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  • Upregulation of AKR1C1 in mesenchymal stromal cells promotes the survival of acute myeloid leukaemia cells
    Br. J. Haematol. (IF 5.206) Pub Date : 2020-01-14
    Yajing Jiang; Ying Li; Jingying Cheng; Jiao Ma; Qinghua Li; Tianxiang Pang

    The leukaemic bone marrow microenvironment, comprising abnormal mesenchymal stromal cells (MSCs), is responsible for the poor prognosis of acute myeloid leukaemia (AML). Therefore, it is essential to determine the mechanisms underlying the supportive role of MSCs in the survival of leukaemia cells. Through in silico analyses, we identified a total of 271 aberrantly expressed genes in the MSCs derived from acute myeloid leukemia (AML) patients that were associated with adipogenic differentiation, of which aldo‐keto reductase 1C1 (AKR1C1) was significantly upregulated in the AML‐MSCs. Knockdown of AKR1C1 in the MSCs suppressed adipogenesis and promoted osteogenesis, and inhibited the growth of co‐cultured AML cell lines compared to the situation in wild‐ type AML‐derived MSCs. Introduction of recombinant human AKR1C1 in the MSCs partially alleviated the effects of AKR1C1 knockdown. In addition, the absence of AKR1C1 reduced secretion of cytokines such as MCP‐1, IL‐6 and G‐CSF from the MSCs, along with inactivation of STAT3 and ERK1/2 in the co‐cultured AML cells. AKR1C1 is an essential factor driving the adipogenic differentiation of leukaemic MSCs and mediates its pro‐survival effects on AML cells by promoting cytokine secretion and activating the downstream pathways in the AML cells.

    更新日期:2020-01-14
  • Safety and efficacy of eltrombopag plus pulsed dexamethasone as first‐line therapy for immune thrombocytopenia
    Br. J. Haematol. (IF 5.206) Pub Date : 2020-01-13
    Lunqing Zhang; Mingjie Zhang; Xin Du; Yunfeng Cheng; Gregory Cheng

    Current first‐line treatments for immune thrombocytopenia (ITP) usually have transient effects and sustained platelet response off therapy remains low. We evaluated whether eltrombopag plus pulsed dexamethasone as first‐line therapy can increase the proportion of patients maintaining platelet counts >50 × 109/l for a prolonged period without further ITP therapy. Treatment consisted of eltrombopag 25–75 mg daily according to platelet response for 12 weeks plus dexamethasone, 40 mg daily for four consecutive days every four weeks for 1–3 courses. Primary endpoint was durable response off therapy defined as maintaining platelet counts >50 × 109/l for more than six months without further ITP therapy. Fifty ITP subjects were enrolled between November 2014 and March 2019. Out of 46 evaluable subjects, 26 (56·5%) had achieved the primary endpoint. The median platelet counts at six months off‐treatment follow‐up were 158 × 109/l. Only two out of 26 responders had relapsed at eight‐ and nine‐month follow‐up. The remaining 24 are still maintaining platelet counts >50 × 109/l, the longest over three years. All subjects tolerated treatment well and no Grade 3 or above adverse effects were reported. Eltrombopag plus pulsed dexamethasone as a first‐line therapy could result in durable response off therapy in a significant number of ITP subjects.

    更新日期:2020-01-14
  • The meninges enhance leukaemia survival in cerebral spinal fluid
    Br. J. Haematol. (IF 5.206) Pub Date : 2020-01-12
    Patrick Basile; Leslie M. Jonart; Maryam Ebadi; Kimberly Johnson; Morgan Kerfeld; Peter M. Gordon

    Central nervous system (CNS) relapse is a common cause of treatment failure in patients with acute lymphoblastic leukaemia (ALL) despite current CNS‐directed therapies that are also associated with significant short‐ and long‐term toxicities. Herein, we showed that leukaemia cells exhibit decreased proliferation, elevated reactive oxygen species (ROS) and increased cell death in cerebral spinal fluid (CSF) both in vitro and in vivo. However, interactions between leukaemia and meningeal cells mitigated these adverse effects. This work expands our understanding of the pathophysiology of CNS leukaemia and suggests novel therapeutic approaches for more effectively targeting leukaemia cells in the CNS.

    更新日期:2020-01-13
  • Factor VIII: the protein, cloning its gene, synthetic factor and now – 35 years later – gene therapy; what happened in between?
    Br. J. Haematol. (IF 5.206) Pub Date : 2020-01-03
    Gavin Ling; Edward G. D. Tuddenham

    The foundation of haemophilia A therapy in the last 35 years has been critically dependent on isolation of the Factor VIII (FVIII) protein and discovery of the cDNA sequence of the FVIII gene, published in 1984. Identification of the FVIII sequence resulted in a new era of recombinant concentrates and led to significant improvements in safety, set against the tragedy of widespread HIV and hepatitis infections in haemophilia patients from contaminated plasma‐based products. We chronicle the scientific methods and race leading up to the publication of the FVIII DNA sequence and the legacy that follows through to revolutionary gene therapy treatment in clinical trials today.

    更新日期:2020-01-04
  • Long‐term sustained response to fostamatinib in two patients with chronic refractory immune thrombocytopenia (ITP)
    Br. J. Haematol. (IF 5.206) Pub Date : 2020-01-03
    Eun‐Ju Lee; Marina Izak; James B. Bussel

    Care of patients with chronic immune thrombocytopenia (ITP) who are refractory to available treatments can be quite challenging. Fostamatinib, an oral Syk inhibitor, is the newest FDA‐approved agent for ITP. Phase 3 clinical trials demonstrated an overall response in 43% of patients treated with fostamatinib and use for two years has been reported. Herein, we report two patients with long histories of ITP without lasting responses to numerous first‐, second‐ and third‐line therapies with prolonged responses to ongoing fostamatinib. This shows that patients unresponsive to other agents may respond to fostamatinib and can have sustained benefit.

    更新日期:2020-01-04
  • Bortezomib, cyclophosphamide, dexamethasone versus lenalidomide, cyclophosphamide, dexamethasone in multiple myeloma patients at first relapse
    Br. J. Haematol. (IF 5.206) Pub Date : 2020-01-02
    Vittorio Montefusco; Alessandro Corso; Monica Galli; Ilaria Ardoino; Sara Pezzatti; Cristina Carniti; Francesca Patriarca; Filippo Gherlinzoni; Renato Zambello; Simona Sammassimo; Magda Marcatti; Andrea Nozza; Claudia Crippa; Anna Maria Cafro; Luca Baldini; Paolo Corradini

    Bortezomib‐ and lenalidomide‐containing regimens are well‐established therapies in multiple myeloma (MM). However, despite their extensive use, head‐to‐head comparisons have never been performed. Therefore, we compared bortezomib and lenalidomide in fixed‐duration therapies. In this open‐label, phase III study, we randomized MM patients at first relapse to receive either nine cycles of bortezomib plus cyclophosphamide plus dexamethasone (VCD) or lenalidomide plus cyclophosphamide plus dexamethasone (RCD). The primary endpoint was achievement of a very good partial response (VGPR) or better at six weeks after nine treatment cycles. From March 2011 to February 2015, 155 patients were randomized. VGPR or better was achieved by 12 patients (15%) in the VCD arm and 14 patients (18%) in the RCD arm (P = 0·70). Median progression‐free survival (PFS) was 16·3 (95% CI: 12·1–22·4) with VCD and 18·6 months (95% CI: 14·7–25·5) with RCD, and the two‐year overall survival (OS) was 75% (95% CI: 66–86%) and 74% (95% CI: 64–85%) respectively. In subgroup analyses, no differences in PFS were observed in bortezomib‐ and lenalidomide‐naïve patients, nor in patients who received a bortezomib‐based regimen in first line. Adverse events were consistent with the well‐established safety profiles of both drugs. Bortezomib and lenalidomide treatments were equally effective in terms of depth of response, PFS, and OS in MM patients at first relapse.

    更新日期:2020-01-04
  • 5‐(Hydroxymethyl)furfural restores low‐oxygen rheology of sickle trait blood in vitro
    Br. J. Haematol. (IF 5.206) Pub Date : 2019-12-30
    Scott Hansen; David K. Wood; John M. Higgins

    Sickle cell trait (SCT) is the benign heterozygous carrier state for the sickle variant of the HBB gene. Most of the ~300 million people with SCT worldwide will not experience any significant complications. However, accumulating evidence finds SCT associated with increased risk for the common conditions of chronic kidney disease and venous thromboembolism, and severe but rare renal medullary carcinoma and exercise‐induced rhabdomyolysis. The mechanism is uncertain, but probably involves pathological rheology of SCT blood in regions of low oxygen tension, resulting from sickle haemoglobin polymerization in SCT red cells and leading to reduced blood flow and further tissue hypoxia and damage. Here, we used an in vitro microfluidic flow system to study the oxygen‐dependent rheology of SCT blood and show that 5‐(hydroxymethyl)furfural, a natural breakdown product of glucose and fructose‐containing foods, such as fruit juices, can reduce the effects of hypoxia on SCT blood rheology in vitro, restoring near‐normal flow velocities at very low oxygen. While opinions regarding the clinical significance of the risks associated with SCT are still evolving, these results suggest that a compound present in some food may provide a potential approach for managing risks that may be associated with SCT.

    更新日期:2019-12-31
  • Increased ferritin levels in non‐transfusion‐dependent β°‐thalassaemia/HbE are associated with reduced CXCR2 expression and neutrophil migration
    Br. J. Haematol. (IF 5.206) Pub Date : 2019-12-29
    Chayada Thiengtavor; Sirikwan Siriworadetkun; Kittiphong Paiboonsukwong; Suthat Fucharoen; Kovit Pattanapanyasat; Jim Vadolas; Saovaros Svasti; Pornthip Chaichompoo

    Severe bacterial infection is a major complication causing morbidity and mortality in β‐thalassaemia/HbE patients. Innate immunity constitutes the first line of defence against bacterial infection. This study aimed to comprehensively investigate the innate immune phenotype and function related to factors predisposing to infection in non‐transfusion‐dependent (NTD) β°‐thalassaemia/HbE patients. Twenty‐six patients and 17 healthy subjects were recruited to determine complement activity (C3, C4, mannose‐binding lectin and CH50) and surface receptor expression including markers of phagocytosis (CD11b, CD16 and C3bR), inflammation (C5aR) and migration (CD11b, CXCR1 and CXCR2) on neutrophils and monocytes. In addition, phagocytosis and oxidative burst activity of neutrophils and monocytes against Escherichia coli and neutrophil migration were examined. Decreased C3 and surface expression of CD11b and C3bR on neutrophils were found in patients. However, phagocytosis of neutrophils in patients was still in the normal range. Interestingly, patients displayed a significant reduction of surface expression of CXCR2 [1705 ± 217 mean fluorescent intensity (MFI)] on neutrophils, leading to impaired neutrophil migration (9·2 ± 7·7%) when compared to neutrophils from healthy subjects (2261 ± 627 MFI and 27·8 ± 9% respectively). Moreover, surface expression of CXCR2 on neutrophils was associated with splenectomy status, serum ferritin and haemoglobin levels. Therefore, impaired neutrophil migration could contribute to the increased susceptibility to infection seen in NTD β°‐thalassaemia/HbE patients.

    更新日期:2019-12-30
  • Mucormycosis in children with haematological malignancies is a salvageable disease: a report from the Israeli Study Group of Childhood Leukemia
    Br. J. Haematol. (IF 5.206) Pub Date : 2019-12-29
    Sarah Elitzur; Nira Arad‐Cohen; Assaf Barg; Naomi Litichever; Bella Bielorai; Ronit Elhasid; Salvador Fischer; Yariv Fruchtman; Gil Gilad; Joseph Kapelushnik; Mira Kharit; Osnat Konen; Ruth Laor; Itzhak Levy; Dror Raviv; Yael Shachor‐Meyouhas; Yulia Shvartser‐Beryozkin; Amos Toren; Isaac Yaniv; Ronit Nirel; Shai Izraeli; Shlomit Barzilai‐Birenboim

    Mucormycosis has emerged as an increasingly important cause of morbidity and mortality in immunocompromised patients, but contemporary data in children are lacking. We conducted a nationwide multicentre study to investigate the characteristics of mucormycosis in children with haematological malignancies. The cohort included 39 children with mucormycosis: 25 of 1136 children (incidence 2·2%) with acute leukaemias prospectively enrolled in a centralized clinical registry in 2004–2017, and an additional 14 children with haematological malignancies identified by retrospective search of the databases of seven paediatric haematology centres. Ninety‐two percent of mucormycosis cases occurred in patients with acute leukaemias. Mucormycosis was significantly associated with high‐risk acute lymphoblastic leukaemia (OR 3·75; 95% CI 1·51–9·37; P = 0·004) and with increasing age (OR 3·58; 95% CI 1·24–9·77; P = 0·01). Fifteen patients (38%) died of mucormycosis. Rhinocerebral pattern was independently associated with improved 12‐week survival (OR 9·43; 95% CI 1·47–60·66; P = 0·02) and relapsed underlying malignancy was associated with increased 12‐week mortality (OR 6·42; 95% CI, 1·01–40·94; P = 0·05). In patients receiving frontline therapy for their malignancy (n = 24), one‐year cumulative mucormycosis‐related mortality was 21 ± 8% and five‐year overall survival was 70 ± 8%. This largest paediatric population‐based study of mucormycosis demonstrates that children receiving frontline therapy for their haematological malignancy are often salvageable.

    更新日期:2019-12-30
  • Acute lymphoblastic leukaemia patients treated with PEGasparaginase develop antibodies to PEG and the succinate linker
    Br. J. Haematol. (IF 5.206) Pub Date : 2019-12-27
    Robin Kloos; Inge M. van der Sluis; Enrico Mastrobattista; Wim Hennink; Rob Pieters; Jan‐Jaap Verhoef

    Polyethylene glycol (PEG) conjugated asparaginase (PEGasparaginase) is essential for treatment of paediatric acute lymphoblastic leukaemia. We developed an assay identifying antibodies against the PEG‐moiety, the linker and the drug itself in patients experiencing hypersensitivity reactions to PEGasparaginase. Eighteen patients treated according to the DCOG ALL‐11 protocol, with a neutralizing hypersensitivity reaction to PEGasparaginase to the first PEGasparaginase doses in induction (12 patients) or during intensification after interruption of several months (6 patients) were included. ELISA was used to measure antibodies, coating with the succinimidyl succinate linker conjugated to BSA, PEGfilgrastim and Escherichia coli asparaginase, and using hydrolysed PEGasparaginase and mPEG5,000 for competition. Anti‐PEG antibodies were detected in all patients (IgG 100%; IgM 67%) of whom 39% had anti‐PEG antibodies exclusively. Pre‐existing anti‐PEG antibodies were also detected in patients who not previously received a PEGylated therapeutic (58% IgG; 21% IgM). Antibodies against the SS‐linker were predominantly detected during induction (50% IgG; 42% IgM). Anti‐asparaginase antibodies were detected in only 11% during induction but 94% during intensification. In conclusion, anti‐PEG and anti‐SS‐linker antibodies predominantly play a role in the immunogenic response to PEGasparaginase during induction. Thus, switching to native E. coli asparaginase would be an option for adequate asparaginase treatment.

    更新日期:2019-12-29
  • Pixantrone plus rituximab versus gemcitabine plus rituximab in patients with relapsed aggressive B‐cell non‐Hodgkin lymphoma not eligible for stem cell transplantation: a phase 3, randomized, multicentre trial (PIX306)
    Br. J. Haematol. (IF 5.206) Pub Date : 2019-12-27
    Ruth Pettengell; Monika Długosz‐Danecka; David Andorsky; David Belada; Pencho Georgiev; Donald Quick; Jack W. Singer; Simran B. Singh; Athanasios Pallis; Anton Egorov; Gilles Salles

    PIX306 was a phase 3, randomised, single‐blind, multicentre trial conducted in adult patients with diffuse large B‐cell lymphoma (DLBCL) or follicular lymphoma (FL) grade 3 who relapsed after ≥1 rituximab‐containing regimen and were not eligible for a stem cell transplant. Patients were randomised 1:1 to pixantrone 50 mg/m2 or gemcitabine 1000 mg/m2 on days 1, 8 and 15 of a 28‐day cycle, combined with rituximab 375 mg/m2 on day 1, for up to six cycles. Patients were followed for up to 96 weeks. The primary endpoint was progression‐free survival (PFS). Secondary endpoints included overall survival (OS), complete response (CR) rate, overall response rate (ORR) and safety. Overall, 312 patients were randomised (median age 73·0 years). The study did not meet its primary endpoint. Median PFS [95% confidence interval (CI)] was 7·3 months (5·2–8·4) with pixantrone + rituximab (PIX + R) and 6·3 months (4·4–8·1) with gemcitabine + rituximab [GEM + R; hazard ratio (HR): 0·85; 95% CI 0·64–1·14; P = 0·28]. Median OS was 13·3 (10·1–19·8) months with PIX + R and 19·6 (12·4–31·9) months with GEM + R (HR: 1·13; 95% CI 0·83–1·53). ORR was 61·9% and 43·9% respectively and CR rate 35·5% and 21·7%. The incidence of adverse events, including cardiac events, was not statistically significant different between PIX + R and GEM + R.

    更新日期:2019-12-27
  • What do we know about duodenal‐type follicular lymphoma? From pathological definition to treatment options
    Br. J. Haematol. (IF 5.206) Pub Date : 2019-12-27
    Guilherme Duffles Amarante; Graham Collins; Vanderson Rocha

    Duodenal‐type follicular lymphoma (DFL) is a newly recognised variant of follicular lymphoma (FL), although little is known about its biology and clinical evolution. In general, patients tend to have mild symptoms and do not require therapy, comparable with other forms of low‐tumour burden asymptomatic FL. Specific pathological features, such as a dendritic cell meshwork, low expression of CD10 and upregulation of activation‐induced cytidine deaminase can help the diagnosis. The molecular landscape of DFL is similar to the classical nodal presentation of FL, although studies using gene expression profiling demonstrate a close relation with MALT lymphomas. Markers associated with inflammation have suggested that the microenvironment plays a likely role in the pathogenesis of DFL and its low progression rate. Clinical series published vary between 20–63 patients with an estimated overall survival between 92–100% and a median follow‐up ranging between 20 and 107 months. Treatment options include a watch and wait strategy, rituximab monotherapy and radiotherapy. In this review, we summarise current pathological data and treatment studies in DFL.

    更新日期:2019-12-27
  • The role of anti‐complement factor H antibodies in the development of atypical haemolytic uremic syndrome: a possible contribution to abnormality of platelet function
    Br. J. Haematol. (IF 5.206) Pub Date : 2019-12-26
    Madoka Fujisawa; Atsushi Yasumoto; Hideki Kato; Yuka Sugawara; Yoko Yoshida; Yutaka Yatomi; Masaomi Nangaku

    Atypical haemolytic uremic syndrome (aHUS) is associated with complement system abnormality, such as production of complement factor H (CFH) autoantibodies. The growing evidence indicates complement overactivation on platelets is intimately involved in aHUS pathogenesis, besides endothelial injury. We here showed plasma from patients with anti‐CFH antibodies induced aggregation of washed platelets, while purified anti‐CFH antibodies suppressed aggregation. This suggested anti‐CFH antibody itself suppressed thrombosis, while other plasma factor including complement factors could overactivate the platelets, leading to aggregation, which augmented the notion the state of complement activation influenced by anti‐CFH antibodies is important in the aggregation of platelets in aHUS.

    更新日期:2019-12-27
  • Smoking, blood cells and myeloproliferative neoplasms: meta‐analysis and Mendelian randomization of 2·3 million people
    Br. J. Haematol. (IF 5.206) Pub Date : 2019-12-25
    Nimesh A. Jayasuriya; Alisa D. Kjaergaard; Kasper M. Pedersen; Anders L. Sørensen; Marie Bak; Morten K. Larsen; Børge G. Nordestgaard; Stig E. Bojesen; Yunus Çolak; Vibe Skov; Lasse Kjær; Janne S. Tolstrup; Hans C. Hasselbalch; Christina Ellervik

    Meta‐analyses and Mendelian randomization (MR) may clarify the associations of smoking, blood cells and myeloproliferative neoplasms (MPN). We investigated the association of smoking with blood cells in the Danish General Suburban Population Study (GESUS, n = 11 083), by meta‐analyses (including GESUS) of 92 studies (n = 531 741) and MR of smoking variant CHRNA3 (rs1051730[A]) in UK Biobank, and with MPN in a meta‐analysis of six studies (n (total/cases):1 425 529/2187), totalling 2 307 745 participants. In the meta‐analysis the random‐effects standardized mean difference (SMD) in current smokers versus non‐smokers was 0·82 (0·75–0·89, P = 2·0 * 10−108) for leukocytes, 0·09 (−0·02 to 0·21, P = 0·12) for erythrocytes, 0·53 (0·42–0·64, P = 8·0 * 10−22) for haematocrit, 0·42 (0·34–0·51, P = 7·1 * 10−21) for haemoglobin, 0·19 (0·08–0·31, P = 1·2 * 10−3) for mean corpuscular haemoglobin (MCH), 0·29 (0·19–0·39, P = 1·6 * 10−8) for mean corpuscular volume (MCV), and 0·04 (−0·04 to 0·13, P = 0·34) for platelets with trends for ever/ex‐/current smokers, light/heavy smokers and female/male smokers. Analyses presented high heterogeneity but low publication bias. Per allele in CHRNA3, cigarettes per day in current smokers was associated with increased blood cell counts (leukocytes, neutrophils), MCH, red cell distribution width (RDW) and MCV. The pooled fixed‐effects odds ratio for MPN was 1·44 [95% confidence interval (CI): 1·33–1·56; P = 1·8 * 10−19; I2 = 0%] in current smokers, 1·29 (1·15–1·44; P = 8·0 * 10−6; I2 = 0%) in ex‐smokers, 1·49 (1·26–1·77; P = 4·4 * 10−6; I2 = 0%) in light smokers and 2·04 (1·74–2·39, P = 2·3 * 10−18; I2 = 51%) in heavy smokers compared with non‐smokers. Smoking is observationally and genetically associated with increased leukocyte counts and red blood cell indices (MCH, MCV, RDW) and observationally with risk of MPN in current and ex‐smokers versus non/never‐smokers.

    更新日期:2019-12-27
  • Post‐chimeric antigen receptor T‐cell therapy haematopoietic stem cell transplantation for 52 cases with refractory/relapsed B‐cell acute lymphoblastic leukaemia
    Br. J. Haematol. (IF 5.206) Pub Date : 2019-12-23
    Yan Zhang; Huiren Chen; Yanzhi Song; Xiyou Tan; Yongqiang Zhao; Xiaodong Liu; Zhihui Li; Fan Yang; Min Jiang; Zhiyong Gao; Tong Wu

    Although chimeric antigen receptor T cells (CAR‐T) targeted at CD19 or CD22 have achieved high complete remission (CR) in refractory/relapsed B‐cell acute lymphoblastic leukaemia (B‐ALL), it is uncertain if allogeneic haematopoietic stem cell transplantation (allo‐HSCT) should be performed after CAR‐T therapy to accomplish a sustainable remission. Fifty‐two cases with relapsed/refractory B‐ALL who underwent allo‐HSCT after CR by CD19 or CD22 CAR‐T were enrolled. The median time from CAR‐T infusion to allo‐HSCT was 50 (34–98) days. Myeloablative reduced‐intensity conditioning (RIC) with total body irradiation/fludarabine‐based or busulfan/fludarabine‐based regimens was used. Incidences of grade II–IV acute graft‐versus‐host disease (aGVHD) and severe aGVHD were 23·1% and 5·8% respectively. Of 48 evaluable cases, 16 developed chronic GVHD (cGVHD) and in three of them the pattern was extensive. With a median follow‐up of 334 (41–479) days, one‐year overall survival and event‐free survival (EFS) were 87·7% and 73·0%. One‐year relapse rate and transplant‐related mortality (TRM) were 24·7% and 2·2% respectively. With quick bridge to allo‐HSCT after CAR‐T therapy, high EFS for refractory/relapsed B‐ALL has been achieved in this relatively large cohort. Our myeloablative RIC regimens have resulted in low incidences of aGVHD, cGVHD, viral reactivation and very low TRM even majority of transplants from haploidentical donors. Long‐term follow‐up is warranted.

    更新日期:2019-12-25
  • Resource utilization and cost effectiveness of treating acute promyelocytic leukaemia using generic arsenic trioxide
    Br. J. Haematol. (IF 5.206) Pub Date : 2019-12-21
    Aniket Bankar; Anu Korula; Uday P. Kulkarni; Anup J. Devasia; Fouzia NA; Sharon Lionel; Aby Abraham; Poonkuzhali Balasubramanian; Nancy Beryl Janet; Sukesh C. Nair; Sezlian S; Visali Jeyaseelan; Jeyaseelan N; Jasmine Prasad; Biju George; Vikram Mathews

    Arsenic trioxide (ATO)‐based regimens are the standard of care for treating acute promyelocytic leukaemia (APL) and have replaced chemotherapy‐based approaches. However, the cost of “patented” ATO is prohibitive because of patent rights. “Generic” ATO has been used in a few countries, but its implications for health resource utilization (HRU) and cost of treatment are unknown. We hypothesized that treating APL patients using generic ATO (APL‐ATO) will be cost effective compared to the chemotherapy‐based regimen (APL‐CT). In a single‐centre retrospective study, we used a bottom‐up costing method to compare the direct medical cost of treatment and HRU between APL‐ATO and APL‐CT. These costs and the survival and relapse probabilities were imputed in a three‐state Markov decision model to estimate the cost effectiveness of APL‐ATO compared to APL‐CT. The mean cost of treatment for APL‐ATO (n = 30, $8500 ± 2078) was significantly less than for APL‐CT (n = 30, $22 600 ± 5528) (P < 0·001). APL‐ATO reduced hospitalization, antibiotic and antifungal usage (P < 0·001). In the Markov model, five‐year treatment costs were significantly lower for APL‐ATO ($11 131) than for APL‐CT ($17 926) (P < 0·001). Treatment cost and health resource utilization were significantly lower for generic ATO‐treated APL patients compared to the chemotherapy‐based regimen.

    更新日期:2019-12-21
  • Practical management of tumour lysis syndrome in venetoclax‐treated patients with chronic lymphocytic leukaemia
    Br. J. Haematol. (IF 5.206) Pub Date : 2019-12-19
    John G. Gribben

    The treatment landscape in relapsed/refractory chronic lymphocytic leukaemia (CLL) has rapidly evolved over the past five years, with one such emergent treatment being the BCL2 inhibitor, venetoclax. This oral treatment has demonstrated significant clinical advantages in indicated patients, but rapid tumour debulking can lead to a treatment‐related risk of the acute condition known as tumour lysis syndrome (TLS). Here, I present real patient cases to show how I have used the recommended predose monitoring and prophylactic procedures to mitigate the risk of TLS. I also used the ramp‐up dose escalation schedule of venetoclax therapy initiation to safely take patients through the treatment, successfully providing them with sustained clinical benefits.

    更新日期:2019-12-20
  • Long‐term outcome evaluation of medium/high risk acute lymphoblastic leukaemia children treated with or without cranial radiotherapy in the EORTC 58832 randomized study
    Br. J. Haematol. (IF 5.206) Pub Date : 2019-12-13
    Caroline Piette; Stefan Suciu; Yves Bertrand; Anne Uyttebroeck; Els Vandecruys; Geneviève Plat; Catherine Paillard; Claire Pluchart; Nicolas Sirvent; Renée Maurus; Maryline Poirée; Pauline Simon; Alina Ferster; Claire Hoyoux; Françoise Mazingue; Robert Paulus; Claire Freycon; Caroline Thomas; Pierre Philippet; Caroline Gilotay; Jutte van der Werff Ten Bosch; Pierre S. Rohrlich; Yves Benoit

    We investigated the long‐term outcome, the incidence of second neoplasms (SN) and the rate of late adverse effects (LAE) in children with central nervous system (CNS) negative medium/high‐risk de novo acute lymphoblastic leukaemia (ALL), in first complete remission (CR1) at end of late intensification, randomized to receive no cranial radiotherapy (No CRT, n = 92) versus CRT (standard arm, n = 84) in the non‐inferiority EORTC 58832 study (1983–1989). Median follow‐up was 20 years (range 4–32 years). The 25‐year disease‐free survival rate (±SE) was 67·4 ± 4·9% without CRT and 70·2 ± 5·0% with CRT. The 25‐year incidence of isolated (6·5 ± 2·6% vs. 4·8 ± 2·3%) and any CNS relapse {8·7 ± 2·9% vs. 11·9 ± 3·5%; hazard ratio (HR) 0·71 [95% confidence interval (CI) 0·28–1·79]; test of non‐inferiority: P = 0·01} was not increased without CRT. The 25‐year SN incidence in CR1 was 7·9 ± 4·6% vs. 11·0 ± 4·2%. The 25‐year event‐free and overall survival rates were quite similar in both arms [59·5 ± 6·3% vs. 60·5 ± 5·9%, HR 0·94 (95% CI 0·57–1·52), and 78·1 ± 4·3% vs. 78·5 ± 4·5%, HR 1·00 (95% CI 0·53–1·88)]. Omission of CRT was associated with dramatic decrease in CNS and endocrine LAE rates. In conclusion, our data suggest that, with proper systemic and intrathecal CNS prophylaxis, CRT could totally be omitted in CR1 without jeopardizing survival, while decreasing LAE in childhood ALL.

    更新日期:2019-12-17
  • Evaluating sixty years of UK trials research in acute myeloid leukaemia: lessons for trial design, past, present and future
    Br. J. Haematol. (IF 5.206) Pub Date : 2019-12-12
    Robert K. Hills

    Since the launch of their first trial in Acute myeloid leukaemia (AML) in 1959, the Medical Research Council (and latterly National Cancer Research Institute) has conducted randomised trials in AML uninterrupted for six decades. These sixty years have seen a transformation in the way we diagnose, characterise and treat the disease, (and indeed a sea change in clinical trial regulations) and a continuing improvement in outcomes. The increasing refinement of diagnosis, leading to the advent of tailored therapies, and the use of disease monitoring both have the potential to improve outcomes further, but the associated complexities will require an evolution in our approach to trial design. This article looks at the extent to which the guiding principles of the first AML trials remain relevant today, and the challenges facing the next generation of trials methodologists.

    更新日期:2019-12-13
  • The face of remission induction
    Br. J. Haematol. (IF 5.206) Pub Date : 2019-12-12
    Shilpa Paul; Caitlin R. Rausch; Elias J. Jabbour

    Acute myeloid leukaemia (AML) is a heterogeneous disease in which prognosis is determined by cytogenetic and molecular aberrations as well as patient‐related factors, including age, prior haematologic disorders, and comorbidities. Despite the diverse disease biology, the standard of care for remission induction therapy has changed very little since its inception in 1973. Next generation sequencing has helped to increase our knowledge of the disease pathogenesis, allowing us to develop targeted and possibly more effective treatment options. Seven new agents have been approved for the treatment of AML since 2017, all of which are directed toward a specific molecular subtype or patient population. With the advent of these therapies, a more optimal, patient‐specific approach rather than the historical ‘one‐size fits all’ model can be utilised. This review will discuss the role of these novel therapies in the remission induction setting.

    更新日期:2019-12-13
  • The role of allogeneic stem cell transplantation in the management of acute myeloid leukaemia: a triumph of hope and experience
    Br. J. Haematol. (IF 5.206) Pub Date : 2019-12-10
    Justin Loke, Ram Malladi, Paul Moss, Charles Craddock

    Acute myeloid leukaemia (AML) is the commonest indication for allogeneic stem cell transplantation (allo‐SCT) worldwide. The accumulated experience of allografting in AML over the last four decades has provided critical insights into both the contribution of the conditioning regimen and the graft‐versus‐leukaemia effect to the curative potential of the most common form of immunotherapy utilised in standard clinical practice. Coupled with advances in donor availability and transplant technologies, this has resulted in allo‐SCT becoming an important treatment modality for the majority of adults with high‐risk AML. At the same time, advances in genomic classification, coupled with progress in the accurate quantification of measurable residual disease, have increased the precision with which allo‐mandatory patients can be identified, whilst simultaneously permitting accurate identification of those patients who can be spared the toxicity of an allograft. Despite this progress, disease recurrence still remains a major cause of transplant failure and AML has served as a paradigm for the development of strategies to reduce the risk of relapse ‒ notably the novel concept of post‐transplant maintenance, utilising pharmacological or cellular therapies.

    更新日期:2019-12-11
  • Changes in neurocognitive function and central nervous system structure in childhood acute lymphoblastic leukaemia survivors after treatment: a meta‐analysis
    Br. J. Haematol. (IF 5.206) Pub Date : 2019-12-10
    Chendan Zhou, Yong Zhuang, Xingjie Lin, Alan D. Michelson, Aijun Zhang

    Acute lymphoblastic leukaemia (ALL) is the most common malignancy in children. Although the survival rate has increased dramatically over the last decades, patients struggle with the adverse side effects of treatment. Treatment for ALL includes chemotherapy and irradiation ‐ both of which are linked to cognitive impairments and alterations in central nervous system (CNS) structure and function detected by neuroimaging and in neurocognitive studies. The present article is a meta‐analysis of the existing evidence for the mechanisms underlying changes in the CNS and neurocognitive function in ALL survivors after treatment. We found that compared with controls, ALL survivors develop: (i) cognitive sequelae in intelligence, academics, attention, memory, processing speed and executive function domains; (ii) decreased grey and white matter volume in cortical and several subcortical brain regions, with functional changes particularly in frontal regions and the hippocampus; (iii) neurocognitive impairments related to CNS changes; and (iv) reduction, but not resolution, of late neurocognitive sequelae in patients in whom prophylactic irradiation was replaced by systemic/intrathecal chemotherapy. Continued work with advanced functional magnetic resonance imaging techniques will hopefully allow the detection of early CNS changes as biomarkers to help guide early diagnosis and intervention for neurocognitive defects in patients with childhood ALL.

    更新日期:2019-12-11
  • Validation of a simplified international prognostic score (IPS‐3) in patients with advanced‐stage classic Hodgkin lymphoma
    Br. J. Haematol. (IF 5.206) Pub Date : 2019-12-10
    Anna R. Hayden, Derrick G. Lee, Diego Villa, Alina S. Gerrie, David W. Scott, Graham W. Slack, Laurie H. Sehn, Joseph M. Connors, Kerry J. Savage

    A novel prognostic score (IPS‐3), comprised of only three of the seven IPS‐7 indicators (age ≥45, stage IV, haemoglobin <105 g/l), was recently proposed as a simplified model for advanced‐stage classic Hodgkin lymphoma (cHL). We aimed to validate this model in advanced‐stage cHL patients treated with doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) in British Columbia. The estimated five‐year freedom from progression (FFP) for scores of 0, 1, 2 and 3 were very similar to the original report at 84%, 76%, 72% and 68% respectively. The IPS‐3 score is highly reproducible in this independent dataset and its simplicity makes it appealing for everyday clinical practice.

    更新日期:2019-12-11
  • Clonal hierarchy of main molecular lesions in acute myeloid leukaemia
    Br. J. Haematol. (IF 5.206) Pub Date : 2019-12-10
    Zdenka Herudkova, Martin Culen, Adam Folta, Ivana Jeziskova, Jana Cerna, Tomas Loja, Nikola Tom, Jiri Smejkal, Lukas Semerad, Dana Dvorakova, Jiri Mayer, Zdenek Racil

    Genetic mutations in acute myeloid leukaemia (AML) are assumed to occur in a sequential order; however, the predominant hierarchical roles of specific mutated genes have not been fully described. In this study, we aimed to determine the clonal involvement of the most frequent AML‐associated mutations. Using a targeted sequencing panel for 18 genes, we traced changes and relative clonal contribution of mutations in 52 patients. We analysed 35 pairs of diagnosis and relapse samples, 27 pairs of primary samples and corresponding patient‐derived xenografts, and 34 pairs of total leukocytes and corresponding isolated primitive cells or blast populations. In both relapse and xenografts, we observed conservation of main leukaemic clones and variability was limited to subclones with late‐acquired mutations. AML evolution thus mainly involved modification of subclones while the clonal background remained unchanged. NPM1 mutations were identified as the most probable leukaemia‐transformation lesion, remaining conserved in contrast to high variation of accompanying subclonal FLT3 and NRAS mutations. DNMT3A mutations represented the most stable mutations forming a preleukaemic background in most samples. Mutations in genes IDH1/2, TET2, RUNX1, ASXL1 and U2AF1 were detected both as preleukaemic and as subclonal lesions, suggesting a non‐specific order of acquisition.

    更新日期:2019-12-11
  • Daratumumab in high‐risk relapsed/refractory multiple myeloma patients: adverse effect of chromosome 1q21 gain/amplification and GEP70 status on outcome
    Br. J. Haematol. (IF 5.206) Pub Date : 2019-12-09
    Meera Mohan, Niels Weinhold, Carolina Schinke, Sharmilan Thanedrarajan, Leo Rasche, Jeffrey R. Sawyer, Erming Tian, Frits van Rhee, Maurizio Zangari

    Gain of chromosome 1q21 and the gene expression‐based GEP70 risk score are established prognostic markers for newly diagnosed Multiple Myeloma (MM) patients. Here we addressed the prognostic impact of these two markers in 81 relapsed/refractory (RR) MM patients treated with the CD38‐antibody daratumumab. Fluorescence in situ hybridization for 1q21 was performed at initial presentation, while the GEP70 score was determined at initial presentation and prior to daratumumab treatment. While the GEP70 at initial presentation showed a trend for inferior survival, the GEP70 collected prior to daratumumab treatment was significantly associated with poor outcome (P < 0·05). The worst outcome was seen for patients who were positive for gain(1q) and classified as GEP70 high risk prior to daratumumab [progression‐free (PFS) and overall survival (OS) of 0·3 years (95% CI: 0·15–1·4 years) and 0·8 years (95% CI: 0·5–1·9 years) respectively], while the median PFS and OS were not reached by patients without gain(1q) and GEP70 low‐risk status. In conclusion, gain(1q) and the GEP70 are powerful prognostic markers for RR MM patients treated with daratumumab, and patients classified as high risk according to these markers experience shorter treatment response.

    更新日期:2019-12-11
  • Impact of imaging modality on clinical outcome in Hodgkin lymphoma in a resource constraint setting
    Br. J. Haematol. (IF 5.206) Pub Date : 2019-12-07
    Anu Korula, Anup Joseph Devasia, Uday Kulkarni, Fouzia N. Abubacker, Kavitha M. Lakshmi, Aby Abraham, Alok Srivastava, Biju George, Vikram Mathews

    Treatment of Hodgkin lymphoma (HL) has evolved with risk‐stratified therapy based on PET‐CT scan at multiple timepoints. In a resource constraint setting even a single PET‐CT scan ($400) is inaccessible to many patients, who are re‐assessed with only clinical examination, abdominal ultrasonogram and/or x‐ray (C/U/X) ($10). To compare clinical outcomes in patients with HL who have had suboptimal imaging after completion of chemotherapy for HL, with those who had a CT or PET‐CT, 283 patients were treated for HL from 2011 to 2015, and 268 patients completed six cycles of ABVD therapy with response assessment modality by CT/PET in 185 patients and by C/U/X in 83. There was no difference in the number of patients with advanced (64·1% vs. 61·1%; P = 0·650) or bulk disease (8·1% vs. 7·2%). A significantly higher number of patients in the CT/PET group received IFRT (25·4% vs. 7·7%; P = 0·0005). The three‐year overall survival and progression‐free survival of all treated patients (n = 283) was 83·5 ± 2·3% and 76·7 ± 2·6% respectively [median follow‐up 36 months (range 2–93)]. At three years, the overall relapse‐free survival (RFS) was 80·1 ± 2·5%, with RFS of 77 ± 3·2% vs. 85 ± 4·0% in the CT/PET group and C/U/X groups respectively (P = 0·349). There was no difference in RFS between the two groups either in early‐stage disease (88·1 ± 4·6% vs. 91·8 ± 5·6%; P = 0·671) or late‐stage disease (73·9 ± 4·8% vs. 81·3 ± 6·0%; P = 0·747). The only significant factor adversely affecting RFS was advanced disease (P = 0·004). Factors not affecting RFS were age (P = 0·763), sex (P = 0·925), bulk disease (P = 0·889) and imaging modality (P = 0·352). There was no difference in relapse rates between patients who had suboptimal imaging compared to those who had a PET/CT. It is possible to use these basic imaging modalities when resources are a constraint, with acceptable outcomes.

    更新日期:2019-12-07
  • The power and potential of integrated diagnostics in acute myeloid leukaemia
    Br. J. Haematol. (IF 5.206) Pub Date : 2019-12-06
    Torsten Haferlach, Ines Schmidts

    The field of acute myeloid leukaemia (AML) diagnostics, initially based solely on morphological assessment, has integrated more and more disciplines. Today, state‐of‐the‐art AML diagnostics relies on cytomorphology, cytochemistry, immunophenotyping, cytogenetics and molecular genetics. Only the integration of all of these methods allows for a comprehensive and complementary characterisation of each case, which is prerequisite for optimal AML diagnosis and management. Here, we will review why multidisciplinary diagnostics is mandatory today and will gain even more importance in the future, especially in the context of precision medicine. We will discuss ideas and strategies that are likely to shape and improve multidisciplinary diagnostics in AML and may even overcome some of today's gold standards. This includes recent technical advances that provide genome‐wide molecular insights. The enormous amount of data obtained by these latter techniques represents a great challenge, but also a unique chance. We will reflect on how this increase in knowledge can be incorporated into the routine to pave the way for personalised medicine in AML.

    更新日期:2019-12-07
  • Checkpoint inhibitors in AML: are we there yet?
    Br. J. Haematol. (IF 5.206) Pub Date : 2019-12-06
    Arnab Ghosh, Pere Barba, Miguel‐Angel Perales

    Immunotherapy is distinct from traditional chemotherapy in that it acts on immune cells rather than cancer cells themselves. Monoclonal antibodies targeting immune checkpoints on T cells – CTLA‐4 and PD‐1 – and PD‐L1 on the cells of immune microenvironment are now approved for clinical use in several solid tumors and hematological malignancies. This article provides a general overview of the use of checkpoint inhibitors in hematologic malignancies with a special focus in acute myeloid leukemia.

    更新日期:2019-12-07
  • Poor outcomes for double‐hit lymphoma patients treated with curative‐intent second‐line immunochemotherapy following failure of intensive front‐line immunochemotherapy
    Br. J. Haematol. (IF 5.206) Pub Date : 2019-12-05
    Daniel J. Landsburg, Emily C. Ayers, David A. Bond, Kami J. Maddocks, Reem Karmali, Amir Behdad, Madeira Curry, Nina D. Wagner‐Johnston, Dipenkumar Modi, Radhakrishnan Ramchandren, Sarit E. Assouline, Rawan Faramand, Julio C. Chavez, Pallawi Torka, Angel Mier Hicks, L. Jeffrey Medeiros, Shaoying Li

    While patients with double‐hit lymphoma (DHL) are now frequently treated with intensive front‐line immunochemotherapy, outcomes for those who fail these regimens and subsequently receive curative‐intent second‐line immunochemotherapy are unknown. We identified 55 such patients who achieved an overall/complete response rate of 29%/11%, median progression‐free/overall survival (PFS/OS) of 2/5·1 months and one‐year PFS/OS of 10/19% following the start of second‐line therapy. These outcomes may serve as a standard against which future second‐line treatment strategies for relapsed/refractory DHL can be measured and justify investigation of non‐cytotoxic therapies in the second‐line setting for these patients.

    更新日期:2019-12-05
  • Next‐generation sequencing for measurable residual disease detection in acute myeloid leukaemia
    Br. J. Haematol. (IF 5.206) Pub Date : 2019-12-05
    Jack Ghannam, Laura W. Dillon, Christopher S. Hourigan

    Acute myeloid leukaemia (AML) is a blood cancer characterized by acquired genetic mutations. There is great interest in accurately establishing measurable residual disease (MRD) burden in AML patients in remission after treatment but at risk of relapse. However, inter‐ and intrapatient genetic diversity means that, unlike in the chronic myeloid and acute promyelocytic leukaemias, no single genetic abnormality is pathognomonic for all cases of AML MRD. Next‐generation sequencing offers the opportunity to test broadly and deeply for potential genetic evidence of residual AML, and while not currently accepted for such use clinically, is likely to be increasingly used for AML MRD testing in the future.

    更新日期:2019-12-05
  • Epigenetics of paediatric acute myeloid leukaemia
    Br. J. Haematol. (IF 5.206) Pub Date : 2019-12-05
    Luke Jones, Peter McCarthy, Jonathan Bond

    Comprehensive cataloguing of the acute myeloid leukaemia (AML) genome has revealed a high frequency of mutations and deletions in epigenetic factors that are frequently linked to treatment resistance and poor patient outcome. In this review, we discuss how the epigenetic mechanisms that underpin normal haematopoiesis are subverted in AML, and in particular how these processes are altered in childhood and adolescent leukaemias. We also provide a brief summary of the burgeoning field of epigenetic‐based therapies, and how AML treatment might be improved through provision of better conceptual frameworks for understanding the pleiotropic molecular effects of epigenetic disruption.

    更新日期:2019-12-05
  • Peripheral blood blast rate of clearance is an independent predictor of clinical response and outcomes in acute myeloid leukaemia
    Br. J. Haematol. (IF 5.206) Pub Date : 2019-12-05
    Noa G. Holtzman, Firas El Chaer, Maria R. Baer, Omer Ali, Ameet Patel, Vu H. Duong, Edward A. Sausville, Zeba N. Singh, Rima Koka, Ying S. Zou, Arash Etemadi, Ashkan Emadi

    The day 14 bone marrow aspirate and biopsy (D14BM) is regularly used to predict achievement of complete remission (CR) with induction chemotherapy in acute myeloid leukemia (AML), however its utility has been questioned. Clearance of peripheral blood blasts (PBB) may serve as an early measure of chemosensitivity. PBB rate of clearance (PBB‐RC) was calculated for treatment‐naive AML patients (n = 164) undergoing induction with an anthracycline and cytarabine (7+3) and with detectable PBB at diagnosis. PBB‐RC was defined as the percentage of the absolute PBB count on the day of diagnosis that was cleared with each day of therapy, on average, until D14 or day of PBB clearance. Each 5% increase in PBB‐RC approximately doubled the likelihood of D14BM clearance (OR = 1·81; 95% CI: 1·24–2·64, P < 0·005). PBB‐RC was also associated with improved CR rates (OR per 5% = 1·97; 95% CI: 1·27–3·01, P < 0·005) and overall survival (OS) [hazard ratio (HR) per 5% = 0·67; 95% CI: 0·52–0·87]. African American patients had poorer OS adjusted for PBB‐RC (HR = 2·18; 95% CI: 1·13–4·23), while race was not associated with D14BM or CR rate. PBB‐RC during induction chemotherapy is predictive of D14BM clearance, CR, and OS, and can therefore serve as a prognostic marker for clinical outcomes in AML.

    更新日期:2019-12-05
  • Transfusion errors — can they be eliminated?
    Br. J. Haematol. (IF 5.206) Pub Date : 2019-12-02
    Paula H. B. Bolton‐Maggs, Alison Watt

    The Serious Hazards of Transfusion haemovigilance scheme has documented adverse transfusion incidents for 22 years. Transmission of infection (three in 2018), transfusion‐related lung injury (one in 2018) and transfusion‐associated graft‐versus‐host disease (none since 2012) are rare. Despite national recommendations, guidelines and protocols, most incidents more than 85% of incidents are still due to errors in the transfusion process. European regulation and mandatory competency assessments have been associated with a reduction in ABO‐incompatible transfusion, but errors continue to put patients at risk. What can be done? Errors are reduced by the use of electronic identification systems. Exploration of human factors and ergonomics (HFE) results in amended approaches away from blaming individuals to a full review of the systems and environment. Research examining how transfusion is performed (work‐as‐done) compared to work‐as‐imagined (set out in protocols and guidelines) discovers where variability results in either resilience or error. All staff require HFE training, but this should be alongside employment of suitably qualified and experienced HFE professionals. Good teamwork is key and is undermined by insufficient staffing and poor morale. The five choosing wisely recommendations for transfusion (to ensure appropriate use) need to be widely disseminated to medical staff in all specialties to ensure patients participate in the decision‐making.

    更新日期:2019-12-03
  • First‐line R‐CVP versus R‐CHOP induction immunochemotherapy for indolent lymphoma with rituximab maintenance. A multicentre, phase III randomized study by the Polish Lymphoma Research Group PLRG4
    Br. J. Haematol. (IF 5.206) Pub Date : 2019-12-02
    Jan Walewski, Ewa Paszkiewicz‐Kozik, Wojciech Michalski, Grzegorz Rymkiewicz, Tomasz Szpila, Aleksandra Butrym, Agnieszka Giza, Jan M. Zaucha, Ewa Kalinka‐Warzocha, Agata Wieczorkiewicz, Dagmara Zimowska‐Curyło, Wanda Knopińska‐Posłuszny, Agata Tyczyńska, Joanna Romejko‐Jarosińska, Anna Dąbrowska‐Iwanicka, Beata Gruszecka, Maria Jamrozek‐Jedlińska, Anna Borawska, Waldemar Hołda, Agnieszka Porowska, Agnieszka Romanowicz, Andrzej Hellmann, Beata Stella‐Hołowiecka, Andrzej Deptała, Wojciech Jurczak

    R‐CVP (cyclophosphamide, vincristine, prednisone) and R‐CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone + rituximab) are immunochemotherapy regimens frequently used for remission induction of indolent non‐Hodgkin lymphomas (iNHLs). Rituximab maintenance (RM) significantly improves progression‐free survival (PFS) in patients with complete/partial remission (CR/PR). Here we report the final results of a randomized study comparing R‐CVP to R‐CHOP both followed by RM. Untreated patients in need of systemic therapy with symptomatic and progressive iNHLs including follicular (FL) and marginal zone lymphoma (MZL), mucosa‐associated lymphoid tissue (MALT), small lymphocytic (SLL), and lymphoplasmacytic (LPL) lymphoma were eligible. Patients were randomized to receive R‐CVP or R‐CHOP for eight cycles or until complete response (CR). All patients with CR/PR (partial response) received RM 375 mg/m2 q 2 months for 12 cycles. Primary endpoint was event‐free survival (EFS). Two‐hundred and fifty patients [FL 42%, MZL/MALT 38%, LPL/ Waldenström Macroglobulinaemia (WM) 11%, SLL 9%] were enrolled and randomized (R‐CHOP: 127, R‐CVP: 123). Median age was 56 years (21–85), 44% were male, 90% were in stage III–IV, 43% of FL patients had a Follicular Lymphoma International Prognostic Index (FLIPI) score ≥3, and 33·4% of all patients had an IPI score ≥3. At the end of induction treatment, the CR/PR rate was 43·6/50·9% and 36·3/60·8% in the R‐CHOP and R‐CVP groups (P = 0·218) respectively. After a median follow‐up of 67, 66, and 70 months, five‐year EFS was 61% vs. 56% (not significant), progression‐free survival (PFS) was 71% vs. 69% (not significant) and overall survival (OS) was 84% vs. 89% in the R‐CHOP vs. the R‐CVP arm respectively. Grade III/IV adverse events (65 vs. 22) occurred in 40 (33·1%) and 18 (15·3%) patients, P = 0·001; neutropenia in 16 (11·6%) and 4 (3·4%) patients, P = 0·017; infection in 14 (10·7%) and 3 (2·5%) patients,; P = 0·011; and a second neoplasm in three versus seven patients., in the R‐CHOP and the R‐CVP groups respectively. This multicentre randomized study with >five‐year follow‐up shows similar outcome in patients with indolent lymphoma in need of systemic therapy treated with R‐CVP or R‐CHOP immunochemotherapy and rituximab maintenance in both arms. The minor toxicity of the R‐CVP regimen makes it a reasonable choice for induction treatment, leaving other active agents like doxorubicin or bendamustin for second‐line therapy.

    更新日期:2019-12-03
  • Unexpected low expression of platelet fibrinogen receptor in patients with chronic myeloproliferative neoplasms: how does it change with aspirin?
    Br. J. Haematol. (IF 5.206) Pub Date : 2019-12-02
    Alessandro Lucchesi, Silvia Carloni, Serena De Matteis, Martina Ghetti, Gerardo Musuraca, Monica Poggiaspalla, Accursio F. Augello, Giulio Giordano, Pier P. Fattori, Giovanni Martinelli, Roberta Napolitano

    This study was conducted to evaluate the expression of fibrinogen receptors on platelets of Philadelphia‐negative chronic myeloproliferative neoplasm (MPN) patients. We collected blood samples from 40 consecutive MPN patients and healthy volunteers. We performed flow cytometry analysis of P‐selectin expression and integrin beta‐3, activation of glycoprotein (GP) IIb/IIIa and fibrinogen receptor exposure (PAC‐1 binding). Surprisingly, we found a very low PAC‐1 binding capacity in MPN patients; however, the expression of PAC‐1 was almost completely recovered with aspirin intake. We hypothesize that the hypercoagulable states observed in MPN patients could depend on a primarily plasma‐driven impairment of fibrin turnover and thrombin generation.

    更新日期:2019-12-03
  • Acute myeloid leukaemia and the immune system: implications for immunotherapy
    Br. J. Haematol. (IF 5.206) Pub Date : 2019-11-29
    A. John Barrett

    The recognition of the curative potential of the graft‐versus‐leukaemia effect for patients with acute myeloid leukaemia (AML) undergoing stem cell transplantation, and the emergence of immunotherapy as a powerful weapon to treat cancer, has spurred the exploration of the immune landscape of AML to apply immunotherapeutic approaches to curing the disease. While current concepts of cancer immunology and immunotherapy have relevance, there are also unique aspects of immune dysregulation in AML to be considered when designing rational immunotherapy for this leukaemia. This is timely because rapid advances in cancer immunobiology, together with technological developments have opened up the field of immunotherapy for malignant disease. Here the current knowledge of AML immunobiology is summarized together with a description of new immunotherapies to counter immunosuppression and immune evasion by AML. Recent advances in treatment with recombinant antibodies, adoptive cell therapy and vaccines and their future promise in AML treatment are reviewed.

    更新日期:2019-11-30
  • New prognosis score including absolute lymphocyte/monocyte ratio, red blood cell distribution width and beta‐2 microglobulin in patients with diffuse large B‐cell lymphoma treated with R‐CHOP: Spanish Lymphoma Group Experience (GELTAMO)
    Br. J. Haematol. (IF 5.206) Pub Date : 2019-11-28
    Leyre Bento, Antonio Díaz‐López, Gilberto Barranco, Ana M. Martín‐Moreno, Mónica Baile, Alejandro Martín, Juan M. Sancho, Olga García, Mario Rodríguez, Jose M. Sánchez‐Pina, Silvana Novelli, Antonio Salar, Mariana Bastos, M José Rodríguez‐Salazar, Sonia González de Villambrosia, Raul Córdoba, M. García‐Recio, J. Martínez‐Serra, Raquel del Campo, Hugo Luzardo, Daniel García, Azueg Hong, Pau Abrisqueta, Jorge Sastre‐Serra, Pilar Roca, José Rodríguez, Antonio Gutiérrez,

    The International Prognostic Index (IPI) is the most widely used score for non‐Hodgkin lymphoma but lacks the ability to identify a high‐risk population in diffuse large B‐cell lymphoma (DLBCL). Low absolute lymphocyte count and high monocytes have proved to be unfavourable factors. Red‐cell distribution width (RDW) has been associated with inflammation and beta‐2 microglobulin (B2M) with tumour load. The retrospective study included 992 patients with DLBCL treated with R‐CHOP. In the multivariate analysis, age, Eastern Cooperative Oncology Group performance status (ECOG‐PS), stage, bulky mass, B2M, RDW, and lymphocyte/monocyte ratio (LMR) were independently related to progression‐free survival (PFS). A new prognosis score was generated with these variables including age categorized into three groups (0, 1, 2 points); ECOG ≥ 3–4 with two; stage III/IV, bulky mass, high B2M, LMR < 2·25 and RDW > 0·96 with one each; for a maximum of 9. This score could improve the discrimination of a very high‐risk subgroup with five‐year PFS and overall survival (OS) of 19% and 24% versus 45% and 59% of R (revised)‐IPI respectively. This score also showed greater predictive ability than IPI. A new score is presented including complete blood cell count variables and B2M, which are readily available in real‐life practice without additional tests. Compared to R‐IPI, it shows a more precise high‐risk assessment and risk discrimination for both PFS and OS.

    更新日期:2019-11-30
  • Emergencies in haematology: tumour lysis syndrome
    Br. J. Haematol. (IF 5.206) Pub Date : 2019-11-27
    Urshila Durani, William J. Hogan

    Tumour lysis syndrome (TLS) is a significant complication of haematologic malignancies and their management. The syndrome consists of laboratory abnormalities either alone (laboratory TLS) or with clinical sequelae including renal failure, seizures, and arrhythmias (clinical TLS). Clinical TLS is a predictor for worse overall morbidity and mortality in cancer patients, but can be prevented. Thus, accurate prognostication is critical to appropriate management of patients at risk for TLS, and incorporates both disease factors (tumour type and burden) and patient factors (baseline renal insufficiency or hyperuricaemia). Strategies to prevent TLS include hydration and allopurinol in low‐ and intermediate‐risk patients and rasburicase in high‐risk patients.

    更新日期:2019-11-28
  • Extended experience with a non‐cytotoxic DNMT1‐targeting regimen of decitabine to treat myeloid malignancies
    Br. J. Haematol. (IF 5.206) Pub Date : 2019-11-17
    Hassan Awada, Reda Z. Mahfouz, Ashwin Kishtagari, Teodora Kuzmanovic, Jibran Durrani, Cassandra M. Kerr, Bhumika J. Patel, Valeria Visconte, Tomas Radivoyevitch, Alan Lichtin, Hetty E. Carraway, Jaroslaw P. Maciejewski, Yogen Saunthararajah

    The nucleoside analogue decitabine can deplete the epigenetic regulator DNA methyltransferase 1 (DNMT1), an effect that occurs, and is saturated at, low concentrations/doses. A reason to pursue this molecular‐targeted effect instead of the DNA damage/cytotoxicity produced with high concentrations/doses, is that non‐cytotoxic DNMT1‐depletion can cytoreduce even p53‐null myeloid malignancies while sparing normal haematopoiesis. We thus identified minimum doses of decitabine (0·1–0·2 mg/kg) that deplete DNMT1 without off‐target anti‐metabolite effects/cytotoxicity, and then administered these well‐tolerated doses frequently 1–2X/week to increase S‐phase dependent DNMT1‐depletion, and used a Myeloid Malignancy Registry to evaluate long‐term outcomes in 69 patients treated this way. Consistent with the scientific rationale, treatment was well‐tolerated and durable responses were produced (~40%) in genetically heterogeneous disease and the very elderly.

    更新日期:2019-11-18
  • Single and combined BTK and PI3Kδ inhibition with acalabrutinib and ACP‐319 in pre‐clinical models of aggressive lymphomas
    Br. J. Haematol. (IF 5.206) Pub Date : 2019-07-29
    Filippo Spriano, Chiara Tarantelli, Eugenio Gaudio, Magdalena M. Gerlach, Valdemar Priebe, Luciano Cascione, Elena Bernasconi, Altea Targa, Michele Mascia, Stefan Dirnhofer, Anastasios Stathis, Emanuele Zucca, Francesco Bertoni

    The B‐cell receptor and the phosphatidylinositol 3‐kinase (PI3K) signalling pathways, together with their downstream partners, represent important therapeutic targets for B‐cell lymphomas. Here, we evaluated the activity of acalabrutinib (ACP‐196) and ACP‐319 (AMG‐319), second generation inhibitors of Bruton tyrosine kinase (BTK) and PI3Kδ inhibitor, respectively, in lymphoma pre‐clinical models. The two compounds showed activity in activated B‐cell‐like diffuse large B‐cell lymphoma (ABC DLBCL), mantle cell lymphoma and marginal zone lymphoma. Two in vivo experiments with ABC DLBCL and MCL xenografts confirmed the effect of the single agents. Benefit was achieved by exposing the lymphoma cell lines to both acalabrutinib and ACP‐319. Two cell lines presented a discordant response to first and second generation BTK inhibitors, probably due to the inhibition by ibrutinib of kinases other than BTK. In conclusion, our data sustain the on‐going current trials with acalabrutinib and ACP‐319 as single agents and provide the basis for the investigation of their combination as well.

    更新日期:2019-11-18
  • Survival and specific outcome of sickle cell disease patients after renal transplantation
    Br. J. Haematol. (IF 5.206) Pub Date : 2019-07-26
    Christel Gérardin, Anissa Moktefi, Cécile Couchoud, Alyette Duquesne, Nacera Ouali, Philippe Gataut, Alexandre Karras, Dany Anglicheau, Carmen Lefaucheur, Lucile Figueres, Laetitia Albano, Arnaud Lionet, Marine Novion, Marie‐Julia Ziliotis, Magali Louis, Arnaud Del Bello, Marie Matignon, Karine Dahan, Anoosha Habibi, Frederic Galacteros, Pablo Bartolucci, Philippe Grimbert, Vincent Audard

    The prognosis of sickle cell disease (SCD) patients who need dialysis is poor, but experience with kidney transplantation is limited. This study assessed the characteristics of 36 SCD patients undergoing renal transplantation. Immediate post‐surgical complications occurred in 25% of cases. Cytomegalovirus and bacterial infections were frequently observed. Twelve patients died after a median follow‐up period of 17·4 months. Overall patient survival was significantly lower in SCD than in the control group without significant difference for overall death‐censored graft survival. Our data suggest that renal transplantation should be systematically considered in SCD patients with end‐stage renal disease.

    更新日期:2019-11-18
  • Ten‐year survivors in AL amyloidosis: characteristics and treatment pattern
    Br. J. Haematol. (IF 5.206) Pub Date : 2019-07-12
    Eli Muchtar, Morie A. Gertz, Martha Q. Lacy, Ronald S. Go, Francis K. Buadi, David Dingli, Martha Grogan, Omar F. AbouEzzeddine, Suzanne R. Hayman, Prashant Kapoor, Nelson Leung, Amie Fonder, Miriam Hobbs, Yi Lisa Hwa, Wilson Gonsalves, Rahma Warsame, Taxiarchis V. Kourelis, Stephen Russell, John A. Lust, Yi Lin, Steven Zeldenrust, Robert A. Kyle, S. Vincent Rajkumar, Shaji K. Kumar, Angela Dispenzieri

    Improvement in survival in Light chain (AL) amyloidosis has been seen over recent decades, enabling more patients to achieve long‐term survival. Patients with AL amyloidosis who survived ≥10 years from time of diagnosis (n = 186) were the subject of this study. Ten‐year survivors represented 22% of the total population. These patients were characterized by favourable patient, organ and plasma cell features. Of note, trisomies were less common among 10‐year survivors compared to those who did not survive to 10 years. All‐time best haematological response was complete response in 67%, very good partial response in 30%, partial response in 2% and no response in 1%, with 11% having received a consolidative strategy for inadequate response to first line therapy. The overall organ response rate to first‐line therapy was 76%, which increased to 86% when considering subsequent line(s) of therapy. Forty‐seven percent of the 10‐year survivors did not require a second‐line therapy. The median treatment‐free survival (TFS) among the 10‐year survivors was 10·5 years (interquartile range 7·4‐12·2). On multivariate analysis independent predictors for TFS were the achievement of complete haematological response and lack of cardiac involvement. Long‐term survivors are increasingly seen in AL amyloidosis and present distinct patient, organ and clonal disease features.

    更新日期:2019-11-18
  • Genomic data in prognostic models—what is lost in translation? The case of deletion 17p and mutant TP53 in chronic lymphocytic leukaemia
    Br. J. Haematol. (IF 5.206) Pub Date : 2019-03-05
    Benjamin Chin‐Yee, Bekim Sadikovic, Ian H. Chin‐Yee

    Genomic technologies are revolutionizing the practice of haematology‐oncology, leading to improved disease detection, more accurate prognostication and targeted treatment decisions. These advances, however, have also introduced new clinical challenges, which include problems of prognostic underdetermination and its attendant risks of over‐ and undertreatment. Genomic data is generated from different technologies, from cytogenetics to next‐generation sequencing, which are often interpreted interchangeably and in a binary fashion—as the presence or absence of a given chromosomal deletion or mutation—an oversimplification which may lead to mistaken prognosis. We discuss the clinical use of one such prognostic marker, represented by sequence and copy number alterations in TP53, located on chromosome 17p. Mutations in TP53 are strongly linked to poor prognosis in a variety of haematological malignancies, including chronic lymphocytic leukaemia (CLL). We review studies in CLL which utilize the 17p deletion or TP53 mutations for prognostic stratification with specific focus on the technologies used for detection, the thresholds established for clinical significance, and the clinical contexts in which these alterations are identified. The case of CLL illustrates issues arising from simplistic, binary interpretation of genetic testing and highlights the need to apply a critical lens when incorporating genomics into prognostic models.

    更新日期:2019-11-18
  • Prognostic impact of interim positron emission tomography in mantle cell lymphoma patients treated with frontline R‐CHOP
    Br. J. Haematol. (IF 5.206) Pub Date : 2019-11-16
    Young‐Woo Jeon, Joo‐Hyun O, Kyung‐Sin Park, Gi June Min, Sung‐Soo Park, Jae‐Ho Yoon, Ki‐Seong Eom, Chang‐Ki Min, Seok‐Goo Cho

    Although 18F‐fluorodeoxyglucose positron emission tomography (18F‐FDG PET) is commonly used for initial staging and therapeutic response evaluation in aggressive lymphomas, its prognostic utility for mantle cell lymphoma (MCL) is controversial. Therefore, we retrospectively evaluated the correlations of interim PET (iPET) and end‐of‐treatment PET (ePET) response with survival outcomes in 89 consecutive advanced MCL patients treated with frontline R‐CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone). iPET positivity was strongly associated with inferior five‐year overall survival (OS) [hazard ratio (HR) 7·84, P < 0·0001] and poor five‐year progression‐free survival (PFS) (HR 3·34, P < 0·0001). OS and PFS were more favourable in the order early metabolic responder (iPETneg → ePETneg), delayed responder (iPETpos → ePETneg), loss‐metabolic responder (iPETneg → ePETpos), and never‐metabolic responder (iPETpos → ePETpos). In the autologous haematopoietic stem cell transplantation (auto‐HSCT)‐fit subgroup, OS was more favourable in the order early metabolic responders, delayed metabolic responders, and non‐metabolic responders, with a marginal trend toward statistical significance (HR 3·41, P = 0·051), and PFS was significantly superior in early metabolic responders (HR 4·43, P = 0·002). In a group that was ineligible for auto‐HSCT, OS and PFS were significantly superior in early metabolic responders. Our results suggested that iPET is of prognostic value and an independent predictor of survival in MCL patients receiving frontline R‐CHOP. Therefore, prospective clinical trials of iPET‐guided treatment strategies for these patients are warranted.

    更新日期:2019-11-17
  • The association between haemorrhage and markers of endothelial insufficiency and inflammation in patients with hypoproliferative thrombocytopenia: a cohort study
    Br. J. Haematol. (IF 5.206) Pub Date : 2019-11-15
    Paula F. Ypma, Nan van Geloven, Jean Louis H. Kerkhoffs, Peter te Boekhorst, Jaap J. Zwaginga, Erik A. M. Beckers, Anneke Brand, Pieter F. van der Meer, Jeroen C. J. Eikenboom

    In daily haematological practice, predicting bleeding in thrombocytopenic patients is difficult, and clinicians adhere to transfusion triggers to guide patients through the aplastic phase of chemotherapy. Platelet count is not the only determinant of bleeding and additional mechanisms for impending haemostasis are likely. Beside clot formation, platelets are essential for the maintenance of integrity of vascular beds. We therefore prospectively investigated associations between biomarkers for endothelial damage (urine albumin excretion) and inflammation (C‐reactive protein) and bleeding (WHO grading) in 88 patients with 116 on‐protocol episodes. We found an increase in grade 2 bleeding with a higher urine albumin/creatinine ratio one day after the measurement [odds ratio (OR) 1·24 for every doubling of the ratio, 95% CI 1·05–1·46, P‐value 0·01] and a 29% increase in the odds of grade 2 bleeding for every doubling of serum C‐reactive protein (CRP) (95% CI 1·04–1·60, P‐value 0·02) after correction for morning platelet count. The 24 h post‐transfusion corrected count increment (CCI24) showed a significant association with these biomarkers: increasing urine albumin/creatinine ratio and CRP were associated with lower CCI24. We report two inexpensive and easy‐to‐apply biomarkers that could be useful in designing a prediction model for bleeding risk in thrombocytopenic patients.

    更新日期:2019-11-17
  • TBET‐expressing Th1 CD4+ T cells accumulate in chronic lymphocytic leukaemia without affecting disease progression in Eµ‐TCL1 mice
    Br. J. Haematol. (IF 5.206) Pub Date : 2019-11-14
    Philipp M. Roessner, Bola S. Hanna, Selcen Öztürk, Ralph Schulz, Laura Llaó Cid, Haniyeh Yazdanparast, Annika Scheffold, Dolors Colomer, Stephan Stilgenbauer, Peter Lichter, Martina Seiffert

    Chronic lymphocytic leukaemia (CLL) is associated with alterations in T cell number, subset distribution and function. Among these changes, an increase in CD4+ T cells was reported. CD4+ T cells are a heterogeneous population and distinct subsets have been described to exert pro‐ and anti‐tumour functions. In CLL, controversial reports describing the dominance of IFNγ‐expressing Th1 T cells or of IL‐4‐producing Th2 T cells exist. Our study shows that blood of CLL patients is enriched in Th1 T cells producing high amounts of IFNγ. Moreover, we observed that their frequency remains relatively stable in CLL patients over a time course of five years. Furthermore, we provide evidence for an accumulation of Th1 T cells in the Eµ‐TCL1 mouse model of CLL. As TBET (encoded by Tbx21) is a crucial transcription factor for Th1 polarization, we generated Tbx21−/− bone marrow chimaeric mice which showed a lower number of IFNγ‐producing Th1 T cells, and used them for adoptive transfer of Eµ‐TCL1 leukaemia. Disease development in these mice was, however, comparable to that in wild‐type controls, excluding a major role for TBET‐expressing Th1 cells in Eµ‐TCL1 leukaemia. Collectively, our data highlight that Th1 T cells accumulate in CLL but reducing their number has no impact on disease development.

    更新日期:2019-11-14
  • Superior survival of unmanipulated haploidentical haematopoietic stem cell transplantation compared with intensive chemotherapy as post‐remission treatment for children with very high‐risk philadelphia chromosome negative B‐cell acute lymphoblastic leukaemia in first complete remission
    Br. J. Haematol. (IF 5.206) Pub Date : 2019-11-14
    Yu‐juan Xue, Pan Suo, Xiao‐jun Huang, Ai‐dong Lu, Yu Wang, Ying‐xi Zuo, Chen‐hua Yan, Jun Wu, Jun Kong, Xiao‐hui Zhang, Yu‐hong Chen, Yue‐ping Jia, Kai‐yan Liu, Wei Han, Lan‐ping Xu, Le‐ping Zhang, Yi‐fei Cheng

    We explored the prognostic factors for children with very high‐risk (VHR) Philadelphia chromosome (Ph) negative B‐cell acute lymphoblastic leukaemia (B‐ALL) and compared the therapeutic effects of intensive chemotherapy and unmanipulated haploidentical haematopoietic stem cell transplantation (haplo‐HSCT) as post‐remission treatment in these patients undergoing first complete remission (CR1). A total of 104 paediatric patients with VHR B‐ALL in CR1 were retrospectively enrolled in this study, including 42 receiving unmanipulated haplo‐HSCT (Group A) and 62 receiving ongoing chemotherapy (Group B). Estimated 3‐year overall survival (OS), disease‐free survival (DFS) and cumulative incidence of relapse (CIR) at 36·2 months median follow‐up were 69·5 ± 4·7%, 63·5 ± 4·8% and 32·4 ± 4·7%, respectively. Maintenance of persistent positive or conversion from negative to positive of measurable residual disease (MRD) and chemotherapy were independent risk factors associated with inferior long‐term survival and higher CIR. OS, DFS, and CIR differed significantly between the groups in patients with persistent positive or negative‐to‐positive MRD. Haplo‐HSCT may be an option for children with VHR Ph‐negative B‐ALL in CR1, especially for patients with persistent positive or negative‐to‐positive MRD, and could achieve better survival than intensive chemotherapy as post‐remission treatment.

    更新日期:2019-11-14
  • Comorbidities and sex differences in causes of death among mantle cell lymphoma patients – A nationwide population‐based cohort study
    Br. J. Haematol. (IF 5.206) Pub Date : 2019-11-13
    Ingrid Glimelius, Karin E. Smedby, Sandra Eloranta, Mats Jerkeman, Caroline E. Weibull

    The prognosis for mantle cell lymphoma (MCL) remains poor. Our aim was to assess the impact of comorbidities on survival and causes of death. For 1,385 MCL patients (1,009 males, 376 females) diagnosed in 2000–2014 (median age 71 years, range 22–96) comorbidities ≤ 10 years of diagnosis were classified according to the Charlson comorbidity index (CCI; 0, 1, 2+). Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated to compare lymphoma‐specific and all‐cause mortality rates. Model‐based predictions were used to obtain probabilities of death. Overall, 44% had any comorbidity (CCI 1+) and 28% severe comorbidity (CCI 2+). Over a median follow‐up of 3·7 years (range 0–16), 633 (46%) died, the majority (76%) from lymphoma. Severe comorbidity was independently associated with higher all‐cause [hazard ratio (HR) = 1·52; 95% CI: 1·24–1·85) and lymphoma‐specific mortality (HR = 1·31; 95% CI: 1·04–1·65). Particularly among patients with connective tissue, renal and psychiatric diseases, and dementia. Among females with any comorbidity, non‐lymphoma deaths represented a larger proportion of all deaths, compared to males with any comorbidity. In general, more efficient lymphoma treatments need to be considered also for patients with severe comorbidity. However, among females with any comorbidity, the likelihood of non‐lymphoma death was still considerable, perhaps favouring a more liberal use of a “wait and watch” approach.

    更新日期:2019-11-13
  • Characteristics of graft‐versus‐host disease occurring after alemtuzumab‐containing allogeneic stem cell transplants: incidence, organ involvement, risk factors and survival
    Br. J. Haematol. (IF 5.206) Pub Date : 2019-11-12
    Maria C. Finazzi, Cristina Boschini, Charles Craddock, Alessandro Rambaldi, Janice Ward, Ram K. Malladi

    T‐cell depletion with alemtuzumab represents an effective form of graft‐versus‐host disease (GVHD) prophylaxis after allogeneic haematopoietic stem cell transplantation (allo‐HSCT); however, little is known regarding the impact of in vivo alemtuzumab on either the incidence or clinical characteristics of acute and chronic GVHD. We therefore studied 201 consecutive adult patients who received an alemtuzumab‐based, reduced‐intensity conditioned (RIC) allograft. With a median follow‐up of 24 months, the cumulative incidence of classic acute and late acute (persistent, recurrent and late onset) GVHD grades II–IV (grades III–IV) was 34% (13%) and 20% (8%) respectively; the cumulative incidence of classic chronic GVHD and overlap syndrome were 4% and 7% respectively. A previous diagnosis of classic acute GVHD is a risk factor for chronic GVHD (hazard ratio 10·91, 95% confidence interval 2·35–50·63, P = 0·0023) while late onset acute GVHD is not a risk factor for later development of chronic GVHD. Unrelated donor transplant is a risk factor for the development of classic acute GVHD but not for late onset or chronic GVHD. In conclusion, this study describes a distinctive pattern of GVHD following alemtuzumab‐RIC allografts, identifies the risk factors for GVHD development and provides prognostic information of patients with GVHD.

    更新日期:2019-11-13
  • Paediatric haematologists’ attitudes regarding haematopoietic cell transplantation as treatment for sickle cell disease
    Br. J. Haematol. (IF 5.206) Pub Date : 2019-11-12
    Alicia M. Stallings, Navneet S. Majhail, Amy S. Nowacki, Grace I. Onimoe, Rabi Hanna, Connie M. Piccone

    Beginning early in childhood, patients with sickle cell disease [SCD; a group of genetic haemoglobin disorders characterized by the sickle or HbS mutation (HBB E7V)] are at risk of life‐threatening and debilitating health events. Despite the high morbidity and mortality of this disease, haematopoietic cell transplantation (HCT), a curative therapy for SCD, remains underutilized. A variety of factors, including the limited availability of suitable donors, play a role in this trend, but do not fully explain the low frequency with which this therapy is employed. The objective of this study was to identify paediatric haematologists’ attitudes about HCT as a treatment option for SCD, and to describe the impact of these attitudes on their practices of discussing HCT with families of children affected by this disease. A nationwide survey of paediatric haematologists in the United States was conducted between February and May 2016. Two hundred and eighty‐seven surveys were included in the final analysis (response rate 20%). On average, respondents reported informing 42% of families about HCT as a treatment option (N = 248, 95% confidence interval: 38–46). Clinician attitudes about the cost and safety of HCT were associated with practices of discussing this therapy with families. These findings suggest that clinician attitudes and referral practices may play a role in the underutilization of this therapy in the SCD population.

    更新日期:2019-11-13
  • A randomised controlled trial of extended anticoagulation treatment versus standard treatment for the prevention of recurrent venous thromboembolism (VTE) and post‐thrombotic syndrome in patients being treated for a first episode of unprovoked VTE (the ExACT study)
    Br. J. Haematol. (IF 5.206) Pub Date : 2019-11-12
    Charlotte Bradbury, Kate Fletcher, Yongzhong Sun, Carl Heneghan, Chris Gardiner, Andrea Roalfe, Pollyanna Hardy, Debbie McCahon, Gail Heritage, Helen Shackleford, FD Richard Hobbs, David Fitzmaurice

    Venous thromboembolism (VTE) is prevalent and impactful, with a risk of death, morbidity and recurrence. Post‐thrombotic syndrome (PTS) is a common consequence and associated with impaired quality of life (QoL). The ExACT study was a non‐blinded, prospective, multicentred randomised controlled trial comparing extended versus limited duration anticoagulation following a first unprovoked VTE (proximal deep vein thrombosis or pulmonary embolism). Adults were eligible if they had completed ≥3 months anticoagulation (remaining anticoagulated). The primary outcome was time to first recurrent VTE from randomisation. The secondary outcomes included PTS severity, bleeding, QoL and D‐dimers. Two‐hundred and eighty‐one patients were recruited, randomised and followed up for 24 months (mean age 63, male:female 2:1). There was a significant reduction in recurrent VTE for patients receiving extended anticoagulation [2·75 vs. 13·54 events/100 patient years, adjusted hazard ratio (aHR) 0·20 (95% confidence interval (CI): 0·09 to 0·46, P < 0·001)] with a non‐significant increase in major bleeding [3·54 vs. 1·18 events/100 patient years, aHR 2·99 (95% CI: 0·81–11·05, P = 0·10)]. Outcomes of PTS and QoL were no different between groups. D‐dimer results (on anticoagulation) did not predict VTE recurrence. In conclusion, extended anticoagulation reduced VTE recurrence but did not reduce PTS or improve QoL and was associated with a non‐significant increase in bleeding. Results also suggest very limited clinical utility of D‐dimer testing on anticoagulated patients.

    更新日期:2019-11-13
  • Treatment of classical Hodgkin lymphoma in young adults aged 18–30 years with a modified paediatric Hodgkin lymphoma protocol. Results of a multicentre phase II clinical trial (CRUK/08/012)
    Br. J. Haematol. (IF 5.206) Pub Date : 2019-11-11
    William Townsend, Sarah Leong, Peter Hoskin, Patricia Diez, Pip Patrick, David Linch, Wai‐Lup Wong, Irfan Kayani, Bal Sanghera, Andre Lopes, Stephen Daw, Graham Collins, Laura Clifton‐Hadley, Kirit Ardeshna

    This phase II trial was designed to determine the safety and efficacy of a modified paediatric risk‐stratified protocol in young adults (18–30 years) with classical Hodgkin Lymphoma. The primary end‐point was neurotoxicity rate. The incidence of grade 3 neurotoxicity was 11% (80% CI, 5–19%); a true rate of neuropathy of >15% cannot be excluded. Neuropathy and associated deterioration in quality of life was largely reversible. The overall response rate was 100% with 40% complete remission (CR) rate. Twelve months disease‐free survival (DFS) was 91%. We demonstrate that a risk‐stratified paediatric combined modality treatment approach can be delivered to young adults without significant irreversible neuropathy.

    更新日期:2019-11-13
  • GATA2 deficiency and haematopoietic stem cell transplantation: challenges for the clinical practitioner
    Br. J. Haematol. (IF 5.206) Pub Date : 2019-11-11
    Delfien J. Bogaert, Genevieve Laureys, Leslie Naesens, Dominiek Mazure, Marieke De Bruyne, Amy P. Hsu, Victoria Bordon, Erik Wouters, Simon J. Tavernier, Bart N. Lambrecht, Elfride De Baere, Filomeen Haerynck, Tessa Kerre

    GATA2 deficiency, first described in 2011, is a bone marrow failure disorder resulting in a complex haematological and immunodeficiency syndrome characterised by cytopenias, severe infections, myelodysplasia and leukaemia. The only curative treatment is allogeneic haematopoietic stem cell transplantation (HSCT). Although knowledge on this syndrome has greatly expanded, in clinical practice many challenges remain. In particular, guidelines on optimal donor and stem cell source and conditioning regimens regarding HSCT are lacking. Additionally, genetic analysis of GATA2 is technically cumbersome and could easily result in false‐negative results. With this report, we wish to raise awareness of these pitfalls amongst physicians dealing with haematological malignancies and primary immunodeficiencies.

    更新日期:2019-11-13
  • Sequential mutational evaluation of CALR ‐mutated myeloproliferative neoplasms with thrombocytosis reveals an association between CALR allele burden evolution and disease progression
    Br. J. Haematol. (IF 5.206) Pub Date : 2019-11-11
    Laurane Cottin, Jérémie Riou, Corentin Orvain, Jean Christophe Ianotto, Françoise Boyer, Maxime Renard, Matgorzata Truchan‐Graczyk, Anne Murati, Rébecca Jouanneau‐Courville, Olivier Allangba, Olivier Mansier, Barbara Burroni, Marie-Christine Rousselet, Isabelle Quintin‐Roué, Antoine Martin, Sophie Sadot‐Lebouvier, Yves Delneste, Jean‐Marie Chrétien, Mathilde Hunault‐Berger, Odile Blanchet, Eric Lippert, Valérie Ugo, Damien Luque Paz

    In myeloproliferative neoplasms (MPN), JAK2V617F allele burden measurement has an impact on prognosis that helps in patient monitoring. Less is known about its usefulness in CALR‐mutated cases. Additional mutations found by next‐generation sequencing have also shown an impact on prognosis that may drive therapeutic choices, especially in myelofibrosis, but few studies focused on CALR‐mutated patients. We performed a molecular evaluation combining next‐generation sequencing with a myeloid panel and CALR allele burden measurement at diagnosis and during follow‐up in a cohort of 45 patients with CALR‐mutated essential thrombocythaemia. The bone marrow histology was also blindly reviewed in order to apply the WHO2016 classification. The most frequently mutated gene was TET2 (11/21 mutations). CALR type 1‐like patients appear to have a more complex molecular landscape. We found an association between disease progression and CALR allele burden increase during follow‐up, independently of additional mutations and WHO2016‐reviewed diagnosis. Patients with disease progression at the time of follow‐up showed a significant increase in CALR allele burden (+16·7%, P = 0·005) whereas patients without disease progression had a stable allele burden (+3·7%, P = 0·194). This result argues for clinical interest in CALR allele burden monitoring.

    更新日期:2019-11-13
  • Increased frequency of CD4+PD‐1+HLA‐DR+ T cells is associated with disease progression in CLL
    Br. J. Haematol. (IF 5.206) Pub Date : 2019-11-08
    Lauren Elston, Chris Fegan, Robert Hills, Shaikh S. Hashimdeen, Elisabeth Walsby, Peter Henley, Chris Pepper, Stephen Man

    Chronic lymphocytic leukaemia (CLL) patients often have abnormal expansions of CD4+ and CD8+ T cells and this can be associated with progressive disease. To characterise the key T‐cell populations involved in this phenomenon, we used flow cytometry and 11 phenotypic markers to study 74 CLL patients and 14 controls. T cells of CLL patients were more phenotypically complex than those of healthy controls with significant increases in the frequencies of CD4 and CD8 memory T cells expressing exhaustion‐, activation‐ and senescence‐associated markers. Multivariate analysis of 111 different T‐cell subsets showed that high frequencies of four subsets (three CD8 and one CD4) were associated with shorter progression‐free survival. The most significant association was with CD4+HLA‐DR+PD‐1+ T cells, and patients could be stratified into high‐ and low‐risk groups based on the frequency of these T cells. The expansion of this CD4+ subset could not be accounted for by age, cytomegalovirus infection or increases in Treg cells. Overall, these results highlight two relatively simple biomarkers, percentage CD8+ and percentage CD4+PD‐1+HLA‐DR+ T cells, which can be used to risk‐stratify CLL patients, independent of other tumour‐associated markers. They also provide further evidence for the pivotal role of T cells in modulating the pathology of CLL.

    更新日期:2019-11-08
  • Lenalidomide maintenance for diffuse large B‐cell lymphoma patients responding to R‐CHOP: quality of life, dosing, and safety results from the randomised controlled REMARC study
    Br. J. Haematol. (IF 5.206) Pub Date : 2019-11-08
    Catherine Thieblemont, Susannah Howlett, René‐Olivier Casasnovas, Nicolas Mounier, Aurore Perrot, Franck Morschhauser, Christophe Fruchart, Nicolas Daguindau, Koen van Eygen, Lucie Obéric, Reda Bouabdallah, Gian Matteo Pica, Emmanuelle Nicolas‐Virezelier, Julie Abraham, Olivier Fitoussi, Sylvia Snauwaert, Jean‐Claude Eisenmann, Pauline Lionne‐Huyghe, Dominique Bron, Sabine Tricot, Dries Deeren, Hugo Gonzalez, Régis Costello, Katell Le Du, Maria Gomes da Silva, Sebastian Grosicki, Judith Trotman, John Catalano, Dolores Caballero, Richard Greil, Amos M. Cohen, Philippe Gaulard, Louise Roulin, Kenichi Takeshita, Marie‐Laure Casadebaig, Hervé Tilly, Bertrand Coiffier

    Lenalidomide maintenance therapy prolonged progression‐free survival (PFS) versus placebo in elderly patients with diffuse large B‐cell lymphoma (DLBCL) responding to induction chemotherapy in the phase 3 REMARC study. This subpopulation analysis assessed the impact of lenalidomide maintenance and treatment‐emergent adverse events (TEAEs) on health‐related quality of life (HRQOL). Global health status (GHS), and physical functioning and fatigue subscales were evaluated in patients who completed the European Organisation for Research and Treatment of Cancer quality‐of‐life questionnaire‐C30 v3.0. The impact of TEAEs classified post hoc as subjective (patients can feel) or observable (only measurable by physicians) on dose reductions and discontinuations was assessed. Among 457 patients (lenalidomide, n = 229; placebo, n = 228), mean (standard deviation) GHS was similar between treatment arms [68·2 (20·7) Versus 72·0 (17·8)] at randomisation and remained similar during maintenance. Patients receiving lenalidomide experienced no meaningful changes in GHS, physical functioning, or fatigue. Observable TEAEs were more common (81·1% Versus 66·3%) and more likely to lead to dose reductions, than subjective TEAEs in both arms. PFS was superior in the lenalidomide arm regardless of dose reduction. Lenalidomide maintenance prolonged PFS and did not negatively impact HRQOL in patients with DLBCL despite TEAEs being more common, when compared with placebo.

    更新日期:2019-11-08
  • Improved survival after offspring donor transplant compared with older aged‐matched siblings for older leukaemia patients
    Br. J. Haematol. (IF 5.206) Pub Date : 2019-11-07
    Yu Wang, Qi‐Fa Liu, De‐Pei Wu, Lan‐Ping Xu, Kai‐Yan Liu, Xiao‐Hui Zhang, Sheng‐Ye Lu, Xiao Ma, Fen Huang, Xiao‐Jun Huang

    Donor selection for older leukaemia patients undergoing haematopoietic cell transplant (HCT) is not well defined: outcomes might be improved with a younger offspring donor rather than an older human leukocyte antigen (HLA)‐matched sibling donor (MSD). We extended our multicentre dataset. A total of 185 acute leukaemia patients (≥ 50 years) transplanted in first complete remission who received HCT from offspring (n = 62) or MSD (n = 123) were included. A 1:1 ratio matched‐pair analysis was performed. We were able to match 54 offspring with 54 MSD patients. Outcomes were compared between the two matched‐pair groups. The cumulative incidence of grade II/IV acute graft‐versus‐host disease (GVHD) (26% vs. 35%; P = 0·23) and chronic GVHD (37% vs. 24%; P = 0·19) was comparable between groups (MSD vs. offspring). The lower three‐year transplant‐related mortality (9% vs. 26%; P = 0·023) and relapse incidence (6% vs. 17%; P = 0·066) resulted in higher overall survival (85% vs. 58%; P = 0·003) and leukaemia‐free survival (LFS) (85% vs. 56%; P = 0·001) in offspring HCT compared with that in MSD HCT. These data might favour a young offspring over an older MSD in patients >50 years. The current analyses confirm that non‐HLA donor characteristics, such as kinship and donor age, rather than HLA disparity, predominantly influence survival in older acute leukaemia patients.

    更新日期:2019-11-07
  • Platelet biology of the rapidly failing lung
    Br. J. Haematol. (IF 5.206) Pub Date : 2019-11-07
    A. Valance Washington, Omar Esponda, Angelia Gibson

    Acute respiratory distress syndrome (ARDS) is characterized by a rapid‐onset respiratory failure with a mortality rate of approximately 40%. This physiologic inflammatory process is mediated by disruption of the alveolar‐vascular interface, leading to pulmonary oedema and impaired oxygen exchange, which often warrants mechanical ventilation to increase survival in the acute setting. One of the least understood aspects of ARDS is the role of the platelets in this process. Platelets, which protect vascular integrity, play a pivotal role in the progression and resolution of ARDS. The recent substantiation of the age‐old theory that megakaryocytes are found in the lungs has rejuvenated interest in and raised new questions about the importance of platelets for pulmonary function. In addition to primary haemostasis, platelets provide a myriad of inflammatory functions that are poised to aid the innate immune system. This review focuses on the evidence for regulatory roles of platelets in pulmonary inflammation, with an emphasis on two receptors, CLEC‐2 and TLT‐1. Studies of these receptors identify novel pathways through which platelets may regulate vascular integrity and inflammation in the lungs, thereby influencing the development of ARDS.

    更新日期:2019-11-07
  • Intestinal pathophysiological and microbial changes in sickle cell disease: Potential targets for therapeutic intervention
    Br. J. Haematol. (IF 5.206) Pub Date : 2019-11-06
    Dibyendu Dutta, Amandeep Aujla, Bettina M. Knoll, Seah H. Lim

    There is a large therapeutic gap in the treatment of sickle cell disease (SCD). Recent studies demonstrated the presence of pathophysiological and microbial changes in the intestine of patients with SCD. The intestinal microbes have also been found to regulate neutrophil ageing and possible basal activation of circulating neutrophils. Both aged and activated neutrophils are pivotal for the pathogenesis of vaso‐occlusive crisis in SCD. In this paper, we will provide an overview of the intestinal pathophysiological and microbial changes in SCD. Based on these changes, we will propose therapeutic approaches that could be investigated for treating SCD.

    更新日期:2019-11-06
  • Treatment of acute leukaemia in adult Jehovah's Witnesses
    Br. J. Haematol. (IF 5.206) Pub Date : 2019-11-06
    Firas El Chaer, Karen K. Ballen

    Since Jehovah’s Witness (JW) patients diagnosed with leukaemia refuse blood transfusions, they are often denied intensive chemotherapy for fear they could not survive myeloablation without blood transfusion support. Treatment of JW patients with acute leukaemia is challenging and carries a higher morbidity and mortality; however, the refusal of blood products should not be an absolute contraindication to offer multiple treatment modalities including haematopoietic stem cell transplantation. In this review we discuss their optimal management and describe alternative modalities to blood transfusions to provide sufficient oxygenation and prevent bleeding.

    更新日期:2019-11-06
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