receptors (Qiu et al, 2016). However, whether GPIb desialylation is associated with the exposure of hidden epitopes and the production of anti‐GPIb/IX antibodies still needs further investigation. In summary, our study showed that ITP patients with anti‐GPIIb/IIIa autoantibodies were more responsive to rituximab treatment; therefore, autoantibodies might be useful predictors for rituximab response in ITP treatment.

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Influential voices around Chronic Lymphocytic Leukemia - ASH

Influential voices around Chronic Lymphocytic Leukemia - ASH | Hematology | Scoop.it
Network analysis graph of Chronic Lymphocytic Leukemia convo – American Society of Hematology Annual Meeting.Data from the Healthcare Social Graph® –...
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Paper: Proteomic Landscape of De Novo Pediatric Acute Myeloid Leukemia

Paper: Proteomic Landscape of De Novo Pediatric Acute Myeloid Leukemia | Hematology | Scoop.it
Background: Many genetic drivers that are implicated in disease pathology and risk stratification have been identified for pediatric acute myeloid leukemia (pedi-AML). However, only a minority have been exploited for therapeutic interventions and most of the identified genetic events currently lack targeted therapy to address the mutations. The combined consequences of genetic and epigenetic events culminate in a net effect manifested at the protein level and most of the chemotherapies target proteins. Yet little is known about the proteomic landscape of pedi-AML. Methods: Reverse Phase Protein Array (RPPA) was performed with 291 strictly validated antibodies to determine the protein expression levels of bulk leukemic cells from 505 pedi-AML patient samples that were collected prior to therapy. All patients participated on the COG AAML1031 Phase 3 clinical trial, that compared standard therapy (ADE) to ADE plus bortezomib (ADE+B). Proteins were allocated into 31 protein functional groups (PFG) (e.g. cell cycle, apoptosis) to analyze proteins in relation to related proteins. Progeny clustering was performed to identify patients with correlated protein expression patterns within each PFG (protein cluster). Block clustering searched for protein clusters that recurrently co-occurred (protein constellation), and for subgroups of patients that expressed similar combinations of protein constellations (protein signatures). Protein signatures were correlated with known cytogenetics and mutational state. Results: For each PFG, cluster analysis identified an optimal number of protein clusters, resulting in a total of 120. From this we constructed 11 protein constellations (PRCON) and 10 protein signatures (SIG) (Fig. 1A). A training set (n=334) and test set (n=171) showed high reproducibility (Pearson’s X2; p < 0.001). SIG were prognostic for event-free survival (EFS) (p = 0.029), with a favorable EFS for SIG 1, 2, 3, 5, 7 & 9, and an unfavorable EFS for SIG 4, 6, 8, 10. Notably, patients that formed SIG 3 had a significant better EFS after receiving ADE+B than patients that received ADE (p = 0.039) (Fig. 1B). This SIG was highly enriched for CEBPA mutated cases; 43% vs. 9% overall (p < 0.001). SIG were associated with cytogenetic aberrations (p < 0.001) and mutational state, as well as with the traditional risk groups (p < 0.001). For example, t(8;21) was overrepresented in SIG 9 (39% vs. 16% overall) and MLL-rearrangement in SIG 6 (61% vs. 19% overall). Multivariate analysis was performed using variables definable at time of diagnosis and known prognostic factors. This resulted in a final model including unfavorable protein SIG together with low risk cytogenetics and NPM1 mutation state as independent prognostic factors, suggesting that proteins add to known prognostic factors. Proteomics could also identify aberrantly expressed proteins within each SIG compared to normal CD34+ cells. This recognized 31 proteins as universally down regulated (e.g. CDKN1A, PPP2R2A) and 13 as universally up regulated (e.g. PIK3CA, NCL). Many other proteins were different between SIG, and thus potentially targetable in particular patient groups: high KIT (SIG 3, 4 & 5), high BCL2 (SIG 3, 4, 5, 6, 9 & 10) and high BRD4 (SIG 6). SIG 1 & 2 both had a very characteristic expression pattern and were most distinct from the others. IGFR1, IGFR1.pY1135, AKT3, SMAD5.pS463-7 and RICTOR.pT1135 were all high, whereas they were low in most other SIG. Conversely, STAT3 was normal in SIG 1&2, but changed in the other SIG. SIG 6, 7 & 8 also had relatively similar expression patterns, but had different outcomes. Compared to SIG 6 & 8, SIG 7 had higher GAB2 and MCL1 and lower RAD50, ERCC1. Conclusions: Pedi-AML is characterized by a finite number (n=10) of recurrent protein signatures. SIG were only partially correlated with cytogenetics and mutation state, indicating that protein expression could add to genetics in the process of risk stratification. We identified SIG that did well vs. SIG that did not, independent of known risk factors, and identified a group of patients that could potentially benefit from ADE+B. Recognition of differentially expressed proteins suggest potential targets for combinational treatment (Hoff et al. ASH HSF1 abstract). Figure 1. A. Identification of 11 PRCON (horizontally) and 10 SIG (vertically). B. SIG were prognostic for EFS. C. SIG 3 significantly benefitted from ADE+B (green) compared to ADE alone (blue).

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Leukemia Relapses May Arise From Specialized Cells

Leukemia Relapses May Arise From Specialized Cells | Hematology | Scoop.it
Targeting the transient group of cells could prevent recurrence of the disease.
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Experts present new recommendations on 'overlapping' type of leukemia | EurekAlert! Science News

Experts present new recommendations on 'overlapping' type of leukemia | EurekAlert! Science News | Hematology | Scoop.it
Chronic myelomonocytic leukemia (CMML) is a rare disease with overlapping features of two categories of bone marrow and blood cell disorders that poses challenges in clinical management. Joint recommendations on diagnosis and treatment of CMML from two European specialty societies were published today in HemaSphere, the official journal of the European Hematology Association (EHA). The journal is published in the Lippincott portfolio by Wolters Kluwer.
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Healthy blood stem cells have as many DNA mutations as leukemic cells | EurekAlert! Science News

Healthy blood stem cells have as many DNA mutations as leukemic cells | EurekAlert! Science News | Hematology | Scoop.it
Researchers from the Princess Máxima Center for Pediatric Oncology have shown that the number of mutations in healthy and leukemic blood stem cells does not differ. Rather the location of the mutations in the DNA is relevant.

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Physicians’ Education Resource® to Present Six Satellite Symposia at Annual American Society of Hematology Meeting and Exposition

Physicians’ Education Resource® to Present Six Satellite Symposia at Annual American Society of Hematology Meeting and Exposition | Hematology | Scoop.it
Physicians Education Resource (PER), the nations leader in advancing patient care through continuing medical education (CME), will conduct six CME-Accredited…...
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Thrombotic thrombocytopenic purpura: Toward targeted therapy and precision medicine - Coppo - - Research and Practice in Thrombosis and Haemostasis - Wiley Online Library

Abstract Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy characterized by severe congenital or immune‐mediated deficiency in ADAMTS13, the enzyme that cleaves von Willebrand factor multimers. This rare condition leads invariably and rapidly to a fatal outcome in the absence of treatment, and therefore raises multiple diagnostic and therapeutic challenges. The novel concepts and mechanisms identified in the laboratory for this disease have been rapidly and successfully translated into the clinic for the benefit of patients, making TTP an archetypal disease that has benefited from targeted therapies. After decades of empirical treatment with plasma exchange, identification of ADAMTS13 as the key enzyme involved in TTP pathophysiology provided an explanation for the remarkable efficacy of plasma administration, in which the missing enzyme is replenished, and paved the way for development of a recombinant form of the enzyme. Similarly, the demonstration of a major role of anti‐ADAMTS13 antibodies through models of passive transfer of autoimmunity spurred development of immunomodulatory strategies based on B‐cell depletion. More recently, an inhibitor of the platelet‐von Willebrand factor interaction demonstrated efficacy in large clinical trials through prevention of formation of further microthrombi and protection of organs from ischemia. These translational breakthroughs in TTP are described in our review. Essentials TTP is still under‐diagnosed. A delay in diagnosis remains a prognostic concern. Death rate of acute TTP scarcely changed for > 20 years. Most deaths occur in the first days of the management; these patients need new strategies. An increasing number of targeted therapies based on anti‐vWF agents and recombinant ADAMTS13 should help in decreasing early TTP mortality and relapse. These new therapies were derived from a better understanding of TTP pathophysiology, reflecting a shift from empiricism to targeted therapies. 1 INTRODUCTION Thrombotic thrombocytopenic purpura (TTP) is a devastating disease characterized by microangiopathic hemolytic anemia, thrombocytopenia, and organ failure of variable severity. Historically, TTP had a fatal prognosis. This was transformed with the use of intensive therapeutic plasma exchange (TPE) in 1991.1 In the following years, the rapid and systematic use of TPE in association with corticosteroids until durable remission emerged as the standard regimen for TTP treatment. In 1998, the identification of a dysfunction of the von Willebrand factor (vWF)‐cleaving protease ADAMTS13 (A Disintegrin And Metalloproteinase with ThromboSpondin‐1 motifs; 13th member of the family) as a result of the production of autoantibodies against the enzyme in autoimmune TTP (iTTP) provided a rationale for the evaluation of B‐cell depleting therapies.2, 3 The addition of rituximab to the standard regimen in the mid‐2000s represented the second breakthrough in the management of the disease.4 Indeed rituximab, formerly administered as adjuvant therapy in iTTP in patients with a suboptimal response to the standard regimen, is now increasingly used frontline, and still more recently as a preemptive strategy to prevent relapse.5 In the very near future, this therapeutic arsenal will be strengthened by more targeted therapies stemming directly from our understanding of disease pathophysiology, specifically recombinant ADAMTS13 and caplacizumab, an agent that inhibits platelets‐vWF adhesion. In this review, we discuss recent advances as well as future perspectives in the rapidly evolving therapeutic landscape of TTP. 2 PATHOPHYSIOLOGICAL BASIS OF TTP TREATMENT iTTP episodes occur in patients with severe, autoantibody‐mediated ADAMTS13 deficiency. In this context, highly adhesive vWF multimers accumulate leading to excessive platelet clumping in the microvasculature under high shear stress conditions, with resultant multi‐organ failure and death if effective management is not instituted. Consequently, the basis of current treatment is to supply ADAMTS13 through the administration of very large volumes of plasma, in association with plasmapheresis to prevent fluid overload and possibly to remove unusually large vWF multimers and anti‐ADAMTS13 autoantibodies. Autoantibodies directed against ADAMTS13 block the proteolytic activity of ADAMTS13 and/or increase its clearance from the circulation by forming noncovalent circulating immune complexes. Models of passive transfer of autoimmunity in baboons and rodents have supported these concepts,4 and led to wider use of immunosuppressive treatments. However, the immune cells precisely involved in the production of anti‐ADAMTS13 autoantibodies and accounting for the remarkable efficacy of B‐cell depleting agents in this disease remain to be identified. 3 CLINICAL PRESENTATION The epidemiology of iTTP and clinical features on presentation have now been well characterized from large national registries.4, 5 The incidence of TTP has been reported to be two to four cases per million people per year.6 iTTP occurs more frequently in females (3:2 female‐to‐male ratio) with a median age in the fourth decade. While the onset of disease is typically sudden, prodromic manifestations including fatigue, arthralgias, myalgias, and abdominal and/or lumbar pain suggestive of a flu‐like illness are frequent. iTTP occurs in association with predisposing conditions in 50% of cases that need to be identified for appropriate management: connective tissue diseases, pregnancy, or more rarely HIV infection, and cancer.6 Therefore, unexplained anemia and thrombocytopenia in such contexts should prompt investigation for possible underlying iTTP. Microangiopathic hemolytic anemia and peripheral thrombocytopenia are constant clinical features of TTP and are variably associated with organ injury. Cerebral and digestive manifestations are the most usual. Renal failure is typically mild or absent7 (for a concise review, see Kremer Hovinga et al4). In recent years, clinicians have become increasingly aware of cardiac involvement including infarction, congestive heart failure, arrhythmias, cardiogenic shock, and sudden cardiac arrest. Importantly, an elevated serum troponin level upon presentation is a common event (observed in up to 60% of patients) and represents an independent predictor of death, treatment refractoriness, and subsequent acute myocardial infarction.8, 9 The above clinical features are not specific for TTP, and TTP presentation may overlap with that of other thrombotic microangiopathy (TMA) syndromes. However, there is now accumulating evidence from large series of patients that severe acquired ADAMTS13 deficiency is associated with specific clinical features, such as mild renal involvement and severe thrombocytopenia compared with other TMAs. Lastly, some patients with TMAs other than TTP may have a low but detectable level of ADAMTS13 activity, and it cannot be excluded that subtle dysfunction of ADAMTS13 caused by yet unknown mechanisms may have a role in the TMA process.10 4 IMPORTANCE OF RAPID, ACCURATE DIAGNOSIS With the increasing availability of effective treatments, rapid diagnosis of TTP by sensitive criteria is mandatory, and this urgency led to a decrease in the stringency of the diagnostic criteria in the clinical trial that documented the effectiveness of TPE.1 Consequently, the association of microangiopathic hemolytic anemia with peripheral thrombocytopenia should be enough to strongly suggest a diagnosis of TTP, before organ failure occurs. In line with this view, patients with an apparent diagnosis of immune thrombocytopenia (ITP) or Evan's syndrome who are not responding to the usual therapies should be investigated for schistocytes on repeated blood smears to revisit the diagnosis.11 Although the identification of severe (activity <10%) autoimmune‐mediated ADAMTS13 deficiency is required to document the diagnosis of iTTP, results of ADAMTS13 activity measurements are rarely available in emergency situations. Moreover, commercial kits may provide discrepant results in 12% of cases.5 Until assays are able to provide accurate ADAMTS13 activity within several hours, clinical scores for rapid prediction of individuals with severe ADAMTS13 deficiency will continue to have an important role in diagnosis.12-14 Two scores (the French score, and more recently the PLASMIC score),12, 13 derived from standard parameters easily available on presentation, offer a comparable and reliable way to identify patients with severe ADAMTS13 deficiency. Both scores use absence of an associated condition (eg, cancer, transplant, and disseminated intravascular coagulation), severe thrombocytopenia (<30 G/L) and mild renal involvement (serum creatinine level < or 2.25 mg/dL) as criteria for identifying patients with probable TTP (Table 1). It is likely that platelet count and serum creatinine level are the most useful and reliable values to predict severe ADAMTS13 deficiency. These scores are not aimed at redefining TTP diagnostic criteria, which are based on severe ADAMTS13 deficiency,15, 16 but they can help to rapidly identify patients who are most likely to have iTTP and therefore most likely to benefit from emergency treatment including TPE. French score PLASMIC score Platelet count <30 G/L (+1) <30 G/L (+1) Serum creatinine level <2.25 mg/dL (+1) <2 mg/dL (+1) Hemolysis Indirect bilirubin >2 mg/dL –a +1 Or reticulocyte count >2.5% Or undetectable haptoglobin No active cancer in previous year –a +1 No history of solid organ or SCT –a +1 INR < 1.5 –a +1 MCV < 90 fLb – +1 Prediction of severe 0: 2% 0‐4: 0%‐4% ADAMTS13 deficiency 1: 70% 5: 5%‐24% (Activity <10%)c 2: 94% 6‐7: 62%‐82% Each item is associated with one point (+1). INR, international normalized ratio; MCV, mean corpuscular value; SCT, stem cell transplantation. a The French score considered patients with a thrombotic microangiopathy (TMA) syndrome (which includes hemolysis with schistocytes in the definition) and assumes that there is no history of or clinical evidence for associated cancer, transplantation or disseminated intravascular coagulopathy; so these items are intrinsic to the score. b MCV was not incorporated in the French score. c Results correspond to those of the derivation cohort and those of a validation by (French score) the bootstrap resampling technique (internal validation) (Coppo et al,12 Bendapudi et al,13 and manuscript in preparation), or (PLASMIC score) different samples of patients from the same institution (internal validation) or from a different institution (external validation).12, 13 5 THE CURRENT STANDARD OF CARE TTP is a medical emergency and requires rapid diagnosis and urgent management. Older age, a very high LDH level (reflecting organ damage as well as hemolysis) and increased cardiac troponin level on diagnosis, are associated with death and treatment refractoriness. Cardiac troponin assessment at the time of initial diagnosis to identify the more severe patients should be part of standard evaluation.8, 9 TPE remains the cornerstone of current management of iTTP and should be started as soon as the diagnosis is strongly suspected. Given the autoimmune nature of iTTP, there is a rationale for the use of corticosteroids, although evidence is limited17-20 (see Figure 1). 6 IMMUNOMODULATION THROUGH B‐CELL DEPLETION: WHERE DO WE STAND? The introduction of the humanized anti‐CD20 monoclonal antibody rituximab has been the second major breakthrough in iTTP management. Clinical studies conducted to assess the role of rituximab in iTTP have faced the usual challenges that confront clinical trials in rare diseases such as difficulty with recruitment and cross‐over.21 These challenges are compounded in iTTP by the necessity to intervene rapidly, leaving little time for determination of eligibility and informed consent. As such, current knowledge about the use of rituximab in iTTP is based on observational studies that enrolled a limited number of patients and provide low to moderate levels of evidence. Rituximab was first introduced in patients with a suboptimal response to conventional treatment (ie, disease exacerbation or refractoriness). From published studies of ≥10 iTTP patients treated with rituximab impressive remission rates of >90% occurring rapidly (typically in less than 4 weeks) were observed.4 In most instances, we administer four infusions of rituximab 375 mg/m2 once or twice weekly. The twice weekly administration schedule is justified by the significant clearance of rituximab by TPE (65% clearance per plasma volume22). Rituximab is started immediately after the end of a TPE session. When feasible, we wait a minimum of 18 hours after rituximab infusion until the next TPE to avoid excessive clearance of rituximab.23, 24 The response rates observed with rituximab exceed those of other historical salvage therapies, such as vincristine and cyclosporine A.4 No relapse was observed during the first year of follow‐up, but there were relapses beyond 1 year. Most significant side effects were mild infections. A rituximab regimen based on B‐cell depletion provided evidence that similar results could be obtained with only two to three rituximab infusions.25 Trials are ongoing to define more accurately the minimal effective dose of rituximab for this indication (ClinicalTrials.gov, NCT01554514). The convincing results reported with rituximab in patients with a suboptimal response to standard therapy prompted investigators to evaluate its efficacy as frontline therapy in all patients with iTTP. In 2011, the UK group reported that frontline treatment with rituximab resulted in shorter hospitalization and fewer relapses that occurred later than in a historical group not treated with rituximab.26 Fewer and later relapses were also seen in rituximab treated patients by the French TMA Reference Center Network23 and the Oklahoma TTP registry.27 Although the time to response with rituximab is shorter in iTTP (median, 2 weeks between the first infusion and durable platelet count recovery) than for many other autoimmune diseases,23, 26 rituximab failed to prevent early deaths occurring in the first 10 days,23 leaving a crucial unmet need. 7 THE UNMET NEEDS WITH STANDARD TREATMENT TPE transformed the historically fatal prognosis of iTTP to a treatable disease with an overall survival rate of 85%. Despite further improvements in the management of iTTP, including immunomodulation with rituximab, the last 20 years have seen only modest gains in survival.1, 23, 28 The two main causes of death are insufficient awareness of TTP diagnosis, leading to diagnostic delay,11 and the unmet need for new weapons for the management of the most severe cases, particularly early in the disease course. Another limitation of standard treatment is that TPE and catheter placement represent a cumbersome procedure associated with major complications including infection, bleeding, catheter‐associated thrombosis, toxicities of plasma infusion, and death.29 It is hoped that new drugs stemming from a better understanding of TTP pathophysiology will potentially bring about further reductions in mortality and healthcare burden. 8 THE FORTHCOMING THERAPEUTIC ARSENAL 8.1 Caplacizumab: inhibiting von Willebrand factor–platelet interaction Caplacizumab (formerly ALX‐0081) is a nanobody (single‐domain antibody) derived from single‐chain antibodies naturally occurring in Camelidae. It was assessed in the TITAN and HERCULES trials, two multicenter randomized placebo‐controlled phase II and phase III studies, respectively, in patients with iTTP. Although the TITAN trial enrolled a lower number of patients than planned due to persistent recruitment challenges, some of whom did not have confirmed severe ADAMTS13 deficiency, both trials provided comparable conclusions. Time‐to‐platelet count recovery was significantly shorter and biomarkers reflecting ischemic organ damage normalized more rapidly in patients who received caplacizumab in addition to standard of care treatment.14, 30 The incidence of exacerbations was also reduced with caplacizumab, as the compound was continued for 30 days after TPE, thus covering the period for exacerbation. Because caplacizumab does not target the ongoing autoimmune response, increased relapses were observed in both trials shortly after withdrawal of caplacizumab. Relapsing patients had persistent severe ADAMTS13 deficiency. These observations raise two novel management considerations in iTTP. First, they provide further evidence that B‐cell depletion and corticosteroids should be initiated as soon as possible to hasten ADAMTS13 recovery. As caplacizumab provides a therapeutic bridge until ADAMTS13 improvement, it may be pursued over a longer period of time in patients with persistent severe ADAMTS13 deficiency, though this strategy must be balanced against the potential bleeding risk. Second, they suggest the potential of caplacizumab to prevent formation of further microthrombi and ischemic organ injury in the early, critical phase of the disease (ie, until rituximab and corticosteroids are effective).31 Caplacizumab substantially reduced the burden of care of iTTP patients by reducing the number of TPE sessions, length of hospital stay, and length of stay in the intensive care unit.14 Minor bleeding was more common in caplacizumab‐treated patients, but importantly there were no major or fatal bleeding cases.14 More safety data are needed from future studies on the risk of bleeding, especially in patients treated concomitantly with anticoagulants or when caplacizumab is administered over a period longer than 30 days (see Figure 1 and Algorithm A1). In conclusion, caplacizumab may improve survival of patients with iTTP in the early phase of the disease until improvement of ADAMTS13 activity with B‐cell depleting therapies, which usually occurs within 30 days.23, 26 Consequently, ADAMTS13 activity should be monitored closely (for example, once per week) after platelet count recovery to determine the optimal time for stopping caplacizumab when ADAMTS13 is no longer severely deficient (for example, ADAMTS13 activity >20%). Forthcoming studies that focus specifically on the impact of caplacizumab on outcomes in the most severely affected patients are anxiously awaited. 9 RECOMBINANT ADAMTS13: THE NEXT STEP? The identification of ADAMTS13 as the key missing component in TTP‐fueled development of a recombinant form of the protein (rADAMTS13) (SHP655; BAX930), for which tolerability and efficacy were recently evaluated in a phase 1 study of patients with congenital TTP. The therapeutic enzyme was reported to be safe and well tolerated, with a half‐life of 53 hours, which is comparable to the half‐life of wild‐type ADAMTS13.32 No significant adverse events were reported; specifically, no anti‐ADAMTS13 antibodies were detected. Finally, the study provided evidence of rADAMTS13 activity: platelet counts increased and the larger multimers of VWF decreased.33 Consequently, a phase 3 randomized controlled trial is planned to assess the efficacy of recombinant ADAMTS13 versus standard, plasma infusion‐based, treatment in congenital TTP (https://clinicaltrials.gov/ct2/show/NCT03393975). In the future, recombinant ADAMTS13 could be important not only for congenital TTP but also for the autoimmune‐mediated form. By saturating anti‐ADAMTS13 antibodies and cleaving large vWF multimers, recombinant ADAMTS13 could, together with immunomodulatory therapies and caplacizumab, decrease the burden of TPE treatment and hospitalization stay. The need to saturate anti‐ADAMTS13 antibodies in patients with iTTP suggests that higher doses of recombinant ADAMTS13 may be required for patients with iTTP than the replacement doses required for cTTP. Alternatively, recombinant forms of the enzyme engineered to be resistant to the autoantibodies could circumvent this limitation and be more cost‐effective.34 As reported for severe hemophilia A,35 the use of recombinant ADAMTS13 in cTTP could enhance the risk of developing inhibitors or boosting inhibitor titers compared with administration of plasma‐derived ADAMTS13 by the activation of ADAMTS13 specific memory B‐ and T‐cells.36 10 MANAGEMENT OF PATIENTS FOLLOWING THE ACUTE PHASE 10.1 Prevention of relapses Historically, 40% of patients with iTTP experience one or multiple relapses.37 Relapses result from severe ADAMTS13 deficiency caused by the persistence or recurrence of anti‐ADAMTS13 autoantibodies. Whereas persistent severe ADAMTS13 deficiency during remission has been consistently associated with clinical relapse, the predictive value of anti‐ADAMTS13 antibodies for iTTP relapse remains controversial.38, 39 Younger age was also associated with an increased risk of relapse in one study.39 Each relapse exposes the patient to risk of death and to complications related to TPE or to intensive care unit hospitalization. Therefore, the prevention of relapse in TTP represents a major goal. As detailed above, the use of rituximab in the acute phase of the disease dramatically decreases the relapse rate at 1 year. However, beyond this period, anti‐ADAMTS13 autoantibodies may recur along with peripheral B‐cell reconstitution, exposing patients to risk of clinical relapse. These observations provided a rationale to evaluate the efficacy of rituximab in iTTP as preemptive therapy for patients in clinical remission, but with persistent or recurrent severe ADAMTS13 deficiency. In this context, rituximab remarkably reduces the incidence of iTTP relapse by diminishing the production of anti‐ADAMTS13 antibodies and rapidly restoring ADAMTS13 activity, which parallels peripheral B cell depletion.40-42 In our practice, we assess ADAMTS13 regularly during follow‐up (typically every 3 months). After serial ADAMTS13 assessments have remained normal (>50%) durably (typically 3 years), measurements are spaced out to twice a year for 2 years and then yearly. When ADAMTS13 activity becomes undetectable (activity <10% or even <20%), a single infusion of rituximab 375 mg/m2 is administered. In >80% of patients, ADAMTS13 activity post‐rituximab is detectable or even normalizes (20% to >50%) as early as 4‐6 weeks after infusion. However, in up to 50% of patients, ADAMTS13 recovery is transient and drops again with peripheral B‐cell reconstitution, typically 12 months later. Consequently, further rituximab infusions may be required to maintain a detectable ADAMTS13 activity and prevent clinical relapse.40-42 Patients with persistent severe (activity <10%‐20%) ADAMTS13 deficiency are exposed to a high risk of relapse, with a 7‐year cumulative incidence of relapse of 74%.42 Moreover, 10%‐15% of patients are primarily unresponsive to rituximab or experience refractoriness after an initial response.40 In these cases, a more intensive regimen inspired from those used in lymphoid malignancies and consisting of 4‐6 weekly infusions and/or maintenance treatment (4 infusions per year for 2 years) may overcome rituximab refractoriness42 (R. Saleem, Z. R. Rogers, C. Neunert, & J. N. George, Submitted). Multiple infusions of rituximab may expose patients to infections or other long‐term complications, although treatment is generally well tolerated. Based on estimates that preemptive treatment with rituximab improves ADAMTS13 activity in 85% of cases and prevents a clinical relapse that may occur in 74% of cases, we can estimate that the number of patients needed to treat to prevent one relapse is only 1/(0.85 × 0.74), ie, 1.6. Moreover, if the risk of death with relapse is 5%,38 the number of patients needed to treat to prevent one death is 1/(0.85 × 0.74 × 0.05), ie, 32.42, 43 The most serious infectious complication associated with rituximab, progressive multifocal leukoencephalopathy, is only observed in one in 25 000 patients, and one in 500 000 if one only considers patients without AIDS or cancer. Therefore, persistent or recurrent severe autoimmune ADAMTS13 deficiency should be considered as a reasonable indication for preemptive treatment with rituximab (See Algorithm A2).40, 44 The pathophysiological mechanisms underlying the different scenarios in iTTP observed after treatment with rituximab (ie, durable response, temporary response with subsequent recurrence of anti‐ADAMTS13 autoantibodies, refractoriness) as well as the specific B‐ and T‐cell and plasma cell subpopulations involved still remain to be elucidated.45 Future studies should also assess whether rituximab selects for survival of long‐lived plasma cells involved in the production of anti‐ADAMTS13 autoantibodies, which would raise new therapeutic challenges.46, 47 Splenectomy has also been reported to decrease relapses with an acceptable safety profile and may therefore represent an alternative to rituximab.4, 48, 49 A comparison of the efficacy of splenectomy versus rituximab to prevent relapse deserves further investigation, possibly through a large international registry. 10.2 Long‐term follow‐up: connective tissue diseases, cognitive disturbances, and greater risk of death iTTP is associated with an increased risk for other autoimmune diseases (mostly systemic lupus erythematosus and Sjögren's syndrome), which may present before, concomitant with, or after diagnosis of iTTP. The cumulative incidence of autoimmune disorders after iTTP diagnosis is 9.9% after 5 years, 13.5% after 10 years, and 25.9% after 12 years.50, 51 The incidence is higher after rather than before the first iTTP episode and increases over time, suggesting a role for increasing age. Recent data have emphasized that after recovery from acute episodes of iTTP, patients report minor cognitive abnormalities as well as problems with concentration and endurance, possibly resulting from posttraumatic stress disorder. Such complications need to be recognized and appropriately managed. Of note, neither depression nor cognitive impairment was significantly associated with the occurrence of relapses or ADAMTS13 activity <10%‐20% during remission.52 Moreover, prevalence of hypertension and major depression is greater as is mortality among iTTP survivors in remission compared with a reference population.51 The excess of early death in patients with a history of iTTP remains unexplained and could result from sudden undiagnosed relapses, increased cardiovascular risk related to persistent severe ADAMTS13 deficiency, organ damage following the acute episode, or other causes.50 The long‐term complications of iTTP were described and recognized only recently and emphasize the need to consider iTTP as a chronic disease. Accordingly, patients should receive long‐term follow‐up and monitoring for associated autoimmune diseases and manifestations of post‐traumatic stress disorder. Future studies should assess whether new targeted therapies lower the burden of long‐term complications. 11 HOW TO IMPROVE TTP MANAGEMENT? 11.1 Make clinicians more aware of TTP diagnosis The rapid diagnosis and early initiation of treatment are clearly related to a favorable outcome. Diagnosis of iTTP in an emergency setting is challenged by the rarity of the disease and nonspecificity of presenting signs and symptoms, which may lead to a delay in initiation of treatment.11, 21 Although the diagnosis of iTTP is still delayed in some patients, clinicians are becoming increasingly aware of this condition. In line with this statement, the frequency of organ failure (especially cerebral involvement) has decreased in the last 10 years.12, 53 In an attempt to further improve management of patients with iTTP, various measures are being developed in a growing number of countries. These include educational programs for generalists, emergency department physicians, and other specialists aimed at enhancing recognition and improving management of the disease. Importantly, there should also be educational programs for patients about the typical features suggestive of a relapse. 11.2 More rapidly identify the most severely affected patients The other important cause of death that must be considered is primary refractory disease. Primary refractory disease is characterized by the absence of platelet count improvement under standard treatment by day 4 and organ involvement, often manifesting as an increased cardiac troponin. These patients require earlier intensified treatment.9, 31, 54, 55 The prompt availability of ADAMTS13 activity or the use of surrogate markers12, 13, 56 to predict severe enzyme deficiency, coupled with early prognostic markers such as cardiac troponin and ADAMTS13 antigen/anti‐ADAMTS13 autoantibody titers,9, 55 could facilitate adjustment of initial treatment to the severity of the disease and improve the historical 10%‐15% death rate in the acute phase. 11.3 Reference centers with experienced practitioners TTP and other TMAs represent rare diseases requiring a high level of skill for their management. These disorders require dedicated national or regional reference centers which have been established in an increasing number of countries.57, 58 In France, the Rare Diseases National Plan provides expertise for management of rare disorders, a platform for conducting studies, and resources and information for patients, their families, and their physicians. Telemedicine allows reference centers to provide services to remote locations. TTP and the other TMA syndromes may be particularly amenable to telemedicine approaches because of the need to answer reports promptly at all hours of the day.58 Future work should evaluate the effectiveness of telemedicine activity from reference centers on outcomes in patients with rare diseases including iTTP. 11.4 Improve the level of evidence of therapeutic studies in TTP Clinical studies in iTTP have been limited by the low incidence of this disease. In particular, conventional methods (eg, randomized controlled trials) are challenging in TTP,21 except for extremely expensive and lengthy pharmaceutical trials.14 However, over the past few years, several groups have established large registries that include hundreds of patients. These registries have shed light on the epidemiology, clinical presentation, prognosis, and long‐term outcomes of the disease.12, 28, 55, 56, 59-62 Those efforts also provide evidence that collaborations at the national and international level remain key to the continued advancement of knowledge and treatment of rare diseases.14 Collaborative efforts have led to proposal of consensus treatment modalities and definitions of treatment responses based on large series of patients.15 Though arbitrary and based only on clinical experience, these consensuses foster a common language and study designs that will facilitate meta‐analyses and data synthesis in the future. There is no doubt that the understanding of iTTP will require close collaboration between multiples disciplines, including hematology, transfusion medicine, nephrology, internal medicine, immunology, and intensive care medicine. 12 UNANSWERED QUESTIONS IN TTP MANAGEMENT As new standards in the management of iTTP are defined15 and new treatments are implemented, new questions will need to be addressed, ideally through international collaborative studies: Are diagnostic algorithms, (particularly platelet count and serum creatinine level),4, 13, 14 which are easily available in real‐time, sufficiently accurate to begin treatments while awaiting the report of ADAMTS13 activity? Such an approach would allow the immediate use of targeted therapies (B‐cell depleting therapies, caplacizumab, and possibly recombinant ADAMTS13) in addition to TPE and corticosteroids; Just as rituximab is being progressively incorporated into standard initial therapy along with TPE and corticosteroids,4, 5 should we also consider caplacizumab as a new standard of care for all iTTP patients from diagnosis? Such a strategy would be expected to facilitate faster platelet count and organ damage recovery and protect patients from exacerbations until ADAMTS13 recovery14; Should preemptive treatment be recommended for all patients with severe (activity <10%‐20%) immune‐mediated ADAMTS13 deficiency in clinical remission? On one hand, this strategy significantly decreases the incidence of relapse and is well tolerated. On the other hand, 50% of patients need multiple courses of rituximab over time to maintain a detectable ADAMTS13 activity, exposing them to possible side effects,40, 42 and some patients with severe ADAMTS13 deficiency do not relapse; Could a recombinant form of ADAMTS13 improve outcomes in patients with iTTP by saturating anti‐ADAMTS13 antibodies and cleaving ultra‐large vWF multimers? One could speculate that recombinant ADAMTS13 may reduce the number of TPE sessions or even replace TPE; Future studies are needed to define the efficacy of additional therapeutic agents. In patients who are refractory to rituximab, it has been hypothesized that long‐lived plasma cells could be the source of anti‐ADAMTS13 antibodies, suggesting a potential role for anti‐plasma cell strategies. So far, promising results were reported with the proteasome inhibitor bortezomib,37, 63 which suggests that monoclonal antibodies targeting the CD38 antigen on plasma cells could also be of interest. N‐acetylcysteine (NAC), an FDA‐approved mucolytic agent, was demonstrated to reduce disulfide bonds in vWF, thereby decreasing VWF multimer size.64 Although animal models suggested efficacy of NAC as a prophylactic agent, the administration of NAC was not effective in treating TTP even though a reduction in vWF multimers was observed.65 A Phase I trial is in progress to assess the possible efficacy of this compound in clinical practice (ClinicalTrials.gov NCT018008521). 13 CONCLUSION: TTP AS A SUCCESSFUL EXAMPLE FOR TRANSLATIONAL MEDICINE The prospect of targeted therapies promises to alter the landscape of TTP therapy in the coming years. In particular, the combination of recombinant ADAMTS13 in association with immunomodulation (steroids and B‐cell depletion) and caplacizumab may constitute a therapeutic triplet that reduces the number of TPE sessions, shortens hospital stay, and improves survival. TTP has entered the era of targeted therapies and the history of this disease can be considered as a convincing example of the success of translational medicine. RELATIONSHIP DISCLOSURES PC is member of the Advisory Boards of Ablynx for the development of caplacizumab, Alexion for the development of eculizumab and Shire for the development of Bax930. He has received funds from Ablynx, Alexion, Octapharma, and Roche. The French Reference Center for Thrombotic Microangiopathies (www.cnr-mat.fr) is in part supported by the French Ministry of Health (Plan National Maladies Rares, Direction Générale de l'Offre de Soin) and the Programme Hospitalier de Recherche Clinique (PHRC 2012 P120118, Clinicaltrials.gov identifier NCT02134171). AC has served as a consultant or advisory board member for Bioverativ, Genzyme, Kedrion, Stago, and Synergy and his institution has received research support on his behalf from Alexion, Bayer, Bioverativ, Novo Nordisk, Pfizer, Shire, and Spark. JG has no competing interests. AUTHOR CONTRIBUTIONS PC, AC, and JNG wrote the manuscript. All authors agreed the submitted version of the manuscript. REFERENCES Notes : Each item is associated with one point (+1). INR, international normalized ratio; MCV, mean corpuscular value; SCT, stem cell transplantation. 3 The French score considered patients with a thrombotic microangiopathy (TMA) syndrome (which includes hemolysis with schistocytes in the definition) and assumes that there is no history of or clinical evidence for associated cancer, transplantation or disseminated intravascular coagulopathy; so these items are intrinsic to the score. 4 MCV was not incorporated in the French score. 5 Results correspond to those of the derivation cohort and those of a validation by (French score) the bootstrap resampling technique (internal validation) (Coppo et al,12 Bendapudi et al,13 and manuscript in preparation), or (PLASMIC score) different samples of patients from the same institution (internal validation) or from a different institution (external validation).12, 13
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Platelet biology and functions: new concepts and clinical perspectives

Platelet biology and functions: new concepts and clinical perspectives | Hematology | Scoop.it
This Review provides an update of the latest developments in our understanding of platelet functions and populations in normal physiology and in haemorrhagic, thrombotic, and inflammatory conditions. These advancements can aid in tailoring new strategies to target platelets in disease states while avoiding the increased risk of bleeding associated with current antiplatelet therapies.
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Cutaneous B‐cell lymphomas: 2019 update on diagnosis, risk stratification, and management - Wilcox - 2018 - American Journal of Hematology - Wiley Online Library

Abstract Disease overview Approximately one‐fourth of cutaneous lymphomas are B‐cell derived and are generally classified into three distinct subgroups: primary cutaneous follicle center lymphoma (PCFCL), primary cutaneous marginal zone lymphoma (PCMZL), and primary cutaneous diffuse large B‐cell lymphoma, leg type (PCDLBCL, LT). Diagnosis Diagnosis and disease classification are based on histologic review and immunohistochemical staining of an appropriate skin biopsy. Pathologic review and an appropriate staging evaluation are necessary to distinguish primary cutaneous B‐cell lymphomas from systemic B‐cell lymphomas with secondary skin involvement. Risk stratification Disease histology remains the most important prognostic determinant. Both PCFCL and PCMZL are indolent lymphomas that infrequently disseminate to extracutaneous sites and are associated with 5‐year survival rates that exceed 95%. In contrast, PCDLBCL, LT is an aggressive lymphoma with an inferior prognosis. Risk‐adapted therapy PCFCL and PCMZL patients with solitary or relatively few skin lesions may be affectively managed with local radiation therapy. While single‐agent rituximab may be employed for patients with more widespread skin involvement, multiagent chemotherapy is rarely appropriate. In contrast, management of patients with PCDLBCL, LT is comparable to the management of patients with systemic DLBCL. 1 DISEASE OVERVIEW Primary cutaneous lymphomas are a heterogeneous group of extranodal non‐Hodgkin lymphomas, approximately 25% of which are B‐cell derived and are classified into three major entities in the 2008 World Health Organization‐European Organization for Research and Treatment of Cancer (EORTC) joint classification: primary cutaneous follicle center lymphoma (PCFCL), primary cutaneous diffuse large B‐cell lymphoma, leg type (PCDLBCL, LT), and primary cutaneous marginal zone lymphoma (PCMZL).1 The incidence of cutaneous B‐cell lymphomas (CBCLs) has been increasing and is currently ≈4 per million persons, based on Surveillance, Epidemiology, and End Results registry data, with the highest incidence rates being reported among males, non‐Hispanic whites, and adults over the age of 50 years.2, 3 2 DIAGNOSIS Diagnosis and classification of a CBCL requires an excisional or punch biopsy for careful morphologic and immunohistochemical analysis, and an appropriate staging evaluation to exclude systemic disease.4 The use of appropriate immunohistochemical stains (eg, CD5, cyclin D1) may also aid in distinguishing CBCL from secondary skin involvement by a systemic lymphoma. 2.1 Primary cutaneous follicle center lymphoma PCFCLs are commonly solitary plaques or tumors involving the trunk, particularly the head or scalp. While grouped lesions may be observed, multifocal disease is less common. Histologically, PCFCLs are characterized by a follicular, diffuse, or mixed growth pattern comprised of large centrocytes derived from germinal‐center B cells.1, 5, 6 In contrast to systemic follicular lymphomas, the majority of PCFCLs do not harbor the t(14;18) translocation involving the bcl‐2 locus, and do not strongly express bcl‐2 by immunohistochemistry, although weak expression may be observed in a minority of cases.7-9 These CBCLs express bcl‐6, variably express CD10, and are MUM‐1/IRF‐4 negative, consistent with their origin from germinal‐center B cells. 2.2 Primary cutaneous diffuse large B‐cell lymphoma, leg type In contrast to PCFCL, which is an indolent CBCL largely involving the head and trunk commonly affecting middle‐aged adults, PCDLBCL, LT commonly affects elderly females and presents with rapidly progressive tumors involving the lower legs.10, 11 Approximately 10% of cases may involve other cutaneous sites apart from the lower legs, and extracutaneous dissemination is common.11 These lymphomas are characterized by diffuse sheets of centroblasts and immunoblasts that spare the epidermis, but frequently extend deep into the dermis and subcutaneous tissue. In contrast to PCFCL, lymphoma cells highly express bcl‐2, likely due to gene amplification,12, 13 as t(14;18) is not observed in PCDLBCL, LT. Dual expression of both bcl‐2 and c‐myc is common, and is associated with inferior overall survival compared with the minority of PCDLBCL, LT that do not express c‐myc.13 C‐myc translocations (and “double hits”) are rare among PCDLBCL, LT.13 Most cases are MUM‐1/IRF‐4 and bcl‐6 positive, CD10 negative, and have a gene expression profile resembling activated B cells.6 Perhaps not surprisingly, the genetic landscape observed in PCDLBCL, LT is similar to that observed in activated B‐cell‐type diffuse large B‐cell lymphoma (ABC‐DLBCL), with NF‐κB‐activating mutations being observed in CD79B, CARD11, and MYD88.14-17 Of these, somatic MYD88 L265P mutations appear most common with a prevalence rate of ≈75%.13, 15-17 Despite the use of somatically hypermutated immunoglobulin heavy‐chain variable (IGHV) regions, Staphylococcal superantigen binding sites within the IGHV are preserved, thus implicating superantigen‐dependent B‐cell receptor signaling in disease pathogenesis.18 2.3 Primary cutaneous marginal zone lymphoma Patients with PCMZL frequently present with multifocal patches, plaques or nodules involving the trunk and arms. While an association with Borrelia burgdorferi has been observed in Europe, a similar association has not been observed in cases from the United States.19-22 PCMZLs are composed of a mixed infiltrate of small, marginal zone B cells, lymphoplasmacytic cells, plasma cells, and reactive T cells. Marginal zone B cells characteristically express bcl‐2, but lack bcl‐6 or CD10 expression. 3 RISK STRATIFICATION The International Society for Cutaneous Lymphomas (ISCL) and EORTC recently proposed staging recommendations for cutaneous lymphomas other than mycosis fungoides and Sezary syndrome.4 Staging should include a history, physical examination, appropriate laboratory studies (including lactate dehydrogenase), and imaging (either CT, PET, or increasingly PET/CT) of the chest, abdomen, pelvis, and neck (in cases with involvement of the head or neck). A bone marrow biopsy and aspirate should be performed in cases of PCDLBCL, LT. The joint ISCL/EORTC does not endorse routine bone marrow examination in cases of PCFCL or PCMZL, although approximately 10% of patients with PCFCL have bone marrow involvement.23 Bone marrow involvement was associated with significantly inferior disease‐specific survival. While the TNM staging classification describes the extent of disease, staging in CBCL is of limited prognostic value, as the disease histology is the major determinant in risk stratification. This is highlighted by a population‐based study which identified histology and the site of skin involvement as important prognostic factors.24 In contrast, the International Extranodal Lymphoma Study Group identified three independent prognostic factors (ie, elevated LDH, >2 skin lesions, and nodular lesions) among patients with PCFCL and PCMZL. These factors were combined to form the cutaneous lymphoma international prognostic index (CLIPI). The absence of any adverse prognostic factor was associated with a 5‐year progression‐free survival of 91%. In contrast, the presence of two or three adverse prognostic factors was associated with a 5‐year progression‐free survival of 48%. As the vast majority of relapses were confined to the skin, the CLIPI was unable to risk‐stratify patients by overall survival. The presence of multiple skin lesions was associated with inferior disease‐free survival in a European series,25 but was not associated with disease‐free survival in a large North American series.26 The most important factor for risk stratification among the CBCLs remains the histologic classification. Indolent CBCL (PCFCL and PCMZL) are associated with 5‐year disease‐specific survival ≥95%.1, 26 Differences in growth pattern, the density of centroblasts, and cytogenetic findings do not appear to provide meaningful prognostic information. Bcl‐2 expression among PCFCL with a diffuse large B‐cell histology may be a notable exception.27 In contrast, PCDLBCL, LT is associated with a 5‐year disease‐specific survival of approximately 50%, and dual bcl‐2 and c‐myc expression is associated with inferior survival.1, 13, 15, 28 The presence of a somatic MYD88L265P mutation is also associated with inferior disease‐specific and overall survival.15 In contrast to patients presenting with only a single tumor, involvement of multiple sites, on one or both legs, is associated with a significantly inferior disease‐specific survival.29 4 TREATMENT As no randomized controlled trials are available, treatment recommendations for CBCL are largely based on small retrospective studies and institutional experience. The EORTC and ISCL have published consensus treatment recommendations that are consistent with NCCN guidelines.30 In most cases, optimal patient management requires a multidisciplinary approach, including dermatology, medical oncology, and radiation oncology. 4.1 Primary cutaneous follicle center lymphoma For patients with solitary lesions, low‐dose radiation therapy is safe and highly affective, with a complete remission rate approaching 100%. Radiation does not appear inferior to multiagent chemotherapy among patients with multiple lesions that can be included in multiple radiation fields.31 In a large North American series, the rate of local control for indolent CBCL with radiation alone was 98%.26 In the same series, a local recurrence requiring radiation therapy was observed in 25% of patients who had undergone surgical excision alone. Reserving radiation until disease recurrence did not appear to compromise disease‐specific or overall survival.26 Therefore, complete excision alone, deferring radiation until disease recurrence, is also reasonable. Intralesional (eg, corticosteroids or rituximab32) or topical therapies may also be considered.33, 34 While radiation therapy is generally recommended for patients with a solitary lesion, radiation therapy, or observation (ie, “watch and wait”) are reasonable options for those patients with multiple lesions. Patients with more extensive skin involvement are effectively managed with single‐agent rituximab.30 Approximately one‐third of patients may relapse following either radiation or single‐agent rituximab, but relapses are usually confined to the skin and are approached in a manner similar to that described for the initial management of PCFCL. 4.2 Primary cutaneous marginal zone lymphoma Patients with PCMZL are approached in a manner analogous to that described in the initial management of PCFCL. Radiation therapy is associated with a similarly high response rate for patients with a single or few lesions.30 Those with more widespread skin involvement may be observed. Once symptomatic, culprit lesion may be irradiated (or surgically excised). As for PCFCL, single‐agent rituximab may be utilized in patients with symptomatic, widespread skin lesions. An initial trial of antibiotics for those with B. burgdorferi‐associated PCMZL has been recommended,35 but is less relevant for North American patients. 4.3 Primary cutaneous diffuse large B‐cell lymphoma, leg type As previously noted, the natural history of PCDLBCL, LT more closely resembles that of systemic DLBCL. Therefore, R‐CHOP (with or without radiation therapy) is utilized in these patients. While few reports are available in the literature, the use of R‐CHOP in these patients is associated with disease‐free survival rates rivaling those reported for patients with high‐risk systemic DLBCL.10, 11, 26, 30 Most patients present with disease confined to the leg(s) and are managed like patients with limited stage systemic DLBCL with R‐CHOP and involved field radiation therapy. The management of relapsed disease is comparable to that for relapsed systemic ABC‐DLBCL (eg, lenalidomide36 and ibrutinib37). In a small phase II study (n = 19), the 6‐month overall response rate with single‐agent lenalidomide in relapsed/refractory PCDLBCL, LT was 26%, but was significantly higher in patients without the MYD88L265P mutation.38 ACKNOWLEDGMENT This work was supported in part by the National Institutes of Health (K08CA172215) and the Leukemia and Lymphoma Society Translational Research Program. CONFLICT OF INTEREST Nothing to report. REFERENCES Notes : Funding information Leukemia and Lymphoma Society; National Institutes of Health, Grant/Award Number: K08CA172215
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Complement-driven anemia: more than just paroxysmal nocturnal hemoglobinuria. - PubMed - NCBI

Complement-driven anemia: more than just paroxysmal nocturnal hemoglobinuria. - PubMed - NCBI | Hematology | Scoop.it
Hematology Am Soc Hematol Educ Program. 2018 Nov 30;2018(1):371-376. doi: 10.1182/asheducation-2018.1.371.Review...
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Approach to the treatment of the older, unfit patient with myeloma from diagnosis to relapse: perspectives of a US hematologist and a geriatric hem... - PubMed - NCBI

Approach to the treatment of the older, unfit patient with myeloma from diagnosis to relapse: perspectives of a US hematologist and a geriatric hem... - PubMed - NCBI | Hematology | Scoop.it
Hematology Am Soc Hematol Educ Program. 2018 Nov 30;2018(1):88-96. doi: 10.1182/asheducation-2018.1.88.Review...
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Navigating the treatment landscape in multiple myeloma: which combinations to use and when? | Read by QxMD

Navigating the treatment landscape in multiple myeloma: which combinations to use and when? | Read by QxMD | Hematology | Scoop.it
JOURNAL ARTICLEREVIEW Navigating the treatment landscape in multiple myeloma: which combinations to use and when? Hartmut Goldschmidt, John Ashcroft, Zsolt Szabo, Laurent Garderet Annals of Hematology 2018 November 23 Multiple myeloma is one of the most common hematological malignancies, affecting mainly elderly patients. The treatment landscape for the management of this disease has evolved significantly over the past 15 years, and a vast array of therapeutics is now available, including immunomodulatory drugs, proteasome inhibitors, histone deacetylase inhibitors, and monoclonal antibodies. As a result, deciding which drugs to use and when, and whether these should be used in a particular order or combination, can be challenging. Although combination regimens are often associated with deeper responses and better long-term outcomes than monotherapy, and are becoming the standard of care, they may result in significant incremental toxicity; hence, a sequential approach may be more appropriate for some patients. In particular, treatment choices can vary depending on whether the patient has newly diagnosed multiple myeloma, is eligible for transplant, has relapsed and/or refractory multiple myeloma, or is considered to have high-risk disease. In this review, we discuss factors to be taken into account when making treatment decisions in each of these settings. We also briefly discuss possible therapeutic strategies involving agents that may become available in the future. Read this article (multiple options) Comments You need to log in or sign up for an account to be able to comment. No comments yet, be the first to post one! Related Papers
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Chronic lymphocytic leukemia conversations from ASH

Chronic lymphocytic leukemia conversations from ASH | Hematology | Scoop.it
Trending terms around CLL from American Society of Hematology Annual Meeting. Data from the Healthcare Social Graph® – Symplur. #ASH18.Twitter December...
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The distribution of T-cell subsets and the expression of immune checkpoint receptors and ligands in patients with newly diagnosed and relapsed acut... - PubMed - NCBI

The distribution of T-cell subsets and the expression of immune checkpoint receptors and ligands in patients with newly diagnosed and relapsed acut... - PubMed - NCBI | Hematology | Scoop.it
Cancer. 2018 Nov 30. doi: 10.1002/cncr.31896.[Epub ahead of print]...
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The First Year of HemaSphere and Many More to Come : HemaSphere

The First Year of HemaSphere and Many More to Come : HemaSphere | Hematology | Scoop.it
An abstract is unavailable. This article is available as a PDF only.
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A Novel and Rapid Assay for Sickle Cell Disease Screening

A Novel and Rapid Assay for Sickle Cell Disease Screening | Hematology | Scoop.it
Children born with sickle cell disease in low-resource regions of the world often remain undiagnosed and therefore do not receive appropriate treatment.
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T Prolymphocytic Leukemia, a rare disease, case presentation with typical pathological findings and review of management

T Prolymphocytic Leukemia, a rare disease, case presentation with typical pathological findings and review of management | Hematology | Scoop.it
T Prolymphocytic Leukemia, a rare disease, case presentation with typical pathological findings and review of management Mohammad AJ.Abdulla1, Firyal...
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Frontiers | CD38-Specific Biparatopic Heavy Chain Antibodies Display Potent Complement-Dependent Cytotoxicity Against Multiple Myeloma Cells | Immunology

Frontiers | CD38-Specific Biparatopic Heavy Chain Antibodies Display Potent Complement-Dependent Cytotoxicity Against Multiple Myeloma Cells | Immunology | Hematology | Scoop.it
CD38 is overexpressed by multiple myeloma cells and has emerged as a target for therapeutic antibodies. Nanobodies are soluble single domain antibody fragments derived from the VHH variable domain of heavy chain antibodies naturally occurring in camelids. We previously identified distinct llama nanobodies that recognize three non-overlapping epitopes of the extracellular domain of CD38. Here, we fused these VHH domains to the hinge, CH2, and CH3 domains of human IgG1, yielding highly soluble chimeric llama/human heavy chain antibodies (hcAbs). We analyzed the capacity of these hcAbs to mediate complement dependent cytotoxicity (CDC) to CD38-expressing human multiple myeloma and Burkitt lymphoma cell lines. Combinations of two hcAbs that recognize distinct, non-overlapping epitopes of CD38 mediated potent CDC, in contrast to the hcAb monotherapy with only weak CDC capacity. Similarly, combining daratumumab with a hcAb that recognizes a non-overlapping epitope resulted in dramatically enhanced CDC. Further, introducing the E345R HexaBody mutation into the CH3 domain strongly enhanced the CDC potency of hcAbs to CD38-expressing cells. Harnessing their high solubility, we genetically fused two distinct nanobodies into heteromeric dimers via a flexible peptide linker and then fused these nanobody dimers to the hinge, CH2 and CH3 domains of human IgG1, yielding highly soluble, biparatopic hcAbs. These biparatopic hcAbs elicited CDC toward CD38-expressing myeloma cells mor
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Hematopathology & Hematopathologists

Hematopathology & Hematopathologists | Hematology | Scoop.it
Hemato Pathology is medical sub-specialty which deals with the study of diseased hematopoietic cells. The term Hematopoiesis means the cre...
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Risk of hematologic toxicities with programmed cell death-1 inhibitors in cancer patients: a meta-analysis of current studies. - PubMed - NCBI

Drug Des Devel Ther. 2018 Jun 8;12:1645-1657. doi: 10.2147/DDDT.S167077. eCollection 2018.Meta-Analysis...
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Immune Escape of Relapsed AML Cells after Allogeneic Transplantation | NEJM

Original Article from The New England Journal of Medicine — Immune Escape of Relapsed AML Cells after Allogeneic Transplantation...
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