Showing papers in "British Journal of Haematology in 2019"

Eculizumab in paroxysmal nocturnal haemoglobinuria and atypical haemolytic uraemic syndrome: 10-year pharmacovigilance analysis

Abstract: Eculizumab is the first and only medication approved for paroxysmal nocturnal haemoglobinuria (PNH) and atypical haemolytic uraemic syndrome (aHUS) treatment. However, eculizumab safety based on long-term pharmacovigilance is unknown. This analysis summarises safety data collected from spontaneous and solicited sources from 16 March 2007 through 1 October 2016. Cumulative exposure to eculizumab was 28 518 patient-years (PY) (PNH, 21 016 PY; aHUS, 7502 PY). Seventy-six cases of meningococcal infection were reported (0·25/100 PY), including eight fatal PNH cases (0·03/100 PY). Susceptibility to meningococcal infections remained the key risk in patients receiving eculizumab. The meningococcal infection rate decreased over time; related mortality remained steady. The most commonly reported serious nonmeningococcal infections were pneumonia (11·8%); bacteraemia, sepsis and septic shock (11·1%); urinary tract infection (4·1%); staphylococcal infection (2·6%); and viral infection (2·5%). There were 434 reported cases of eculizumab exposure in pregnant women; of 260 cases with known outcomes, 70% resulted in live births. Reporting rates for solid tumours (≈0·6/100 PY) and haematological malignancies (≈0·74/100 PY) remained stable over time. No new safety signals affecting the eculizumab benefit-risk profile were identified. Continued awareness and implementation of risk mitigation protocols are essential to minimise risk of meningococcal and other Neisseria infections in patients receiving eculizumab.

Diagnosis of Hodgkin lymphoma in the modern era

Abstract: The Hodgkin lymphomas are a family of unique lymphoma subtypes, in which the nature of the neoplastic cell was enigmatic for many years. Much of the mystery has been solved, with all forms now considered to be of B-cell origin, in most cases of germinal centre derivation. Today we recognize Hodgkin lymphoma as an eponym that encompasses multiple entities. One of the unifying themes is the major contribution from the tumour microenvironment. Both the character of the neoplastic cells and the nature of the immune environment are critical to accurate diagnosis. Moreover, an understanding of the molecular alterations that characterize both the neoplastic cells and their microenvironment have led to therapeutic advances, targeting both neoplastic and reactive components. Other conditions may foster a similar inflammatory milieu and lead to lymphoproliferations that mimic the Hodgkin lymphomas. In this review we provide an update on the diagnostic features of the various subtypes and include additional information relevant for prognostic evaluation and investigation of potential therapeutic targets. Additionally, we also discuss those conditions that often cause confusion in diagnosis and need to be distinguished from the Hodgkin lymphomas.

A guideline for the diagnosis and management of polycythaemia vera. A British Society for Haematology Guideline.

Abstract: Mary Frances McMullin, Claire N. Harrison, Sahra Ali, Catherine Cargo, Frederick Chen, Joanne Ewing, Mamta Garg, Anna Godfrey, Steven Knapper S, Donal P. McLornan, Jyoti Nangalia, Mallika Sekhar, Frances Wadelin, Adam J. Mead and on behalf of the BSH Committee Centre for Medical Education, Queen’s University, Belfast, Guy’s and St Thomas’ NHS Foundation Trust, London, Castle Hill Hospital, Hull and East Yorkshire Hospitals NHS Trust, Hull, Leeds Teaching Hospitals NHS Trust, Leeds, The Royal London Hospital, Bart’s Health NHS Trust, London, Birmingham Heart of England NHS Foundation Trust, Birmingham, University Hospital of Leicester NHS Trust, Leicester (BSH representative), Department of Haematology and Haematopathology and Oncology Diagnostic Service, Cambridge University Hospitals NHS Foundation Trust, Cambridge, Cardiff University School of Medicine, Cardiff, Wellcome Trust Sanger Institute, Cambridge, Royal Free London NHS Foundation Trust, London, Nottingham University Hospital, Nottingham, and MRC Weatherall, Institute of Molecular Medicine, University of Oxford, Oxford, UK

Guidelines for the diagnosis and management of primary central nervous system diffuse large B-cell lymphoma

Abstract: Clinical Haematology, Nottingham University Hospitals NHS Trust, Nottingham, Department of Haematology, University College Hospital, London, Department of Haematology, Division of Cancer Sciences, School of Medical Sciences, Aintree Hospital NHS Trust, Liverpool, University of Manchester, Manchester, Velindre Cancer Centre, Cardiff, Department of Haematology, Barking, Havering and Redbridge University Hospitals, Essex, Division of Clinical Neuroscience, Radiological Sciences, University of Nottingham, Nottingham, Department of Neuropsychology, Barking, Havering and Redbridge University Hospitals, Essex, Department of Medical Oncology, Southampton General Hospital, Southampton, and Department of Haematology, Beatson West of Scotland Cancer Centre, Glasgow, UK

Differentiation syndrome in acute promyelocytic leukaemia.

Abstract: Acute promyelocytic leukaemia differentiation syndrome (APL DS) is seen when patients with APL are treated with all-trans retinoic acid (ATRA) and/or arsenic trioxide (ATO). Presenting symptoms are varied but frequently include dyspnoea, unexplained fever, weight gain >5 kg, unexplained hypotension, acute renal failure and a chest radiograph demonstrating pulmonary infiltrates or pleural or pericardial effusion. Immediate treatment with steroids at the first clinical suspicion is recommended and ATRA/ATO should be stopped in severe cases or if there is no response to treatment. The utility of steroid prophylaxis in order to prevent APL DS is less certain. Here we provide a detailed review of the pathogenesis, clinical signs and symptoms as well as management and prophylaxis strategies of APL DS.

Incidence of and risk factors for major haemorrhage in patients treated with ibrutinib: An integrated analysis.

Abstract: Ibrutinib, a Bruton tyrosine kinase inhibitor, is approved for treatment of various B-cell malignancies. In ibrutinib clinical studies, low-grade haemorrhage was common, whereas major haemorrhage (MH) was infrequent. We analysed the incidence of and risk factors for MH from 15 ibrutinib clinical studies (N = 1768), including 4 randomised controlled trials (RCTs). Rates of any-grade bleeding were similar for single-agent ibrutinib and ibrutinib combinations (39% and 40%). Low-grade bleeding was more common in ibrutinib-treated than comparator-treated patients (35% and 15%), and early low-grade bleeding was not associated with MH. The proportion of MH in RCTs was higher with ibrutinib than comparators (4.4% vs. 2.8%), but after adjusting for longer exposure with ibrutinib (median 13 months vs. 6 months), the incidence of MH was similar (3.2 vs. 3.1 per 1000 person-months). MH led to treatment discontinuation in 1% of all ibrutinib-treated patients. Use of anticoagulants and/or antiplatelets (AC/AP) during the study was common (~50% of patients) and had an increased exposure-adjusted relative risk for MH in both the total ibrutinib-treated population (1.9; 95% confidence interval, 1.2-3.0) and RCT comparator-treated patients (2.4; 95% confidence interval, 1.0-5.6), indicating that ibrutinib may not alter the effect of AC/AP on the risk of MH in B-cell malignancies.

CXCR4 mutation subtypes impact response and survival outcomes in patients with Waldenström macroglobulinaemia treated with ibrutinib.

Abstract: Ibrutinib is associated with response rate of 90% and median progression-free survival (PFS) in excess of 5 years in Waldenstrom macroglobulinaemia (WM) patients. CXCR4 mutations are detected in 30-40% of patients with WM and associate with lower rates of response and shorter PFS to ibrutinib therapy. Both frameshift (CXCR4FS ) and nonsense (CXCR4NS ) CXCR4 mutations have been described. The impact of these mutations on outcomes to ibrutinib have not been evaluated in WM patients. We studied consecutive patients with a diagnosis of WM, on ibrutinib therapy, for the presence of CXCR4FS and CXCR4NS mutations and evaluated the differences in response and PFS between groups. Of 180 patients, 68 patients (38%) had CXCR4 mutations; 49 (27%) had CXCR4NS and 19 (11%) had CXCR4FS mutations. In multivariate models, patients with CXCR4NS had lower odds of major response (Odds ratio 0·25, 95% confidence interval [CI] 0·12-0·53; P < 0·001) and worse PFS (Hazard ratio 4·02, 95% CI 1·95-8·26; P < 0·001) than patients without CXCR4 mutations. CXCR4FS was not associated with worse major response or PFS rates than patients without CXCR4 mutations. Our results suggest different response and PFS rates to ibrutinib for WM patients with CXCR4NS and CXCR4FS , and advocate in favour of CXCR4 mutational testing as well as CXCR4-directed therapy.

Prophylactic donor lymphocyte infusion after allogeneic stem cell transplantation in acute leukaemia - a matched pair analysis by the Acute Leukaemia Working Party of EBMT

Abstract: Strategies for relapse prevention after allogeneic transplantation in acute leukaemia are warranted. A registry-based matched-pair analysis evaluated the efficacy of prophylactic donor lymphocyte infusion (proDLI). Adults receiving proDLI in complete remission (CR) and controls were pair-matched for age, diagnosis, cytogenetics, stage, donor, gender, conditioning and T-cell depletion. Eighty-nine pairs were identified (median follow-up: 6.9 years). Within the entire cohort, no difference was observed. However, among patients with high-risk acute myeloid leukaemia (AML) (unfavourable cytogenetics and/or transplanted beyond first CR), proDLI recipients had improved overall survival (69.8% vs. 40.2% in controls, P = 0.027). ProDLI has moderate efficacy, but can contribute to improved outcome in high-risk AML.

How we manage patients with pyruvate kinase deficiency.

Abstract: Novel therapies in development have brought a new focus on pyruvate kinase deficiency (PKD), the most common congenital haemolytic anaemia due to a glycolytic enzyme deficiency. With an improved recognition of its clinical presentation and understanding of the diagnostic pathway, more patients are likely to be identified with this anaemia. Complications, including gallstones and non-transfusion-related iron overload, require monitoring for early diagnosis and management. Current management remains supportive with red cell transfusions, chelation and splenectomy. Decisions to transfuse and/or splenectomise must be individualised. Haematopoietic stem cell transplant has been pursued in a small number of patients with mixed outcomes. Novel treatment approaches, which range from a small molecule pyruvate kinase activator to gene therapy, may transform the way in which PKD is managed in the future. In this review, we discuss the pathophysiology of PKD and present our approaches to diagnosis, monitoring and management of patients with this anaemia.

Citrullinated histone H3, a biomarker for neutrophil extracellular trap formation, predicts the risk of mortality in patients with cancer.

Abstract: Prior studies indicate that neutrophil extracellular traps (NETs) are associated with arterial thromboembolism (ATE) and mortality. We investigated the association between NET formation biomarkers (citrullinated histone H3 [H3Cit], cell-free DNA [cfDNA], and nucleosomes) and the risk of ATE and all-cause mortality in patients with cancer. In this prospective cohort study, H3Cit, cfDNA and nucleosome levels were determined at study inclusion, and patients with newly diagnosed cancer or progressive disease after remission were followed for 2 years for ATE and death. Nine-hundred and fifty-seven patients were included. The subdistribution hazard ratios for ATE of H3Cit, cfDNA and nucleosomes were 1·0 per 100 ng/ml increase (95% confidence interval [95% CI]: 0·7-1·4, P = 0·949), 1·0 per 100 ng/ml (0·9-1·2, P = 0·494) increase and 1·1 per 1-unit increase (1·0-1·2, P = 0·233), respectively. Three-hundred and seventy-eight (39·5%) patients died. The hazard ratio (HR) for mortality of H3Cit and cfDNA per 100 ng/ml increase was 1·1 (1·0-1·1, P < 0·001) and 1·1 (1·0-1·1, P < 0·001), respectively. The HR for mortality of nucleosome levels per 1-unit increase was 1·0 (1·0-1·1, P = 0·233). H3Cit, cfDNA and nucleosome levels were not associated with the risk of ATE in patients with cancer. Elevated H3Cit and cfDNA levels were associated with higher mortality in patients with cancer.

Lymphoblastic lymphoma in children and adolescents: review of current challenges and future opportunities.

Abstract: Lymphoblastic lymphoma (LBL) is the second most common type of Non-Hodgkin Lymphoma (NHL) in childhood and adolescence, accounting for 25-35% of all cases. The majority, 70-80%, is of T-lymphoblastic origin while 20-25% arise from B lymphoblasts. With current therapy, the event-free and overall survivals for paediatric LBL patients now exceeds 80%. Therapy, especially in T-LBL with large mediastinal tumours, is challenging, with both significant morbidity and late sequela. An additional challenge is the dismal prognosis of patients with refractory or relapsed disease. This review article will focus on the growing knowledge of the pathogenesis and biology of LBL, recent advances and challenges in the therapy of LBL, and ongoing and future efforts and opportunities in optimizing therapy and developing novel targeted treatment approaches.

Advances in understanding the pathogenesis of red cell membrane disorders

Abstract: Hereditary erythrocyte membrane disorders are caused by mutations in genes encoding various transmembrane or cytoskeletal proteins of red blood cells. The main consequences of these genetic alterations are decreased cell deformability and shortened erythrocyte survival. Red blood cell membrane defects encompass a heterogeneous group of haemolytic anaemias caused by either (i) altered membrane structural organisation (hereditary spherocytosis, hereditary elliptocytosis, hereditary pyropoikilocytosis and Southeast Asian ovalocytosis) or (ii) altered membrane transport function (overhydrated hereditary stomatocytosis, dehydrated hereditary stomatocytosis or xerocytosis, familial pseudohyperkalaemia and cryohydrocytosis). Herein we provide a comprehensive review of the recent literature on the molecular genetics of erythrocyte membrane defects and their reported clinical consequences. We also describe the effect of low-expression genetic variants on the high inter- and intra-familial phenotype variability of erythrocyte structural defects.

A guideline for the management of specific situations in polycythaemia vera and secondary erythrocytosis: A British Society for Haematology Guideline

Abstract: The previous BSH guideline for the management of erythrocytosis was published in 2005 (McMullin et al, 2005) and amended in 2007 (McMullin et al, 2007). Here, we re‐evaluate the literature formulate guidance on the management of specific situations encountered in polycythaemia vera (PV) and the management of the other types of secondary erythrocytosis. Recommendations for the diagnostic pathway of investigation of an erythrocytosis, risk stratification and management of PV are in the accompanying guideline (McMullin et al, 2018). We review evidence and outline guidance on management of acute thrombotic events and secondary prevention of thrombosis in PV. The unusual thrombotic events, splanchnic vein and cerebral vein thromboses are discussed and haemorrhage. The specific situations of surgery and pregnancy and guidance on management of pruritus are included. The evidence for the management of other causes of erythrocytosis, including idiopathic erythrocytosis, congenital erythrocytosis, hypoxic pulmonary disease and post‐transplant erythrocytosis, is reviewed and recommendations made.

Phase 1 study of selinexor plus carfilzomib and dexamethasone for the treatment of relapsed/refractory multiple myeloma.

Abstract: Selinexor, an oral Selective Inhibitor of Nuclear Export, targets Exportin 1 (XPO1, also termed CRM1). Non‐clinical studies support combining selinexor with proteasome inhibitors (PIs) and corticosteroids to overcome resistance in relapsed/refractory multiple myeloma (RRMM). We conducted a phase I dose‐escalation trial of twice‐weekly selinexor in combination with carfilzomib and dexamethasone (SKd) to determine maximum tolerated dose in patients with RRMM (N = 21), with an expansion cohort to assess activity in carfilzomib‐refractory disease and identify a recommended phase II dose (RP2D). During dose escalation, there was one dose‐limiting toxicity (cardiac failure). The RP2D of twice‐weekly SKd was selinexor 60 mg, carfilzomib 20/27 mg/m2 and dexamethasone 20 mg. The most common grade 3/4 treatment‐emergent adverse events included thrombocytopenia (71%), anaemia (33%), lymphopenia (33%), neutropenia (33%) and infections (24%). Rates of ≥minimal response, ≥partial response and very good partial response were 71%, 48% and 14%, respectively; similar response outcomes were observed for dual‐class refractory (PI and immunomodulatory drug)/quad‐exposed (carfilzomib, bortezomib, lenalidomide and pomalidomide) patients (n = 17), and patients refractory to carfilzomib in last line of therapy (n = 13). Median progression‐free survival was 3·7 months, and overall survival was 22·4 months in the overall population. SKd was tolerable and re‐established disease control in RRMM patients, including carfilzomib‐refractory patients. Registered at ClinicalTrials.gov ({"type":"clinical-trial","attrs":{"text":"NCT02199665","term_id":"NCT02199665"}}NCT02199665)

Identification of high-risk DUSP22-rearranged ALK-negative anaplastic large cell lymphoma.

Abstract: Recent studies have identified two mutually exclusive recurrent rearrangements in anaplastic lymphoma kinase (ALK)negative anaplastic large cell lymphoma (ALCL) that have important clinical significance (Feldman et al, 2011) (Vasmatzis et al, 2012). The DUSP22 rearrangement, which involves the DUSP22-IRF4 locus on 6p25.3, most commonly occurs as a t(6;7)(p25.3;q32.3)(2) and the TP63 rearrangement, which results from a TP63-TBL1XR1 inversion (Vasmatzis et al, 2012). In the first clinical report, DUSP22 rearrangements occurred in ~30% of all ALK-negative ALCL and were associated with a very favourable prognosis [5-year overall survival (OS) 90%] whereas TP63 rearrangements occurred in 8% and were associated with a dismal prognosis (5-year OS 17%) (Parrilla Castellar et al, 2014). The majority of ALK-negative ALCL were ‘triple negative’, lacking any known rearrangements, and had an intermediate prognosis (5-year OS 42%) (Parrilla Castellar et al, 2014). More recently, five cases of DUSP22-rearranged ALK-negative ALCL from a Danish series (Pedersen et al, 2017a) and eight cases (including one PTCL-not otherwise specified) from an upfront transplant Phase 2 study (Pedersen et al, 2017b), were evaluated, with similar favourable outcomes (5 year OS >80%). These data have led to treatment guideline modifications, but represent a limited number of cases (NCCN 2018). Herein, we evaluated the frequency, clinical features and outcome of previously defined ALCL genetic subgroups in an independent series of systemic ALCL. In addition, the prognostic significance of immunohistochemical (IHC) markers was explored. All cases of newly diagnosed ALCL were identified in the British Columbia Cancer Lymphoid Cancer database and confirmed by expert haematopathologists based on the World Health Organization classification (GWS, PF). A tissue microarray was constructed and IHC and fluorescence in situ hybridisation (FISH) was performed as previously described using in-house bacterial artificial chromosome break-apart probes for DUSP22 and TP63 loci (Figs S1 and S2) (Scott et al, 2012). Of 62 ALK-negative ALCL cases evaluated, 12 (19%) harboured a DUSP22 rearrangement, one (2%) had a TP63 rearrangement and the remainder were triple negative (n = 49, 79%). All DUSP22 rearrangements were verified on whole sections and at an independent laboratory (AF). Most patients (78%) received CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone)/CHOP-like chemotherapy (92% in DUSP22) (Table I, Table SI). Some high-risk clinical features were noted in the DUSP22-rearranged cases: Median age 61 5 years; extranodal involvement (67%); bone/bone marrow involvement (42%); high lactate dehydrogenase (42%) (Table I). The median follow-up for all living patients was 8 6 years (range 1 8–34 years). Consistent with prior studies, outcomes in ALK-negative ALCL were inferior to those with ALK-positive ALCL [5-year progression-free survival (PFS) 23% vs. 62%, P < 0 002; 5-year OS 32% vs. 69%, P < 0 01] (Fig S3A,B). Of note, survival estimates for ALCL in our study are lower than some, but not all other series (Hapgood & Savage, 2015), possibly reflecting the population-based nature of this analysis. Surprisingly, the outcome of DUSP22-rearranged ALKnegative ALCL cases was lower than that observed in published series, with a 5-year PFS and OS of 40% (Fig 1A,B) and 5-year disease-specific survival of 45%, with similar findings when only those treated with curative intent chemotherapy are evaluated (DUSP22-rearranged, n = 11), 5-year PFS and OS 44%. One patient had a central nervous system (CNS) parenchymal relapse (Table SI). Interestingly, five of the relapses occurred over 1 year from diagnosis, including two ≥4 years. Further details on the clinical course are provided in the Supplementary Material. Of note, the 5-year PFS and OS estimates were poor for triple negative ALKnegative ALCL (19% and 28%, respectively) but comparable to the Danish series (n = 20, 5-year OS 33%) (Fig 1A,B). The sole case with a TP63 rearrangement died within 6 months of diagnosis. Excluding the case with a TP63 rearrangement, multivariable Cox proportional hazard models were used to estimate hazard ratios (HR) using ALK-positive ALCL as the reference group (Table SII). There was no statistical difference in OS and PFS in both crude and adjusted [for international prognostic index (IPI) and age] analyses. Similarly, no differences were observed using triple negative cases as the reference group (results not shown). This may reflect the challenge of analysing small datasets with limited power. Regardless, the outcome observed in DUSP22-rearranged cases remains of clinical significance. Despite the aggressive clinical course in some patients, the IHC features of DUSP22-rearranged cases were in keeping with prior reports and highlight that it is a defined entity. CD2 and CD3 expression was frequent and all cases were

Advances in understanding the pathogenesis of graft-versus-host disease

Abstract: Acute graft-versus-host disease (GVHD) remains a major complication after allogeneic haematopoietic stem cell transplantation (allo-HSCT). The emergence of different immuno-prophylaxis strategies, such as post-transplant cyclophosphamide or anti-thymocyteglobulin has reduced the incidence of acute GVHD in recent years. The biology of the acute GVHD we observe in the clinic may change due to the use of novel immuno-stimulatory agents, including immune checkpoint inhibitors or anti-neoplastic immune-modifiers, like lenalidomide, given before or after allo-HSCT. Here we discuss the recent advances in our understanding of acute GVHD with a focus on early events of the disease, including tissue damaging factors, innate immune cells, costimulatory pathways, immune cell signalling, immuno-regulatory cell types, biomarkers of GVHD and regenerative approaches. New insight in the pathogenesis of acute GVHD has revealed the role of pro-inflammatory intracellular signalling, defects in intestinal tissue regeneration and anti-bacterial defence, as well as a reduced diversity of the microbiome, which will be the basis for the development of novel therapies.

Fetal and neonatal alloimmune thrombocytopenia: recommendations for evidence-based practice, an international approach.

Abstract: Fetal and neonatal alloimmune thrombocytopenia (FNAIT) may result in severe bleeding, particularly fetal and neonatal intracranial haemorrhage (ICH). As a result, FNAIT requires prompt identification and treatment; subsequent pregnancies need close surveillance and management. An international panel convened to develop evidence-based recommendations for diagnosis and management of FNAIT. A rigorous approach was used to search, review and develop recommendations from published data for: antenatal management, postnatal management, diagnostic testing and universal screening. To confirm FNAIT, fetal human platelet antigen (HPA) typing, using non-invasive methods if quality-assured, should be performed during pregnancy when the father is unknown, unavailable for testing or heterozygous for the implicated antigen. Women with a previous child with an ICH related to FNAIT should be offered intravenous immunoglobulin (IVIG) infusions during subsequent affected pregnancies as early as 12 weeks gestation. Ideally, HPA-selected platelets should be available at delivery for potentially affected infants and used to increase the neonatal platelet count as needed. If HPA-selected platelets are not immediately available, unselected platelets should be transfused. FNAIT studies that optimize antenatal and postnatal management, develop risk stratification algorithms to guide management and standardize laboratory testing to identify high risk pregnancies are needed.

Pembrolizumab combined with lenalidomide and low‐dose dexamethasone for relapsed or refractory multiple myeloma: phase I KEYNOTE‐023 study

Abstract: Funding for this research was provided by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Bortezomib reinduction chemotherapy in high-risk ALL in first relapse: a report from the Children's Oncology Group

Abstract: While survival in paediatric acute lymphoblastic leukaemia (ALL) is excellent, survival following relapse is poor. Previous studies suggest proteasome inhibition with chemotherapy improves relapse ALL response rates. This phase 2 Children’s Oncology Group study tested the hypothesis that adding the proteasome inhibitor bortezomib to chemotherapy increases complete response rates (CR2). Evaluable patients (n=135, 103 B-ALL, 22 T-ALL, 10 T-lymphoblastic lymphoma) were treated with reinduction chemotherapy plus bortezomib. Overall CR2 rates were 68%±5% for precursor B-ALL patients (<21 years of age), 63%±7% for very early relapse (<18 months from diagnosis) and 72%±6% for early relapse (18–36 months from diagnosis). Relapsed T-ALL patients had an encouraging CR2 rate of 68%±10%. End of induction minimal residual disease (MRD) significantly predicted survival. MRD negative (MRDneg; MRD <0.01%) rates increased from 29% (post-cycle 1) to 64% following cycle 3. Very early relapse, end-of-induction MRDneg precursor B-ALL patients had 70%±14% 3-year event-free (EFS) and overall survival (OS) rates, vs. 3-year EFS/OS of 0–3% (p=0.0001) for MRDpos (MRD ≥0.01) patients. Early relapse patients had similar outcomes (MRDneg 3-year EFS/OS 58–65% vs. MRDpos 10–19%, EFS p=0.0014). These data suggest that adding bortezomib to chemotherapy in certain ALL subgroups, such as T-cell ALL, is worthy of further investigation. This study is registered at http://www.clinical.trials.gov as {"type":"clinical-trial","attrs":{"text":"NCT00873093","term_id":"NCT00873093"}}NCT00873093.

Diagnosis of intravascular large B cell lymphoma: novel insights into clinicopathological features from 42 patients at a single institution over 20 years.

Abstract: This study aimed to clarify the comprehensive clinical, laboratory, pathological and imaging features of intravascular large B‐cell lymphoma (IVLBCL) using data on 42 IVLBCL patients diagnosed at our hospital over the past 20 years. The majority of patients were diagnosed via random skin biopsy (29/42, 69·0%) followed by bone marrow biopsy alone (8/42, 19·0%). Characteristic features included persistent fever (41/42, 97·6%), decreased performance status (≥2) (100%), hypoxaemia (32/40, 80·0%), impaired consciousness (19/42, 45·2%), hypoalbuminemia (42/42, 100%) and extreme elevation of lactate dehydrogenase and soluble interleukin 2 receptor levels. Brain magnetic resonance imaging showed abnormal findings in 32/37 patients (86·4%). Hyperintense lesion in the pons was a peculiar finding that was unrelated to the neurological deficits. Positron emission tomography‐computed tomography revealed a high incidence of bone marrow (26/34, 76·5%), spleen (19/34, 55·9%) and adrenal gland (9/34, 26·5%) involvement. Neurolymphomatosis was noted in 6 patients during the course of the disease. About 60% of IVLBCL patients in whom in vivo diagnosis was possible survived more than 5 years with combination chemotherapy. Our observations provide additional insight into the diagnosis of IVLBCL and indicate that early disease recognition via random skin biopsy combined with imaging, enables in vivo diagnosis of the disease and improved survival for many patients.

Efficacy of venetoclax monotherapy in patients with relapsed chronic lymphocytic leukaemia in the post-BCR inhibitor setting: a UK wide analysis.

Abstract: Venetoclax is a BCL2 inhibitor with activity in relapsed/refractory (R/R) chronic lymphocytic leukaemia (CLL). We conducted a multi-centre retrospective analysis of 105 R/R CLL patients who received venetoclax pre-National Health Service commissioning. The median age was 67 years and median prior lines was 3 (range: 1-15). 48% had TP53 disruption. At ≥2 lines, 60% received a Bruton Tyrosine Kinase inhibitor (BTKi) and no prior phosphoinositide 3-kinase inhibitor (Pi3Ki), 25% received a Pi3Ki and no prior BTKi, and 10% received both. Patients discontinued B cell receptor inhibitor (BCRi) because of toxicity in 44% and progression in 54%. Tumour lysis syndrome risk was low, intermediate or high in 27%, 25%, and 48% respectively. Overall response was 88% (30% complete response [CR]). The overall response rate was 85% (CR 23%) in BTKi-exposed patients, 92% (CR 38%) in Pi3Ki-exposed patients and 80% (CR 20%) in both (P = 0·59). With a median follow-up of 15·6 months, 1-year progression-free survival was 65·0% and 1-year overall survival was 75·1%. Dose reduction or temporary interruption did not result in an inferior progression-free or discontinuation-free survival. Risk of progression or death after stopping a prior BCRi for progression was double compared to those stopping for other reasons (predominantly toxicity) (Hazard Ratio 2·01 P = 0·05). Venetoclax is active and well tolerated in R/R CLL post ≥1 BCRi. Reason(s) for stopping BCRi influences venetoclax outcomes.

Bortezomib plus EPOCH is effective as frontline treatment in patients with plasmablastic lymphoma.

Abstract: Additional Supporting Information may be found in the online version of this article: Figure S1. Histone 3 mutation in T-ALL validation cohort. Table SI. Type 3 histone genes. Table SII. COSMIC version 81 cell lines screened for type 3 histone mutations. Table SIII. T-cell leukaemia lines screened for type 3 histone mutations. Table SIV. Internal database screened for histone 3 mutations. Table SV. TCGA cohort screened for histone 3 mutations. Table SVI. Validation cohort of 38 primary human T-ALL specimens screened by Sanger sequencing of histone 3 genes. Table SVII. Primers used to Sanger sequence hotspot residues in histone 3 genes.

Second‐line and subsequent therapy and outcomes for follicular lymphoma in the United States: data from the observational National LymphoCare Study

Abstract: Follicular lymphoma (FL) is the second most common lymphoma, and by virtue of its chronicity, may be the most prevalent and most treated lymphoma in the United States (Morton et al, 2006). The National LymphoCare Study (NLCS, ClinicalTrials.gov identifier, NCT00097565) is a prospective cohort study of disease presentation, treatment patterns and clinical outcomes that recruited consecutive patients diagnosed with FL between March 2004 and March 2007 in participating sites in the United States. The NLCS prospectively collected quarterly observations regarding disease characteristics, subsequent therapies and observed responses. Patterns of initial management in this cohort were reported previously (Friedberg et al, 2009). The current report describes patterns of subsequent active treatment and outcomes. “First-line treatment” refers to the first active treatment (Rx1), and “second-line treatment” refers to the second active treatment (Rx2), regardless of whether a relapse was recorded after first treatment. Maintenance therapy was not considered a distinct active treatment. Time to Rx2 was defined as the number of days from initiation of Rx1 to initiation of Rx2. Response/progression was determined by the local treating investigator. Patients progressing within 24 months of Rx1 were classified as early progressors (Casulo et al, 2015). Rituximab-refractory patients were identified from those who received rituximab monotherapy (R-mono) or rituximab plus chemotherapy (R-chemo) with or without rituximab maintenance therapy as Rx1. Patients with progressive disease (PD) within 6 months of completing rituximab-containing Rx1 or following rituximab maintenance therapy were considered rituximab-refractory. After a median follow-up of 8 years (range: 0 02–10 34), 2429/2652 patients had received Rx1. Of those, 889 (37%) had received Rx2, 438 (18%) had received a third active treatment (Rx3), and 229 (9%) and 123 (5%) had received four and five active treatments, respectively (Fig 1). Overall, 1465 (53%) patients remained in active follow-up at study closure; 23% had died and 24% were lost to followup, withdrew or discontinued for other reasons. The distribution of treatment choices for Rx1 to Rx5 is shown in Table I. The median time from initiation of Rx1 to Rx2 (n = 889) was 16 months (range: 0 1–112). Of patients who received Rx2, 62% did so within the first 24 months (Fig S1). The distribution of treatment choices for Rx1 is notably different than for Rx2, with a substantial increase in the use of R-mono, a mild increase in chemotherapy without rituximab, and a substantial drop in patients receiving chemoimmunotherapy for Rx2 compared with Rx1. Rituximab remained a treatment component (alone or with chemotherapy) in 70% of patients receiving Rx2. Of the patients receiving R-mono for Rx1, 44% continued to use R-mono for Rx2, while 34% switched to R-chemo. Of the patients receiving R-chemo for Rx1, 41% also used R-chemo for Rx2, 26% switched to R-mono and 33% to other therapy. The rate of anthracycline use was only 18% for Rx2, and 28% of patients remained anthracycline-na€ıve after five active treatments. Bendamustine was unavailable in the United States during the time of patient enrolment and was used in 9/2429 patients for Rx1, 50/889 for Rx2 and 56/438 for Rx3. The participation rate in a clinical trial for Rx2 remained low at 5%; 22% of patients who participated in a clinical trial for Rx2 had also participated in a clinical trial for Rx1. Overall, 341 patients were classified as early progressors. The distribution of Rx2 choices was notably similar between early progressors and others who received Rx2, with early progressors only slightly less likely to receive R-mono (30% vs. 36%) or investigational therapy (4 4% vs. 6 5%), and slightly more likely to receive any anthracycline (18% vs. 13%) or radioimmunotherapy (6 8% vs. 4 0%). Remarkably, although more frequently than others (1 1%), only 3 5% of early progressors received Rx2 strategies that included bone marrow transplant (BMT). Among patients who had received ≥5 treatments, use of radioimmunotherapy in the relapse/progression setting (n = 77) outpaced BMT (n = 53). Of 237 rituximab-refractory patients who received Rx2, 77 and 160 had received Rx1 of R-mono (217 rituximab-refractory patients) and R-chemo (486 rituximab-refractory patients), respectively. Among rituximab-refractory patients, 62% received rituximab-containing Rx2, including 22% who received R-mono; compared with 36% of patients receiving R-mono in the non-refractory cohort. Other Rx2 choices among rituximab-refractory patients included chemotherapy alone (13%), radioimmunotherapy (9%), radiation therapy (7%) and BMT (5%). Correspondence

How I manage children with Diamond-Blackfan anaemia.

Abstract: Diamond-Blackfan anaemia (DBA) is a rare inherited marrow failure disorder, characterized by hypoplastic anaemia, congenital anomalies and a predisposition to cancer as a result of ribosomal dysfunction. Historically, treatment is based on glucocorticoids and/or blood transfusions, which is accompanied by significant toxicity and long-term sequelae. Currently, stem cell transplantation is the only curative option for the haematological DBA phenotype. Whereas this procedure has been quite successful in the last decade in selected patients, novel therapies and biological insights are still warranted to improve clinical care for all DBA patients. In addition to paediatric haematologists, other physicians (e.g. endocrinologist, gynaecologist) should ideally be involved in the care of this chronic condition from an early age, to improve lifelong management of haematological and non-haematological symptoms, and screen for DBA-associated malignancies. Here we provide an overview of current knowledge and recommendations for the day-to-day care of DBA patients.

Phase 1b trial of pembrolizumab monotherapy for relapsed/refractory multiple myeloma: KEYNOTE-013.

Abstract: Agnelli, G., Buller, H.R., Cohen, A., Curto, M., Gallus, A.S., Johnson, M., Porcari, A., Raskob, G.E., Weitz, J.I. & AMPLIFY-EXT Investigators. (2013) Apixaban for extended treatment of venous thromboembolism. New England Journal of Medicine, 368, 699–708. Iorio, A., Kearon, C., Filippucci, E., Marcucci, M., Macura, A., Pengo, V., Siragusa, S. & Palareti, G. (2010) Risk of recurrence after a first episode of symptomatic venous thromboembolism provoked by a transient risk factor. Archives of Internal Medicine, 170, 1710–1716. Kearon, C., Ginsberg, J.S., Kovacs, M.J., Anderson, D.R., Wells, P., Julian, J.A., MacKinnon, B., Weitz, J.I., Crowther, M.A., Dolan, S., Turpie, A.G. & Geerts, W. (2003) Comparison of lowintensity warfarin therapy with conventionalintensity warfarin therapy for long-term prevention of recurrent venous thromboembolism. New England Journal of Medicine, 349, 631–639. Linkins, L.-A., Choi, P.T. & Douketis, J.D. (2003) Clinical impact of bleeding in patients taking oral anticoagulant therapy for venous thromboembolism. A meta-analysis. Annals of Internal Medicine, 139, 893–900. MacDonald, S., Chengal, R., Hanxhiu, A., Symington, E., Sheares, K., Besser, M. & Thomas, W. (2018) Utility of the DASH score after unprovoked venous thromboembolism; single centre study. British Journal of Haematology. published online first at https://doi.org/10.1111/ bjh.15597 Martin, K., Beyer-Westendorf, J., Davidson, B.L., Huisman, M.V., Sandset, P.M. & Moll, S. (2016) Use of the direct oral anticoagulants in obese patients: guidance from the SSC of the ISTH. Journal of Thrombosis and Haemostasis, 14, 1308–1313. Ridker, P.M., Goldhaber, S.Z., Danielson, E., Rosenberg, Y., Eby, C.S., Deitcher, S.R., Cushman, M., Moll, S., Kessler, C.M., Elliot, C.G., Paulson, R. & Wong, T. (2003) Long-term, low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism. New England Journal of Medicine, 348, 1425– 3144. Schreiber, K., Sciascia, S., de Groot, P.G., Devreese, K., Jacobsen, S., Ruiz-Irastorza, G., Salmon, J.E., Shoenfeld, Y., Shovman, O. & Hunt, B.J. (2018) Antiphospholipid syndrome. Nat Rev Dis Primers, 11, 17103. Schulman, S., Kearon, C. & Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. (2005) Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. Journal of Thrombosis and Haemostasis, 356, 692–694. Weitz, J.I., Lensing, A.W.A., Prins, M.H., Bauersachs, R., Beyer-Westendorf, J., Bounameaux, H., Brighton, T.A., Cohen, A.T., Davidson, B.L., Decousus, H., Freitas, M.C.S., Holberg, G., Kakkar, A.K., Haskell, L., van, Bellen, B., Pap, A.F., Berkowitz, S.D., Verhamme, P., Wells, P.S., Prandoni, P. & for the EINSTEIN CHOICE Investigators. (2017) Rivaroxaban or aspirin for extended treatment of venous thromboembolism. New England Journal of Medicine, 376, 1211–1222.

Biology and Therapy of Primary Mediastinal B-cell Lymphoma: Current Status and Future Directions

Abstract: Primary mediastinal B-cell lymphoma (PMBCL) is a distinct disease closely related to classical nodular sclerosing Hodgkin lymphoma. Conventional diagnostic paradigms utilising clinical, morphological and immunophenotypical features can be challenging due to overlapping features with other B-cell lymphomas. Reliable diagnostic and prognostic biomarkers that are applicable to the conventional diagnostic laboratory are largely lacking. Nuclear factor kappa B (NF-κB) and Janus kinase/signal transducers and activators of transcription (JAK-STAT) signalling pathways are characteristically dysregulated in PMBCL and implicated in several aspects of disease pathogenesis, and the latter pathway in host immune evasion. The tumour microenvironment is manipulated by PMBCL tumours to avoid T-cell mediated destruction via strategies that include loss of tumour cell antigenicity, T-cell exhaustion and activation of suppressive T-regulatory cells. R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) and DA-EPOCH-R (dose-adjusted etoposide, prednisolone, vincristine, cyclophosphamide, doxorubicin, rituximab) are the most common first-line immunochemotherapy regimens. End of treatment positron emission tomography scans are the recommended imaging modality and are being evaluated to stratify patients for radiotherapy. Relapsed/refractory disease has a relatively poor outcome despite salvage immunochemotherapy and subsequent autologous stem cell transplantation. Novel therapies are therefore being developed for treatment-resistant disease, targeting aberrant cellular signalling and immune evasion.

Daratumumab proves safe and highly effective in AL amyloidosis.

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Venetoclax and hypomethylating agents in TP53-mutated acute myeloid leukaemia.

Abstract: TP53 mutations occur in nearly 10% of adults with de novo acute myeloid leukaemia (AML); however, these mutations are encountered at higher frequency in therapy-related AML (t-AML) (~35%) and AML with complex cytogenetics (50– 60%) (Rucker et al, 2012; Ok et al, 2015). The presence of the TP53 mutation (TP53m) conveys an extremely poor prognosis (Grossmann et al, 2012; Rucker et al, 2012). Patients with TP53m AML are generally older in age (Rucker et al, 2012), and their physical fitness, especially in those with t-AML, is poor (Granfeldt Ostgard et al, 2015). The clinical response of TP53m AML to standard induction regimens has been disappointing, and if achieved, is usually short-lived (Grossmann et al, 2012; Rucker et al, 2012). Venetoclax (VEN) has shown encouraging activity when combined with hypomethylating agents (HMAs) in both newly diagnosed and relapsed/refractory (r/r) AML (Aldoss et al, 2018; DiNardo et al, 2019). The combination is welltolerated even in frail patients and is associated with low treatment-related mortality (TRM) (DiNardo et al, 2019). Apoptosis mediated by venetoclax appears to be TP53-independent (Anderson et al, 2016), and VEN/HMA activity was observed across various high-risk leukaemia genetics (Aldoss et al, 2018; DiNardo et al, 2019). We conducted a retrospective analysis of AML patients treated with the combination of VEN/HMA at our institution between June 2016 and April 2019. We identified TP53m utilizing an in-house next generation sequencing panel. The study was approved by the City of Hope Institutional Review Board. Response was defined as either complete remission (CR) or CR with incomplete count recovery (CRi). In univariate analysis, descriptive statistics were used to summarize the covariates for both response and non-response groups. The correlations between response to VEN/ HMA and these covariates were assessed by the Pearson Chisquare test for categorical variables. A logistic multivariable regression model was applied to the three covariates with P values not exceeding 0 1; odds ratios and 95% confidence intervals (CI) are listed in Table S1. The median leukaemiafree survival (LFS) and overall survival (OS) were summarized for the response group only. All analyses were performed with R 3.5.1 (http://www.R-project.org) or SAS 9.4 (SAS Institute Inc, Cary, NC). We identified 32 adults with TP53m AML who were treated with VEN/HMA. One patient with r/r AML was unevaluable for response because of death from sepsis 10 days after initiating therapy. The median age was 68 years (22–85). Sixteen (52%) patients had r/r AML while 15 (48%) patients were newly diagnosed. The majority of patients had complex cytogenetics (n = 24, 77%). The median variant allele frequency (VAF) for TP53m was 56% (range, 3–95%), and 9 (29%) patients had more than one TP53 mutation. Nineteen (61%) patients had additional somatic mutations. Decitabine was the HMA used in the majority of cases (90%) and was more frequently given as a 5-day schedule rather than a 10day schedule (52% vs. 39%). Among the 31 evaluable patients, 16 (52%) experienced a response, including 7 CR and 9 CRi. Response was achieved after a median of 2 (range, 1–3) cycles. Minimal residual disease (MRD), defined as >0 01% by multiparameter flow cytometry in a reference laboratory, was evaluated in 10 of the responders, and 7 (70%) achieved MRD negativity. Prior HMA monotherapy was the only factor observed to be associated with a lower response compared to that in patients who were HMA-naive (14% vs. 63%, P = 0 025). There was a trend toward a higher CR/CRi rate in patients with more than one TP53 mutation (78% vs. 41%, P = 0 062) and in those who were treated with VEN/HMA in the frontline setting (67% vs. 38%, P = 0 1). Response was comparable across patient age, sex, AML type, receipt of prior allogeneic haematopoietic cell transplantation (alloHCT), cytogenetics, presence of additional mutations and type and duration of HMA therapy. Table I depicts patient characteristics and response rates. In multivariate analysis of response, prior exposure to HMA was associated with a non-significant trend toward lower response (odds ratio = 0 12; 95%CI: 1 69 to 1 27; P = 0 092) (Table S2). Response to VEN/HMA in TP53m AML according to associated additional mutations is shown in Table S1. The location and pattern of TP53 mutations for responders and non-responders is depicted in Fig 1. The median TP53 VAF was comparable for responders and non-responders (56% vs. 52%). The median LFS and OS for responders was 234 days (95% CI: 101–329) and 329 days (95% CI: 284–not reached), respectively. Five responders (31%) underwent alloHCT in CR. Consistent with previous reports (DiNardo et al, 2019), we illustrate that the response to this regimen in the frontline setting is encouraging for this high-risk group, especially considering the fact that the majority of patients with TP53m AML carried complex cytogenetics. Furthermore, we Correspondence