Showing papers in "British Journal of Haematology in 2018"

Cobomarsen, an oligonucleotide inhibitor of miR-155, co-ordinately regulates multiple survival pathways to reduce cellular proliferation and survival in cutaneous T-cell lymphoma

Abstract: miR-155, a microRNA associated with poor prognosis in lymphoma and leukaemia, has been implicated in the progression of mycosis fungoides (MF), the most common form of cutaneous T-cell lymphoma (CTCL). In this study, we developed and tested cobomarsen (MRG-106), a locked nucleic acid-modified oligonucleotide inhibitor of miR-155. In MF and human lymphotropic virus type 1 (HTLV-1+) CTCL cell lines in vitro, inhibition of miR-155 with cobomarsen de-repressed direct miR-155 targets, decreased expression of multiple gene pathways associated with cell survival, reduced survival signalling, decreased cell proliferation and activated apoptosis. We identified a set of genes that are significantly regulated by cobomarsen, including direct and downstream targets of miR-155. Using clinical biopsies from MF patients, we demonstrated that expression of these pharmacodynamic biomarkers is dysregulated in MF and associated with miR-155 expression level and MF lesion severity. Further, we demonstrated that miR-155 simultaneously regulates multiple parallel survival pathways (including JAK/STAT, MAPK/ERK and PI3K/AKT) previously associated with the pathogenesis of MF, and that these survival pathways are inhibited by cobomarsen in vitro. A first-in-human phase 1 clinical trial of cobomarsen in patients with CTCL is currently underway, in which the panel of proposed biomarkers will be leveraged to assess pharmacodynamic response to cobomarsen therapy.

The use of viscoelastic haemostatic assays in the management of major bleeding: A British Society for Haematology Guideline.

Abstract: Nicola S. Curry, Ross Davenport, Sue Pavord, Susan V. Mallett, Dianne Kitchen, Andrew A. Klein, Helena Maybury, Peter W. Collins and Mike Laffan Department of Haematology, Oxford University Hospitals NHS Foundation Trust, NIHR BRC, Blood Theme, Oxford University, Oxford, Centre for Trauma Sciences, Blizard Institute, Queen Mary University of London, Department of Anaesthesia, Royal Free London NHS Foundation Trust, London, UK NEQAS for Blood Coagulation, Sheffield, Department of Anaesthesia and Intensive Care, Royal Papworth Hospital, Cambridge, Department of Obstetrics, Leicester Royal Infirmary, Leicester, Department of Haematology, School of Medicine, Cardiff University, Cardiff, and Department of Haematology, Imperial College and Hammersmith Hospital, London, UK

Cytokine release syndrome and neurotoxicity after CD19 chimeric antigen receptor-modified (CAR-) T cell therapy

Abstract: Chimeric antigen receptor-modified (CAR)-T cells have demonstrated impressive results in the treatment of haematological malignancies. However, cytokine release syndrome (CRS) and neurotoxicity are common toxicities which are potentially life-threatening in severe cases. Risk factors for CRS and neurotoxicity identified so far include disease burden, lymphodepletion intensity and CAR-T cell dose administered. Risk-adapted dosing, with lower CAR-T cell doses administered to B-cell acute lymphoblastic leukaemia patients with high marrow blast counts, has been successful at decreasing severe CRS rates in this population. Intervention with therapies, such as tocilizumab and corticosteroids, have been effective at ameliorating toxicity, enabling CAR-T cells to be administered safely to many patients without significantly compromising efficacy. Deeper understanding of the pathophysiology of underlying CRS and neurotoxicity will enable the development of novel approaches to reduce toxicity and improve outcomes.

The full spectrum of Castleman disease: 273 patients studied over 20 years

Abstract: The spectrum of Castleman disease (CD) has considerably extended since its first description in 1956. Recently, an international collaborative working group has reached consensus on the diagnostic criteria and classification of CD. We herein report 273 patients with lymph node histopathology consistent with CD and investigate the newly established diagnostic criteria. Twenty of these patients with Castleman-like histopathology were removed from analyses, because they were diagnosed with an exclusionary disorder (18 with haematological malignancy). Among the 253 remaining patients, 57 were considered unicentric CD (UCD), 169 were multicentric CD associated with Human Herpesvirus 8 (HHV-8+MCD), including 140 patients with human immunodeficiency virus (HIV) infection and 29 patients without HIV infection, and 27 were HHV-8 negative/idiopathic multicentric CD (iMCD). 2-(18 F)fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography was useful in 62 patients for staging/classification of the disease and for excluding associated lymphoma. UCD was mainly associated with hyaline-vascular histopathological features, and most patients were asymptomatic. Of the 27 patients that we had originally diagnosed with iMCD, 26 met the newly established diagnostic criteria. Patients with iMCD and HHV-8+ MCD demonstrated similar characteristics, including fever, splenomegaly, cytopenia and inflammatory symptoms. However, the disease was more aggressive in HHV-8+ MCD, particularly in HIV-infected patients.

How I manage patients with relapsed/refractory diffuse large B cell lymphoma.

Abstract: Despite progress in the upfront treatment of diffuse large B cell lymphoma (DLBCL), patients still experience relapses. Salvage chemotherapy followed by autologous stem cell transplantation (ASCT) is the standard second-line treatment for relapsed and refractory (R/R) DLBCL. However, half of the patients will not be eligible for transplantation due to ineffective salvage treatment, and the other half will relapse after ASCT. In randomized studies, no salvage chemotherapy regimen is superior to another. The outcomes are affected by the secondary International Prognostic Index at relapse and various biological factors. The strategy is less clear in patients who require third-line treatment. A multicohort retrospective non-Hodgkin lymphoma research (SCHOLAR-1) study conducted in 636 patients with refractory DLBCL showed an objective response rate of 26% (complete response 7%) to the next line of therapy with a median overall survival of 6·3 months. In the case of a response followed by transplantation, long-term survival can be achieved in DLBCL patients. There is clearly a need for new drugs that improve salvage efficacy. Encouraging results have been reported with chimeric antigen receptor -T cell engineering, warranting further studies in a well-defined control group of refractory patients. The Collaborative Trial in Relapsed Aggressive Lymphoma (CORAL) was used as a handy framework to build the discussion.

British Society of Haematology Guidelines on the spectrum of fresh frozen plasma and cryoprecipitate products: their handling and use in various patient groups in the absence of major bleeding

Abstract: Laura Green, Paula Bolton-Maggs, Craig Beattie, Rebecca Cardigan, Yiannis Kallis, Simon J Stanworth, Jecko Thachil and Sharon Zahra NHS Blood and Transplant, Barts Health NHS Trust, Blizard Institute, Queen Mary University of London, London, Serious Hazards of Transfusion Office, Manchester Blood Centre, Manchester, Dept of Anaesthesia, Critical Care and Pain Medicine, Royal Infirmary of Edinburgh, Edinburgh, NHS Blood and Transplant/Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, Department of Hepatology, Barts Health NHS Trust, London, Oxford University Hospitals NHS Trust/NHS Blood and Transplant, University of Oxford, Oxford, Haematology Department, Manchester Royal Infirmary, Manchester, and Scottish National Blood Transfusion Service, Edinburgh, UK

Phase 3 randomised study of avatrombopag, a novel thrombopoietin receptor agonist for the treatment of chronic immune thrombocytopenia.

Abstract: Avatrombopag, an oral thrombopoietin receptor agonist, was compared with placebo in a 6-month, multicentre, randomised, double-blind, parallel-group Phase 3 study, with an open-label extension phase, to assess the efficacy and safety of avatrombopag (20 mg/day) in adults with chronic immune thrombocytopenia (ITP) and a platelet count <30 × 109 /l (ClinicalTrials.gov identifier NCT01438840). The primary endpoint was the cumulative number of weeks of platelet response (platelet count ≥50 × 109 /l) without rescue therapy for bleeding; secondary endpoints included platelet response rate at day 8 and reductions in the use of concomitant medications. Amongst the 49 patients randomised, avatrombopag (N = 32) was superior to placebo (N = 17) in the median cumulative number of weeks of platelet response (12·4 vs. 0·0 weeks, respectively; P < 0·0001). At day 8, a greater platelet response rate was also observed for patients treated with avatrombopag compared with placebo (65·63% vs. 0·0%; P < 0·0001), and use of concomitant ITP medications was also reduced amongst patients receiving avatrombopag. The safety profile of avatrombopag was consistent with Phase 2 studies; the most common adverse events were headache and contusion. Overall, avatrombopag was well tolerated and efficacious for the treatment of chronic ITP.

Investigation and management of a raised serum ferritin

Abstract: Serum ferritin level is one of the most commonly requested investigations in both primary and secondary care. Whilst low serum ferritin levels invariably indicate reduced iron stores, raised serum ferritin levels can be due to multiple different aetiologies, including iron overload, inflammation, liver or renal disease, malignancy, and the recently described metabolic syndrome. A key test in the further investigation of an unexpected raised serum ferritin is the serum transferrin saturation. This guideline reviews the investigation and management of a raised serum ferritin level. The investigation and management of genetic haemochromatosis is not dealt with however and is the subject of a separate guideline.

A Phase 2 Study of Modified Lenalidomide, Bortezomib, and Dexamethasone in Transplant-Ineligible Multiple Myeloma

Abstract: We sought a regimen that incorporates optimal novel agents and balances efficacy with toxicity in transplant-ineligible multiple myeloma (MM) patients. Our study evaluated modified lenalidomide-bortezomib-dexamethasone (RVD lite) in this population and was administered over a 35-day cycle. Lenalidomide 15 mg was given orally on days 1-21; bortezomib 1·3 mg/m2 weekly subcutaneously on days 1, 8, 15 and 22; and dexamethasone 20 mg orally was given on the day of and day after bortezomib for 9 cycles followed by 6 cycles of consolidation with lenalidomide and bortezomib. The primary objective was to evaluate the overall response rate (ORR); secondary objectives included safety, progression-free survival (PFS) and overall survival (OS). Fifty-three eligible patients were screened between April 2013 and May 2015; 50 received at least one dose of therapy. Median age at study entry was 73 years (range 65-91). The ORR was 86% and 66% of patients achieved a very good partial response or better. Median PFS was 35·1 months (95% confidence interval 30·9-not reached) and median OS was not reached at a median follow-up of 30 months. Peripheral neuropathy was reported in 31 (62%) patients with only 1 patient experiencing grade 3 symptoms. RVD lite is a well-tolerated and highly effective regimen, with robust PFS and OS, in the transplant-ineligible MM population.

A tale of two antibodies: obinutuzumab versus rituximab

Abstract: While rituximab has dramatically improved outcomes for patients with CD20+ malignancies for two decades, responses are not universal and resistance can develop. Obinutuzumab was developed to potentiate activity and overcome resistance. Pre-clinical data suggests obinutuzumab is superior to rituximab at effecting B cell depletion; however recent phase III clinical trial results have been mixed. The decision of which antibody to employ will probably be further complicated by the approval of a subcutaneous preparation of rituximab and several anti-CD20 biosimilars. Clinicians are now challenged with deciding whether to switch to obinutuzumab in approved settings, accepting the potential for increased toxicity and probable increased cost. The benefit conferred by obinutuzumab over rituximab may be context-specific and vary based on histological subtype and immune integrity. This comprehensive review will explore the preclinical differences, investigate the proposed pathogenesis of rituximab resistance, compare the employed dosing strategies and interrogate available clinical results to help inform practice.

Haemostasis and innate immunity - a complementary relationship: A review of the intricate relationship between coagulation and complement pathways.

Abstract: Coagulation and innate immunity are linked evolutionary processes that orchestrate the host defence against invading pathogens and injury. The complement system is integral to innate immunity and shares numerous interactions with components of the haemostatic pathway, helping to maintain physiological equilibrium. The term 'immunothrombosis' was introduced in 2013 to embrace this process, and has become an area of much recent interest. What is less apparent in the literature however is an appreciation of the clinical manifestations of the coagulation-complement interaction and the consequences of dysregulation of either system, as seen in many inflammatory and thrombotic disease states, such as sepsis, trauma, atherosclerosis, antiphospholipid syndrome (APS), paroxysmal nocturnal haemoglobinuria (PNH) and some thrombotic microangiopathies to name a few. The growing appreciation of this immunothrombotic phenomenon will foster the drive for novel therapies in these disease states, including anticoagulants as immunomodulators and targeted molecular therapies.

Targeted next generation sequencing of breast implant‐associated anaplastic large cell lymphoma reveals mutations in JAK/STAT signalling pathway genes, TP53 and DNMT3A

Abstract: Breast implant-associated anaplastic large cell lymphoma (BI-ALCL) is an uncommon neoplasm occurring in women with either cosmetic or reconstructive breast implants (Clemens et al, 2016). Until now, most studies have focused on defining the clinico-pathological features of BI-ALCL, leading to its inclusion as a new provisional entity, a subtype of anaplastic lymphoma kinase (ALK)-negative ALCL, in the revised World Health Organization classification of lymphoid malignancies (Swerdlow et al, 2016). BI-ALCL is characterized by the presence of CD30 large atypical lymphocytes frequently confined to the peri-implant seroma fluid. Nevertheless, solid infiltrating masses and cases pursuing an aggressive clinical course have been reported. The surgical and pathological staging system designed by Clemens et al (2016) suggests that BI-ALCL has a pattern of progression similar to that of solid tumours rather than non-Hodgkin lymphomas, and that the effusionand solid-types might represent different stages of the same disease rather than two distinct variants. The molecular pathogenesis and mechanisms of progression of BI-ALCL, however, remain largely unknown, thus limiting the identification of biomarkers that enable disease prognostication and optimal treatment. Hence, we performed targeted next generation sequencing of seven BI-ALCL, identified in the archives of three institutions over 7 years, to investigate the presence of underlying somatic mutations. Informed consent was obtained from patients and the study was performed in accordance with the Declaration of Helsinki. DNA extracted from micro-dissected tumour cells of formalin-fixed paraffin-embedded BI-ALCL samples (QIAamp DNA Mini kit; Qiagen, Germantown, MD, USA) was used to prepare DNA libraries (Sureselect kit; Agilent Technologies, Santa Clara, CA, USA). Sequencing was performed on a HiSeq2500 (Illumina, San Diego, CA, USA) using a panel of 465 cancerassociated genes (Table SI). The sequence data were aligned to the human reference genome (hg19) and variants were identified using NextGENe (SoftGenetics, State College, PA, USA). The average read depth of the samples was 4009 (Table SII). Somatic mutations were identified by comparison of variants detected in lymphoma with those from matched constitutional DNA. Common variants (>1% frequency) present in the 1000 genomes database, and the database of Columbia University were removed. Somatic mutations were classified using the prior literature, and two different prediction algorithms (SIFT http://sift.bii.a-star.edu.sg and Polyphen-2 [PP2] http://genetics.bwh.harvard.edu/pph2/). The exonic somatic variants were confirmed by bidirectional Sanger sequencing using Big-Dye terminators v3.1 (Applied Biosystems, Carlsbad, CA, USA). The clinical and pathological features of the patients are summarized in Table I. Informative results were obtained in five of seven cases (Table SII); analysis failed in two cases due to the poor quality of DNA. Five somatic variants affecting four genes were identified in two cases: one intronic and four within coding regions (Fig 1 and Table SIII). A STAT3 missense variant (p.S614R) affecting the SH2 domain, which mediates STAT3 dimerization, was detected in one of these two BI-ALCLs. JAK/STAT signalling is implicated in cell proliferation, differentiation and apoptosis, and aberrant activation of STAT3 has been reported in several human cancers associated with persistent immune stimulation and/or inflammation. Notably, the gain-of-function mutation (S614R) was recently described in one BI-ALCL (Blombery et al, 2016), and has been reported in angioimmunoblastic T cell lymphomas, chronic lymphoproliferative disorders of natural killer cells, and T-cell large granular lymphocyte leukaemias (Odejide et al, 2014). Moreover, gain-of-function mutations in STAT3 have been reported in 18% of systemic ALK-negative ALCLs and 5% of cutaneous ALCLs (Crescenzo et al, 2015). An in vitro study using BI-ALCL-derived cell lines also showed activation of the JAK/STAT pathway through autocrine production of interleukin 6, suggesting a possible pathogenic mechanism (Lechner et al, 2012). A frameshift deletion causing a premature stop codon in SOCS1 (p.P83Rfs*20) was detected in the BI-ALCL harbouring the STAT3 mutation. SOCS1 is a negative feedback regulator of the JAK/STAT pathway. The p.P83Rfs*20 mutation deletes the C-terminal SOCS box domain and partially deletes the SH2 domain, which downregulates the kinase activity of JAK. Loss-of-function mutations of SOCS1, leading to constitutive activation of JAK/STAT signalling, have been described in B-cell lymphomas and in classical Hodgkin lymphomas (Mottok et al, 2009). Moreover, SOCS1 was found to be silenced by miR-155 in ALK-negative ALCL (Merkel et al, 2015). Mutations in STAT3 and SOCS1 suggest that deregulated activation of the JAK/STAT pathway may contribute to the development of BI-ALCL. A missense mutation of TP53 (p.D259Y) affecting the DNA binding domain was also observed in the Correspondence

Advances in targeted therapy for acute myeloid leukaemia.

Abstract: In the past few years, research in the underlying pathogenic mechanisms of acute myeloid leukaemia (AML) has led to remarkable advances in our understanding of the disease. Cytogenetic and molecular aberrations are the most important factors in determining response to chemotherapy as well as long-term outcome, but beyond prognostication are potential therapeutic targets. Our increased understanding of the pathogenesis of AML, facilitated by next-generation sequencing, has spurred the development of new compounds in the treatment of AML, particularly the creation of small molecules that target the disease on a molecular level. Various new agents, such as tyrosine kinase inhibitors, immune checkpoint inhibitors, monoclonal or bispecific T-cell engager antibodies, metabolic and pro-apoptotic agents are currently investigated within clinical trials. The highest response rates are often achieved when new molecularly targeted therapies are combined with standard chemotherapy. Presented here is an overview of novel therapies currently being evaluated in AML.

How I manage patients with cold agglutinin disease.

Abstract: Cold agglutinin disease (CAD) is an uncommon autoimmune haemolytic anaemia in which a well-defined, clonal low-grade lymphoproliferative disorder of the bone marrow results in erythrocyte destruction mediated by the classical complement pathway. The pathogenesis, clinical features and diagnostic criteria are reviewed. Although anaemia is mild in some patients, approximately one-third of untreated patients have a haemoglobin level of ≤80 g/l, and about 50% have been considered transfusion dependent for shorter or longer periods. Therapy has improved greatly during the last 15 years. Mild disease can be managed by avoidance of cold and adequate precautions in specific situations, without drug therapy. Corticosteroids should not be used to treat CAD. Patients requiring pharmacological therapy should be considered for prospective trials. Outside clinical studies, the rituximab-bendamustine combination or rituximab monotherapy is recommended in the first line, depending on individual patient characteristics. Second-line options are rituximab-fludarabine in fit patients or, although less strongly documented, a bortezomib-based regimen. Therapies targeting the classical complement pathway are promising, and the complement C1s inhibitor, BIVV009, has shown favourable results in preliminary studies.

Final results from a defibrotide treatment-IND study for patients with hepatic veno-occlusive disease/sinusoidal obstruction syndrome

Abstract: Hepatic veno‐occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life‐threatening complication of haematopoietic stem cell transplant (HSCT) conditioning and chemotherapy. Defibrotide is approved for treatment of hepatic VOD/SOS with pulmonary or renal dysfunction [i.e., multi‐organ dysfunction (MOD)] after HSCT in the United States and severe VOD/SOS after HSCT in patients aged older than 1 month in the European Union. Defibrotide was available as an investigational drug by an expanded‐access treatment programme (T‐IND; {"type":"clinical-trial","attrs":{"text":"NCT00628498","term_id":"NCT00628498"}}NCT00628498). In the completed T‐IND, the Kaplan–Meier estimated Day +100 survival for 1000 patients with documented defibrotide treatment after HSCT was 58·9% [95% confidence interval (CI), 55·7–61·9%]. Day +100 survival was also analysed by age and MOD status, and post hoc analyses were performed to determine Day +100 survival by transplant type, timing of VOD/SOS onset (≤21 or >21 days) and timing of defibrotide treatment initiation after VOD/SOS diagnosis. Day +100 survival in paediatric patients was 67·9% (95% CI, 63·8–71·6%) and 47·1% (95% CI, 42·3–51·8%) in adults. All patient subgroups without MOD had higher Day +100 survival than those with MOD; earlier defibrotide initiation was also associated with higher Day +100 survival. The safety profile of defibrotide in the completed T‐IND study was similar to previous reports.

Recent progress in understanding and manipulating haemoglobin switching for the haemoglobinopathies

Abstract: The major β-haemoglobinopathies, sickle cell disease and β-thalassaemia, represent the most common monogenic disorders worldwide and a steadily increasing global disease burden. Allogeneic haematopoietic stem cell transplantation, the only curative therapy, is only applied to a small minority of patients. Common clinical management strategies act mainly downstream of the root causes of disease. The observation that elevated fetal haemoglobin expression ameliorates these disorders has motivated longstanding investigations into the mechanisms of haemoglobin switching. Landmark studies over the last decade have led to the identification of two potent transcriptional repressors of γ-globin, BCL11A and ZBTB7A. These regulators act with additional trans-acting epigenetic repressive complexes, lineage-defining factors and developmental programs to silence fetal haemoglobin by working on cis-acting sequences at the globin gene loci. Rapidly advancing genetic technology is enabling researchers to probe deeply the interplay between the molecular players required for γ-globin (HBG1/HBG2) silencing. Gene therapies may enable permanent cures with autologous modified haematopoietic stem cells that generate persistent fetal haemoglobin expression. Ultimately rational small molecule pharmacotherapies to reactivate HbF could extend benefits widely to patients.

Advances in understanding the pathogenesis of acquired aplastic anaemia

Abstract: This review examines the evidence that bone marrow failure (BMF) in aplastic anaemia (AA) is due to loss of haematopoietic stem cells (HSCs), which, in turn, is caused by deranged immunity and inflammation. We also consider how the course of the disease and the response to immuno-suppressive therapy are influenced by the nature and specificity of the pathogenic process. A somatic mutation of the PIGA gene underlies the clonal disease paroxysmal nocturnal haemoglobinuria (PNH): there is direct evidence that the expansion of the PIGA mutant clone results from Darwinian selection exerted by a glycosyl-phosphatidyl-inositol -specific auto-immune attack. Thus, PNH patients are a unique subset of patients with AA, in whom haematopoiesis recovers through this escape mechanism. A similar process, although less effective, may operate when the auto-immune attack is against a human leucocyte antigen (HLA) molecule and an HLA mutation has produced a clone missing that molecule. We then discuss the significance of other mutant clones that are frequently found in AA, presumably due to a combination of genetic drift and selection. These clones are not causative of AA, but they emerge in AA and they may be pre-leukaemic: unlike a PIGA mutant clone, in general they are unable to effectively reconstitute haematopoiesis.

Newborn screening for sickle cell disease in Europe: recommendations from a Pan-European Consensus Conference.

Abstract: Sickle Cell Disease (SCD) is an increasing global health problem and presents significant challenges to European health care systems. Newborn screening (NBS) for SCD enables early initiation of preventive measures and has contributed to a reduction in childhood mortality from SCD. Policies and methodologies for NBS vary in different countries, and this might have consequences for the quality of care and clinical outcomes for SCD across Europe. A two-day Pan-European consensus conference was held in Berlin in April 2017 in order to appraise the current status of NBS for SCD and to develop consensus-based statements on indications and methodology for NBS for SCD in Europe. More than 50 SCD experts from 13 European countries participated in the conference. This paper aims to summarise the discussions and present consensus recommendations which can be used to support the development of NBS programmes in European countries where they do not yet exist, and to review existing programmes.

MYD88 wild-type Waldenstrom Macroglobulinaemia: differential diagnosis, risk of histological transformation, and overall survival.

Abstract: MYD88 mutations are present in 95% of Waldenstrom Macroglobulinaemia (WM) patients, and support diagnostic discrimination from other IgM-secreting B-cell malignancies. Diagnostic discrimination can be difficult among suspected wild-type MYD88 (MYD88WT ) WM cases. We systematically reviewed the clinical, pathological and laboratory studies for 64 suspected MYD88WT WM patients. World Health Organization and WM consensus guidelines were used to establish clinicopathological diagnosis. Up to 30% of suspected MYD88WT WM cases had an alternative clinicopathological diagnosis, including IgM multiple myeloma. The estimated 10-year survival was 73% (95% confidence interval [CI] 52-86%) for MYD88WT versus 90% (95% CI 82-95%) for mutated (MYD88MUT ) WM patients (Log-rank P < 0·001). Multivariate analysis only showed MYD88 mutation status (P < 0·001) as a significant determinant for overall survival. Diffuse large B-cell lymphoma (DLBCL) was diagnosed in 7 (15·2%) and 2 (0·76%) of MYD88WT and MYD88MUT patients, respectively (Odds ratio 23·3; 95% CI 4·2-233·8; P < 0·001). Overall survival was shorter among MYD88WT patients with an associated DLBCL event (Log-rank P = 0·08). The findings show that among suspected MYD88WT WM cases, an alternative clinicopathological diagnosis is common and can impact clinical care. WM patients with MYD88WT disease have a high incidence of associated DLBCL events and significantly shorter survival versus those with MYD88MUT disease.

Long-term outcomes and mutation profiling of patients with mantle cell lymphoma (MCL) who discontinued ibrutinib.

Abstract: Long term outcomes and mutations in patients with mantle cell lymphoma (MCL) who discontinued ibrutinib have not been described Using deep targeted next generation sequencing, we performed somatic mutation profiling from 15 MCL patients (including 5 patients with paired samples; before and after progression on ibrutinib) We identified 80 patients with MCL who discontinued ibrutinib therapy for various reasons Median follow-up after ibrutinib discontinuation was 38 months The median duration on ibrutinib was 7·6 months Forty-one (51%) patients discontinued ibrutinib due to disease progression/transformation, 20 (25%) for intolerance, 7 (9%) due to patient choice, 5 (6%) for stem cell transplant, 4 (5%) due to second cancers and 3 (4%) other causes The median survival after ibrutinib was 10 and 6 months for disease progression and transformation, respectively, and 25 months for patients with ibrutinib intolerance Overall, BTK mutations were observed in 17% patients after progression on ibrutinib Notably, TP53 alterations were observed after progression in 75% patients Among the 4 patients with blastoid transformation, 3 (75%) had NSD2 mutations (co-existing with TP53) Ibrutinib-refractory MCL patients had a short survival Demonstration of TP53 and NSD2 mutations in patients who developed blastoid transformation and ATM and TP53 mutations in patients who progressed, opens the door for future investigations in ibrutinib-refractory MCL

Resistance to proteasome inhibitors and other targeted therapies in myeloma.

Abstract: The number of novel therapies for the treatment of myeloma is rapidly increasing, as are the clinical trials evaluating them in combination with other novel and established therapies. Proteasome inhibitors, immunomodulatory agents and monoclonal antibodies are the most well known and studied classes of novel agents targeting myeloma, with histone deacetylase inhibitors, nuclear export inhibitors and several other approaches also being actively investigated. However, in parallel with the development and clinical use of these novel myeloma therapies is the emergence of novel mechanisms of resistance, many of which remain elusive, particularly for more recently developed agents. Whilst resistance mechanisms have been best studied for proteasome inhibitors, particularly bortezomib, class effects do not universally apply to all class members, and within-class differences in efficacy, toxicity and resistance mechanisms have been observed. Although immunomodulatory agents share the common cellular target cereblon and thus resistance patterns relate to cereblon expression, the unique cell surface antigens to which monoclonal antibodies are directed means these agents frequently exhibit unique within-class differences in clinical efficacy and resistance patterns. This review describes the major classes of novel therapies for myeloma, highlights the major clinical trials within each class and discusses known resistance mechanisms.

Ibrutinib resistance in mantle cell lymphoma: clinical, molecular and treatment aspects.

Abstract: Mantle cell lymphoma (MCL) is a lymphoproliferative disorder comprising about 6-10% of all B cell lymphoma cases. Ibrutinib is an inhibitor of Bruton tyrosine kinase (BTK), a key component of early B-cell receptor (BCR) signalling pathways. Although treatment with ibrutinib has significantly improved the outcome of MCL patients, approximately one-third of the patients have primary drug resistance while others appear to develop acquired resistance. Understanding the molecular events leading to the primary and acquired resistance to ibrutinib is essential for achieving better outcomes in patients with MCL. In this review, we describe the biology of the BCR signalling pathway and summarize the landmark clinical trials that have led to the approval of ibrutinib. We review the molecular mechanisms underlying primary and acquired ibrutinib resistance as well as recent studies dealing with overcoming ibrutinib resistance.

Management of post-transplant lymphoproliferative disorders

Abstract: The post-transplant lymphoproliferative disorders (PTLDs) are a heterogeneous group of neoplasms that are one of the most serious complications of bone marrow and solid organ transplants. Because these disorders are rare, there are no randomized trials from which to derive optimal treatment. Management can be challenging and must balance the goal of PTLD eradication with the risks of graft rejection, graft-versus-host disease, further delays in immune reconstitution and life-threatening infections, among others. This paper will provide a comprehensive review of PTLD following solid organ transplant and haematopoietic stem cell transplant with a focus on management. Included is a discussion of novel agents that are being studied in clinical trials and, when combined or sequenced with conventional therapy, have the potential to improve outcomes.

R-CHOP versus dose-adjusted R-EPOCH in frontline management of primary mediastinal B-cell lymphoma: a multi-centre analysis

Abstract: Summary Primary mediastinal (thymic) large B-cell lymphoma (PMBCL) is an uncommon subtype of non-Hodgkin lymphoma (NHL) that presents with a mediastinal mass and has unique clinicopathological features. Historically, patients with PMBCL were treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy ± involved field radiation. Since a phase II trial, published in April 2013, demonstrated excellent results using dose-adjusted (DA) R-EPOCH (rituximab, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin), this treatment has gained popularity. We performed a retrospective, multicentre analysis of patients aged ≥18 years with PMBCL since January 2011. Patients were stratified by frontline regimen, R-CHOP versus DA-R-EPOCH. 132 patients were identified from 11 contributing centres (56 R-CHOP and 76 DA-R-EPOCH). The primary outcome was overall survival. Secondary outcomes included progression-free survival, complete response (CR) rate, and rates of treatment-related complications. Demographic characteristics were similar in both groups. DA-R-EPOCH use increased after April 2013 (79% vs. 45%, P < 0·001), and there was less radiation use after DA-R-EPOCH (13% vs. 59%, P < 0·001). While CR rates were higher with DA-R-EPOCH (84% vs. 70%, P = 0·046), these patients were more likely to experience treatment-related toxicities. At 2 years, 89% of R-CHOP patients and 91% of DA-R-EPOCH patients were alive. To our knowledge, this represents the largest series comparing outcomes of R-CHOP to DA-R-EPOCH for PMBCL.

Risk factors for red blood cell alloimmunization in the Recipient Epidemiology and Donor Evaluation Study (REDS-III) database.

Abstract: Despite the significance of red blood cell (RBC) alloimmunization, the lack of standardized registries in the US has prevented the completion of large studies. Data from 3.5 years of the Recipient Epidemiology and Donor Evaluation Study-III (REDS-III) recipient database, containing information from 12 hospitals, were studied. A RBC alloantibody responder had an antibody identified at any point during the study, and a non-responder had a negative antibody screen at least 15 days post-RBC transfusion. Demographics, blood type, ICD9/10 codes, and other potential correlates were evaluated. Of 319 177 (2.07%) screened patients, 6597 had a total of 8892 clinically significant RBC alloantibodies identified, with 75% being in the Rh or Kell families. Alloimmunization was more common in females (2.38%) than males (1.68%), and in RhD negative (2.82%) than RhD positive (1.94%) patients. Age, sex, RhD status and race were associated with being a responder, and certain diagnoses (including sickle cell disease or trait, systemic lupus erythematosus, rheumatoid arthritis and myelodysplastic syndrome) were more common among responders than non-responders. Data collected in this multi-centre recipient database provide the largest RBC alloimmunized patient cohort studied in the US, with previously known demographic and disease associations of responder status confirmed, and new associations identified.

How we manage Gaucher Disease in the era of choices.

Abstract: Treatment of Gaucher Disease (GD) is now beset with the abundance of therapeutic options for an individual patient, making the choice of therapy complex for both expert and non-expert clinicians. The pathogenesis of all disease manifestations is a gene mutation-driven deficiency of glucocerebrosidase, but the clinical expression and response of each of the clinical manifestations to different therapies can be difficult to predict. Enzyme replacement therapy has been available since 1991 and is well-established, with known efficacy and minimal toxicity. Of interest, the three available enzymes are distinct molecules and were registered as new products, not biosimilars. Oral substrate reduction therapy has undergone a revitalisation with a newly approved agent in this class for which some efficacy and toxicity questions have been raised. Herein we present our approach to the management of GD in the era of choices, including a new algorithm for how to manage a newly diagnosed patient.

Allogeneic haematopoietic cell transplantation for extranodal natural killer/T‐cell lymphoma, nasal type: a CIBMTR analysis

Abstract: Author(s): Kanate, Abraham S; DiGilio, Alyssa; Ahn, Kwang W; Al Malki, Monzr; Jacobsen, Eric; Steinberg, Amir; Hamerschlak, Nelson; Kharfan-Dabaja, Mohamed; Salit, Rachel; Ball, Edward; Bashir, Qaiser; Cashen, Amanda; Couriel, Daniel; Diez-Martin, Jose; Katsanis, Emmanuel; Linhares, Yulia; Mori, Shahram; Nash, Richard; Pawarode, Attaphol; Perales, Miguel-Angel; Phipps, Colin D; Richman, Carol; Savani, Bipin N; Shapira, Michael Y; Stiff, Patrick; Strair, Roger; Fenske, Timothy S; Smith, Sonali M; Sureda, Anna; Olteanu, Horatiu; Hamadani, Mehdi

How we treat the platelet glycoprotein defects; Glanzmann thrombasthenia and Bernard Soulier syndrome in children and adults.

Abstract: The inherited platelet glycoprotein deficiencies, Glanzmann thrombasthenia (GT) and Bernard Soulier syndrome (BSS) are rare but important long-term bleeding disorders. Once diagnosed, affected patients should be referred to a specialist centre for bleeding disorders for general advice and ongoing management. Patients do not require prophylactic treatment and so the management of GT and BSS focuses around prophylactic treatment prior to high risk procedures and treatment in response to non-surgical bleeding events and, in women, the management of menorrhagia and pregnancy. There is no consistent approach to the treatment or prevention of bleeding complications. Management must be tailored for each individual and the approach may not be the same for different events, even for the same patient, depending on the type of accident or invasive procedure, the extent of bleeding and the presence or not of platelet refractoriness.

A phase 1 clinical trial evaluating marizomib, pomalidomide and low-dose dexamethasone in relapsed and refractory multiple myeloma (NPI-0052-107): final study results.

Abstract: Marizomib (MRZ) is an irreversible, pan-subunit proteasome inhibitor (PI) in clinical development for relapsed/refractory multiple myeloma (RRMM) and glioma. This study analysed MRZ, pomalidomide (POM) and low-dose dexamethasone (Lo-DEX) [PMD] in RRMM to evaluate safety and determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D). Intravenous MRZ (0·3-0·5 mg/m2 ) was administered over 2 h on days 1, 4, 8, 11; POM (3-4 mg) on days 1-21; and Lo-DEX (5 or 10 mg) on days 1, 2, 4, 5, 8, 9, 11, 12, 15, 16, 22 and 23 of every 28-day cycle. Thirty-eight patients were enrolled that had received a median of 4 (range 1-10) prior lines of therapy; all patients received prior lenalidomide and bortezomib. No dose-limiting toxicities (DLTs) were observed and 0·5 mg/m2 MRZ was determined to be the RP2D. The most common treatment-related ≥Grade 3 adverse events were: neutropenia (11/38 patients: 29%), pneumonia (4/38 patients 11%), anaemia (4/38 patients; 11%) and thrombocytopenia (4/38 patients; 11%). The overall response rate and clinical benefit rate was 53% (19/36) and 64% (23/36), respectively. In conclusion, PMD was well tolerated and demonstrated promising activity in heavily pre-treated, high-risk RRMM patients.

Guidelines for the use of hydroxycarbamide in children and adults with sickle cell disease: A British Society for Haematology Guideline

Abstract: Department of Paediatric Haematology and Oncology, Oxford Children’s Hospital, Oxford University Hospital NHS Trust, Oxford, Department of Paediatric Haematology and Oncology, Royal London Hospitals, Barts Health NHS Trust, London, Department of Haematology, Sandwell and West Birmingham NHS Trust, West Bromwich, Department of Paediatric Haematology, Alderhey Children’s Hospital NHS Trust, Liverpool, Department of Clinical Psychology, Imperial College Healthcare NHS Trust, London, Department of Haematology, Milton Keynes Hospital NHS Trust, Milton Keynes, and Department of Haematology, Guys and St Thomas’s NHS Foundation Trust, London, UK