Hemopoietic Stem Cell Transplantation Research Articles

Red cell and platelet transfusion burden following myeloablative allogeneic haemopoietic stem cell transplantation.

Adult allogeneic haemopoietic stem cell transplant (HSCT) usually requires blood transfusion support of red cells and platelets. There are few studies describing transfusion burden after allogeneic HSCT. This study aims to quantify and identify determinants of transfusion burden after allogeneic HSCT to improve planning, inventory management and patient counselling. A retrospective audit of blood use (red cells and platelets) of all adult HSCT (n = 169) was performed over an 8-year period extracted from pathology and hospital databases. ABO compatibility, graft type, conditioning regimens and patient factors were analysed for up to 12 months post transplant. Transfusion burden was lower than expected and lower than reported by other groups. The median number of units transfused was four red cells and four platelets by day 30, and six red cells and six platelets by day 365. The median time to transfusion independence was 12 days for red cells and 16 days for platelets. Factors associated with increased red cell use included sex, disease stage, graft type (cord blood) and ABO compatibility. Disease stage and graft type (cord blood) were associated with increased platelet transfusion. Donor and patient characteristics are associated with transfusion burden after allogeneic HSCT. Determining transfusion burden in HSCT and identifying determinants of increased transfusion use assist in inventory planning and patient information.

Survival after mesenchymal stromal cell therapy in steroid-refractory acute graft-versus-host disease: systematic review and meta-analysis

Graft-versus-host disease (GVHD) is the major limitation of allogeneic haemopoietic stem-cell transplantation (HSCT), for which no approved treatments are available. Use of mesenchymal stromal cells (MSCs) has become standard practice in some European countries, but controversy exists for their benefit. The aim of this meta-analysis was to analyse available evidence for the benefit of MSC treatments in steroid-resistant acute GVHD. We did a systematic review and meta-analysis to assess response to and survival after MSC treatment in patients with steroid-refractory acute GVHD. We searched MEDLINE, Embase, Ovid, and Cochrane Central databases for published studies, and we used ClinicalTrials.gov and other websites to find unpublished studies and conference abstracts. We included prospective and retrospective studies in which MSCs were administered to patients with steroid-refractory acute GVHD. Data were extracted independently by two investigators based on strict selection criteria. A random-effects model was used to pool outcomes across studies because of anticipated heterogeneity. Our primary outcome was survival at 6 months from the first infusion of MSCs. We identified 628 citations with our search, of which 610 were excluded after review and a further five did not contain pertinent data. Thus, our meta-analysis included 13 non-randomised studies at moderate risk of bias, comprising a total of 336 patients. Six studies provided data for the primary outcome analysis (119 patients). Survival at 6 months after MSC treatment was 63% (95% CI 50-74; I(2)=41%). Survival did not differ with respect to age, MSC culture medium, or dose of MSCs delivered. Available evidence suggests that infusion of MSCs could be an acceptable treatment for patients with steroid-refractory acute GVHD. Randomised clinical trials are needed urgently to assess different treatment modalities for steroid-refractory acute GVHD. None.

Busulfan plus cyclophosphamide versus busulfan plus fludarabine as a preparative regimen for allogeneic haemopoietic stem-cell transplantation in patients with acute myeloid leukaemia: an open-label, multicentre, randomised, phase 3 trial

The standard busulfan-cyclophosphamide myeloablative conditioning regimen is associated with substantial non-relapse mortality in patients older than 40 years with acute myeloid leukaemia who are undergoing allogeneic stem-cell transplantation. Because the combination of busulfan plus fludarabine has been proposed to reduce non-relapse mortality, we aimed to compare this treatment with busulfan plus cyclophosphamide as a preparative regimen in these patients. We did an open-label, multicentre, randomised, phase 3 trial for patients with acute myeloid leukaemia at 25 hospital transplant centres in Italy and one in Israel. Eligible patients were aged 40-65 years, had an Eastern Cooperative Oncology Group performance status less than 3, and were in complete remission. Patients were randomly assigned 1:1 to receive intravenous busulfan plus cyclophosphamide or busulfan plus fludarabine. Treatment allocations were not masked to investigators or patients. Randomisation was done centrally via a dedicated web-based system using remote data entry, with patients stratified by donor type and complete remission status. Patients allocated to busulfan plus cyclophosphamide received intravenous busulfan 0·8 mg/kg four times per day during 2 h infusions for four consecutive days (16 doses from days -9 through -6; total dose 12·8 mg/kg) and cyclophosphamide at 60 mg/kg per day for two consecutive days (on days -4 and -3; total dose 120 mg/kg). Patients allocated to busulfan plus fludarabine received the same dose of intravenous busulfan (from days -6 through -3) and fludarabine at 40 mg/m(2) per day for four consecutive days (from days -6 through -3; total dose 160 mg/m(2)). The primary endpoint was 1-year non-relapse mortality, which was assessed on an intention-to-treat basis; safety outcomes were assessed in the per-protocol population. This trial has been completed and is registered with ClinicalTrials.gov, number NCT01191957. Between Jan 3, 2008, and Dec 20, 2012, we enrolled and randomly assigned 252 patients to receive busulfan plus cyclophosphamide (n=125) or busulfan plus fludarabine (n=127). Median follow-up was 27·5 months (IQR 9·8-44·3). 1-year non-relapse mortality was 17·2% (95% CI 11·6-25·4) in the busulfan plus cyclophosphamide group and 7·9% (4·3-14·3) in the busulfan plus fludarabine group (Gray's test p=0·026). The most frequently reported grade 3 or higher adverse events were gastrointestinal events (28 [23%] of 121 patients in the busulfan plus cyclophosphamide group and 26 [21%] of 124 patients in the busulfan plus fludarabine group) and infections (21 [17%] patients in the busulfan plus cyclophosphamide group and 13 [10%] patients in the busulfan plus fludarabine group had at least one such event). In older patients with acute myeloid leukaemia, the myeloablative busulfan plus fludarabine conditioning regimen is associated with lower transplant-related mortality than busulfan plus cyclophosphamide, but retains potent antileukaemic activity. Accordingly, this regimen should be regarded as standard of care during the planning of allogeneic transplants for such patients. Agenzia Italiana del Farmaco.

Post-remission treatment with allogeneic stem cell transplantation in patients aged 60 years and older with acute myeloid leukaemia: a time-dependent analysis

Acute myeloid leukaemia mainly affects elderly people, with a median age at diagnosis of around 70 years. Although about 50-60% of patients enter first complete remission upon intensive induction chemotherapy, relapse remains high and overall outcomes are disappointing. Therefore, effective post-remission therapy is urgently needed. Although often no post-remission therapy is given to elderly patients, it might include chemotherapy or allogeneic haemopoietic stem cell transplantation (HSCT) following reduced-intensity conditioning. We aimed to assess the comparative value of allogeneic HSCT with other approaches, including no post-remission therapy, in patients with acute myeloid leukaemia aged 60 years and older. For this time-dependent analysis, we used the results from four successive prospective HOVON-SAKK acute myeloid leukaemia trials. Between May 3, 2001, and Feb 5, 2010, a total of 1155 patients aged 60 years and older were entered into these trials, of whom 640 obtained a first complete remission after induction chemotherapy and were included in the analysis. Post-remission therapy consisted of allogeneic HSCT following reduced-intensity conditioning (n=97), gemtuzumab ozogamicin (n=110), chemotherapy (n=44), autologous HSCT (n=23), or no further treatment (n=366). Reduced-intensity conditioning regimens consisted of fludarabine combined with 2 Gy of total body irradiation (n=71), fludarabine with busulfan (n=10), or other regimens (n=16). A time-dependent analysis was done, in which allogeneic HSCT was compared with other types of post-remission therapy. The primary endpoint of the study was 5-year overall survival for all treatment groups, analysed by a time-dependent analysis. 5-year overall survival was 35% (95% CI 25-44) for patients who received an allogeneic HSCT, 21% (17-26) for those who received no additional post-remission therapy, and 26% (19-33) for patients who received either additional chemotherapy or autologous HSCT. Overall survival at 5 years was strongly affected by the European LeukemiaNET acute myeloid leukaemia risk score, with patients in the favourable risk group (n=65) having better 5-year overall survival (56% [95% CI 43-67]) than those with intermediate-risk (n=131; 23% [19-27]) or adverse-risk (n=444; 13% [8-20]) acute myeloid leukaemia. Multivariable analysis with allogeneic HSCT as a time-dependent variable showed that allogeneic HSCT was associated with better 5-year overall survival (HR 0·71 [95% CI 0·53-0·95], p=0·017) compared with non-allogeneic HSCT post-remission therapies or no post-remission therapy, especially in patients with intermediate-risk (0·82 [0·58-1·15]) or adverse-risk (0.39 [0·21-0·73]) acute myeloid leukaemia. Collectively, the results from these four trials suggest that allogeneic HSCT might be the preferred treatment approach in patients 60 years of age and older with intermediate-risk and adverse-risk acute myeloid leukaemia in first complete remission, but the comparative value should ideally be shown in a prospective randomised study. None.

Sweet spot for cyclophosphamide: a balancing act

Severe aplastic anaemia is a rare but life-threatening disorder for which allogeneic haemopoietic stem-cell transplant (HSCT) is a potential cure. In patients younger than 35 years and up to 50 years of age without substantial comorbidities with HLA-matched sibling donor, upfront HSCT is the recommended treatment. Healthy patients without a HLA-matched sibling donor are offered HSCT as a second-line treatment after failure of immunosuppressive therapy. 1 Marsh JC Ball SE Cavenagh J et al. Guidelines for the diagnosis and management of aplastic anaemia. Br J Haematol. 2009; 147: 43-70 Crossref PubMed Scopus (419) Google Scholar Although 60–70% of patients respond to immunosuppressive therapy, blood counts return to normal only in a third of patients, and another third need long-term cyclosporin therapy and the risk of relapse of aplastic anaemia and clonal evolution to myelodysplastic syndromes occurs in a further third of patients. HSCT, however, offers an opportunity for longlasting haematological response and minimises the risk of relapse and reduces the likelihood of clonal evolution. Cyclophosphamide conditioning in patients with severe aplastic anaemia given unrelated marrow transplantation: a phase 1–2 dose de-escalation studyCyclophosphamide at 50 mg/kg and 100 mg/kg with TBI 2 Gy, fludarabine, and anti-thymocyte globulin results in effective conditioning and few early deaths after unrelated donor transplantation for severe aplastic anaemia. These doses of cyclophosphamide provide a framework for further regimen optimisation strategies. Full-Text PDF

Outcomes after use of two standard ablative regimens in patients with refractory acute myeloid leukaemia: a retrospective, multicentre, registry analysis

Cyclophosphamide plus intravenous busulfan has not been compared with cyclophosphamide plus total body irradiation (TBI) in adults with advanced refractory acute myeloid leukaemia before allogeneic haemopoietic stem-cell transplantation (HCT). We aimed to assess whether survival of patients receiving ablative intravenous busulfan-based conditioning regimens before a related or volunteer-unrelated donor HCT for refractory acute myeloid leukaemia is not inferior to that of patients receiving an ablative TBI-based regimen. In this retrospective, multicentre, registry-based study, we obtained data for patients (aged >18 years) with refractory acute myeloid leukaemia in active phase of disease, who had received HCT from an HLA-identical sibling or an unrelated donor after intravenous busulfan plus cyclophosphamide or cyclophosphamide plus TBI conditioning between 2000 and 2012. Data was obtained from the European Group for Blood and Marrow Transplantation registry. The primary endpoints of the study were overall survival and leukaemia-free survival. We obtained data for 514 patients who had received intravenous busulfan plus cyclophosphamide and 338 patients who had received cyclophosphamide plus TBI. The median percentage of blasts before HCT did not differ significantly between groups (20% [range 5-100; IQR 10-32] in the intravenous busulfan plus cyclophosphamide group vs 16% [5-95; 9-33] in the cyclophosphamide plus TBI group; p=0·16). Overall survival at 2 years did not differ between the groups in the univariate analysis (31·2% [95% CI 26·8-35·5] with intravenous busulfan plus cyclophosphamide vs 33·4% [28·1-38·7] wth cyclophosphamide plus TBI; p=0·65). Leukaemia-free survival at 2 years also did not differ between groups (25·0% [95% CI 21·0-29·0] vs 28·4% [23·4-33·5]; p=0·47). In multivariable analysis adjusting for differences between both groups, no difference was noted between the two groups in terms of overall survival (hazard ratio [HR] 0·99 [95% CI 0·83-1·20]; p=0·95) or leukaemia-free survival (HR 0·97 [0·81-1·16]; p=0·71). Main causes of non-relapse mortality were graft-versus-host disease (49 [10%] in the intravenous busulfan plus cyclophosphamide group vs 25 [7%] in the cyclophosphamide plus TBI group) and infection (36 [7%] vs 18 [5%]). From a practical standpoint, the use of intravenous busulfan plus cyclophosphamide is likely to be a valid and efficient alternative to cyclophosphamide plus TBI conditioning regimen for patients with refractory acute myeloid leukaemia, especially for those transplant centres without access to radiation facilities. None.

Oral chronic graft-versus-host disease in Australia: clinical features and challenges in management.

Data from the Australasian Bone Marrow Transplant Recipient Registry show a steady increase in the number of allogeneic haemopoietic stem cell transplantations (HSCT) performed annually in Australia and New Zealand. In 2012, 629 allogeneic HSCT were performed. Allogeneic HSCT is associated with numerous potential complications, including chronic graft-versus-host disease (cGVHD). The oral cavity is one of the most frequent sites affected by cGvHD, often leading to significant disability and reduced quality of life. Management strategies are often complex, of variable efficacy and influenced by the availability of various therapeutic agents, access to compounding pharmacies and associated costs. This paper summarises the current status of allogeneic HSCT in Australia and New Zealand with a focus on oral cGvHD and the associated challenges in its management.

PTU-083 Substantial histological improvement following haemopoetic stem cell transplantation: Abstract PTU-083 Table 1

Introduction Haemopoietic stem cell transplantation (HSCT) leads to complete regression of endoscopic signs of Crohn’s disease in about one third of patients, implying an alteration in the natural history of Crohn’s disease. We investigated whether these substantial changes were also seen histologically. Method Patients with impaired quality-of-life from active Crohn’s disease not amenable to surgery despite treatment with at least 3 immunosuppressive agents all underwent stem cell mobilisation before randomisation to immuno-ablation followed by unselected cyclophosphamide-based conditioning and HSCT after one month (Early HSCT) or one-year (Delayed HSCT). They underwent full ileocolonoscopy at baseline and after one and two years. Endoscopic involvement and activity were assessed using the Simple Endoscopic Score of Crohn’s disease (SES CD) in which a value of zero means no evidence of active or inactive Crohn’s disease in any examined segment of the ileum or colon. In 17 patients segments were biopsied systematically for blinded histological assessment, using ECCO-approved scales for intensity and diffuseness of acute and chronic inflammation, granulomas, ulceration, distortion and metaplasia. Results There was a strong correlation between endoscopic findings and histology (Table 1). The % of colonic biopsy samples that were histologically normal rose from 39% (baseline) to 50% at 1 year and 78% at 2 years after Early HSCT (p = 0.039). In patients undergoing Delayed HSCT values were 52% (baseline), 50% 1 year after mobilisation only and 75% after a further year following delayed HSCT (p = 0.329). Improvements were mainly due to reduction or regression of acute and chronic inflammatory changes. Conclusion Blinded histological assessments fortify the evidence that HSCT can have a profound objective benefit in Crohn’s disease. Disclosure of interest None Declared.

PTU-082 Responders to haemopoietic stem cell transplantation for crohn’s disease: Abstract PTU-082 Table 1

<h3>Introduction</h3> We recently reported that about one third of patients with Crohn’s disease experience prolonged regression of ileocolonic disease following haemopoietic stem cell transplantation (HSCT). Here we compare the characteristics of responders and non-responders. <h3>Method</h3> Patients with impaired quality-of-life from active Crohn’s disease not amenable to surgery despite treatment with at least 3 immunosuppressive agents all underwent stem cell mobilisation before randomisation to immuno-ablation followed by unselected cyclophosphamide-based conditioning and HSCT after one month (Early HRCT) or one-year (Delayed HS CT). Patients in whom all endoscopic evidence of Crohn’s disease disappeared (SES-CD score of zero) were classified as Responders. Supporting histology was available in 17 of them. <h3>Results</h3> Forty four patients with ileocolonic involvement underwent mobilisation before randomisation to Early or Delayed HSCT. Of 38 patients that could be classified 14 were Responders. Ten had SES-CD of zero after 1 year, (maintained in the second in 3 of 4 with available data) and 4 achieved responder status in year 2. Four of 6 followed to 4 years remain free of Crohn’s disease vs 1 of 15 non-responders. Responders were significantly more likely to have histologically normal segments post HSCT (Table 1) A Responder status tended to be more likely with no family history (39% vs 20%), in non-smokers (54% vs 30%), with early-onset of disease (Montreal A1, 46% vs 32%)) and with more than 10 year history (46% vs 17%); those with pure colonic involvement (L2) were less likely to respond than those with ileal involvement (L1, L3, 14% vs 43%) but these fell short of statistical significance on univariate analysis. <h3>Conclusion</h3> A group of patients can be identified who have a substantial and long lasting regression of Crohn’s disease following HSCT. Endoscopic response following HSCT is associated with regression of histological evidence of Crohn’s disease. <h3>Disclosure of interest</h3> None Declared.

Tusanqi-Related Sinusoidal Obstruction Syndrome in China: A Systematic Review of the Literatures.

In West, sinusoidal obstruction syndrome (SOS) is often complicated with hemopoietic stem cell transplantation. By comparison, in China, SOS is frequently caused by Tusanqi-containing pyrrolizidine alkaloids. A systematic review aimed to evaluate the clinical profiles, diagnostic workup, treatment, and outcomes of Tusanqi-related SOS in China. All relevant articles were searched via PubMed, China Knowledge Resource Integrated, VIP, and Wanfang databases. Case reports were defined, as the data were available in every individual patient. Otherwise, case series were defined. Overall, 106 articles were eligible. Fifty-six case reports included 84 individual patients with SOS secondary to Tusanqi alone. All of them presented with ascites, but only 1 patient presented with upper gastrointestinal bleeding. The 1-, 3-, and 6-month cumulative survival rate was 98%, 87%, and 76%, respectively. Increased bilirubin and aspartate transaminase levels were significantly associated with poor outcome. Thirty-one case series included 402 patients with SOS secondary to Tusanqi alone. Ascites was observed in 94% of patients, but upper gastrointestinal bleeding was observed in 40% of patients. Recovery, stabilization, progression, and death were observed in 41%, 30%, 14%, and 16% of patients, respectively. Nineteen case series included 281 patients with SOS secondary to mixed etiologies. The pooled proportion of Tusanqi-related SOS was 66% (95% confidence interval: 56%-75%). Tusanqi is a major cause of SOS in China. Ascites is the most common clinical presentation of Tusanqi-related SOS. Despite a relatively good short-term outcome, further studies should be necessary to explore the long-term outcome and refine the treatment strategy.

Wanted: Prospective Studies of Alternative Donors

Wanted: Prospective Studies of Alternative Donors

Moving towards pathogen‐specific T cells post‐stem cell transplant as standard of care

Infection remains a large contributor to mortality post‐allogeneic haemopoietic stem cell transplantation (HSCT). Non‐bacterial pathogens cause disease post‐HSCT due to impaired cellular immunity that persists for months to years. Treatment with antiviral or antifungal pharmacotherapy is problematic due to drug toxicity, treatment failure and high cost. Pathogen‐specific T cells (PSTs) from transplant donors provide a potential solution to the problem of impaired recipient immunity by directly and rapidly reconstituting immunity, thereby preventing or controlling infections. A number of phases I and II clinical trials of PSTs that have focused primarily on cytomegalovirus, Epstein–Barr virus and adenovirus have now been performed in the prophylactic, pre‐emptive and treatment settings. These trials show that transferred cells are safe and that they expand in vivo, respond to viral antigens and can prevent or control disease. At the current time, manufacture remains the domain of large centres with the necessary expertise and infrastructure, but automation and standardization will allow techniques to be more widely adopted. It is clear that adoptive T cell transfer will form part of the future of transplantation, with the current challenge being to perform large randomized clinical trials demonstrating safety and efficacy to justify the investment in infrastructure required for widespread incorporation of this therapy into routine clinical practice.

One million haemopoietic stem-cell transplants: a retrospective observational study

The transplantation of cells, tissues, and organs has been recognised by WHO as an important medical task for its member states; however, information about how to best organise transplantation is scarce. We aimed to document the activity worldwide from the beginning of transplantation and search for region adapted indications and associations between transplant rates and macroeconomics. Between Jan 1, 2006, and Dec 31, 2014, the Worldwide Network for Blood and Marrow Transplantation collected data for the evolution of haemopoietic stem-cell transplantation (HSCT) activity and volunteer donors in the 194 WHO member states. 953,651 HSCTs (553,350 [58%] autologous and 400,301 [42%] allogeneic) were reported by 1516 transplant centres from 75 countries. No transplants were done in countries with fewer than 300,000 inhabitants, a surface area less than 700 km(2), and a gross national income per person of US$1260 or lower. Use of HSCT increased from the first transplant in 1957 to almost 10,000 by 1985. We recorded a cumulative total of about 100,000 transplants by 1995, and an estimated 1 million by December, 2012. Unrelated donor registries contributed 22·3 million typed volunteer donors and 645,646 cord blood products by 2012. Numbers of allogeneic HSCTs increased in the past 35 years with no signs of saturation (R(2)=0·989). Transplant rates were higher in countries with more resources, more transplant teams, and an unrelated donor infrastructure. Our findings show achievements and high unmet needs and give guidance for decisions; to grant access for patients, to provide a donor infrastructure, and to limit overuse by defining risk and region adapted indications for HSCT as an efficient and cost-effective approach for life-threatening, potentially curable diseases. Funding for this study was indirectly provided by support of the WBMT.

What has happened in the last 50 years in immunology.

Fifty years ago, in 1964, our understanding of the immune system was very rudimentary. Gell and Coombs had just described classes of hypersensitivity reactions, and Bruton had described and commenced immunoglobulin replacement in agammaglobulinaemia. The distinction between T and B cells was not identified and characterised until the 1960s and 1970s. This was followed by increasing recognition of T and B cell collaboration in immune responses and identification of significant immunodeficiencies. CD4 and CD8 T cells were only recognised in the 1970s and 1980s. We now know of five CD4 subsets; dysfunction of each is associated with different disorders. By 2014, advances in technology have enabled identification of the genetic basis of over 240 primary immunodeficiencies. Research into the gut microbiome and vitamin D holds promise for the understanding, treatment and prevention of autoimmune and allergic diseases. Immunoglobulin preparations for the treatment of antibody deficiencies improved with the development of preparations for intravenous then subcutaneous administration, giving patients choice and the ability for home-based treatment, especially if experiencing infusion associated adverse effects. Newborn screening for severe combined immunodeficiency is a reality. Improvements in haemopoietic stem cell transplantation and now gene therapy, albeit still only available in the research setting, are improving long-term survival in primary immunodeficiencies. Biologic therapeutic agents are improving the control of autoimmune disease but potentially leading to secondary immunodeficiency, increasing the risk of opportunistic infection and malignancy. It is an exciting time.

Clinico-serologic co-relation in bi-directional ABO incompatible hemopoietic stem cell transplantation.

Background:The ABO blood group system is of prime significance in red cell transfusion and organ transplantation. However, ABO compatibility is not critical in allogenic hemopoietic stem cell transplantation (HSCT) and approximately 40-50% of hemopoietic stem cell transplants are ABO incompatible. This incompatibility may be major, minor or bi-directional. Though there are descriptions of transfusion practice and protocols in ABO incompatible HSCT, there are considerable variations and transfusion support in these patients can be very challenging.Aims:The immunohematologic observations in two cases of bi-directional ABO incompatible HSCT have been described, and clinico-serologic correlation has been attempted.Materials and Methods:In both cases, peripheral blood stem cell harvests were obtained using the Cobe spectra cell separator. Immunohematologic assessments in the donor and recipient were done as a part of pre HSCT evaluation. Both the standard tube technique and column agglutination method (Ortho Biovue Micro Bead System) was used. Antibody screen was done by column agglutination method using three cell panel (Surgiscreen cells). Isoagglutinin titration was done by the master dilution method and standard validated techniques were used.Results:The pattern of laboratory findings in the two cases was different and so were the clinical outcomes. Although there was early engraftment in the first case, the second case developed pure red cell aplasia and this was well-reflected in the immunohematologic assessments.Conclusion:Immunohematologic assessment correlated well with the clinical picture and could be used to predict clinical outcome and onset of complications in ABO incompatible HSCT.

A case of classic paroxysmal nocturnal hemoglobinuria

Introduction: Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hemolytic anemia characterized by a triad of intravascular hemolysis, pancytopenia and tendency for venous thrombosis. Patients with PNH present with these features which occur in various combinations as described in this case report. several episodes of intravascular hemolysis result in hemoglobinuria associated with thrombosis at unusual sites and these patients may have varying degree of bone marrow disorders. Diagnosis can be confirmed by flow cytometry of blood granulocytes and FLAEr assays. Management was supportive with transfusion and treatment of thrombosis in the past. but in the recent years the evolution of treatment strategies like hemopoietic stem cell transplantation and complement inhibition with eculizumab though very costly have been shown to be very effective. case report: Here we report a young girl who presented with abdominal pain, distension with a history of headache and jaundice. On evaluation, we found there was bicytopenia with evidence for hemolytic anemia

Management of sickle cell disease: a review for physician education in Nigeria (sub-saharan Africa).

Sickle cell disease (SCD) predominates in sub-Saharan Africa, East Mediterranean areas, Middle East, and India. Nigeria, being the most populous black nation in the world, bears its greatest burden in sub-Saharan Africa. The last few decades have witnessed remarkable scientific progress in the understanding of the complex pathophysiology of the disease. Improved clinical insights have heralded development and establishment of disease modifying interventions such as chronic blood transfusions, hydroxyurea therapy, and haemopoietic stem cell transplantation. Coupled with parallel improvements in general supportive, symptomatic, and preventive measures, current evidence reveals remarkable appreciation in quality of life among affected individuals in developed nations. Currently, in Nigeria and other West African states, treatment and control of SCD are largely suboptimal. Improved knowledge regarding SCD phenotypes and its comprehensive care among Nigerian physicians will enhance quality of care for affected persons. This paper therefore provides a review on the aetiopathogenesis, clinical manifestations, and management of SCD in Nigeria, with a focus on its local patterns and peculiarities. Established treatment guidelines as appropriate in the Nigerian setting are proffered, as well as recommendations for improving care of affected persons.

骨髄不全症候群におけるテロメア制御異常

Dyskeratosis congenita (DKC) is an inherited bone marrow failure syndrome characterized by reticulated skin pigmentation, nail dystrophy, and mucosal leukoplakia. Hoyeraal-Hreidarsson syndrome is considered to be a severe form of DKC. Unconventional forms of DKC (cryptic DKC [cDKC]), which develop slowly in adulthood without the physical anomalies characteristic of DKC, have been reported. The genes responsible for them have been identified as a gene cluster forming a telomerase complex (DKC1, TERC, TERT, NOP10, and NHP2); TINF2, which forms a shelterin complex; TCAB1, which transports the telomerase complex to intranuclear Cajal bodies; and RTEL1, which has a function of the DNA helicase. DKC is thought to occur when a mutation in these genes causes shortening of the telomere, resulting in impaired proliferation in hemopoietic stem cells and other proliferative cells, leading to the symptoms described above. The pathogenesis of DKC involves 3 important factors: 1) telomere-related gene abnormality leading to intracellular molecular biological mutation, 2) generational anticipation, and 3) aging. The mutations of TERC and TERT seen in cDKC produce a haploinsufficiency effect, but the extent of the weakening of telomerase activity is small, so that a certain level of generational anticipation and aging is thought to be required before the DKC phenotype develops. Treatment for DKC and cDKC is either by administering anabolic steroid hormones or by allogeneic hemopoietic stem cell transplant. Anabolic steroid hormones are thought to be converted to estrogen in the cell and to enhance telomerase activity through the estrogen-binding region of the TERT promoter region. So far, this treatment has been reported to be effective in approximately two-thirds of cases of DKC, but the proportion of cases in which results can be achieved is unclear. Meanwhile, allogeneic hemopoietic stem cell transplantation (Allo-HSCT) is an effective treatment for serious bone marrow failure in DKC and HHS, but due to posttransplantation lung complications and other issues, the treatment outcomes have been regarded as disappointing. In the future, with the development of conditioning regimens and supportive therapy of Allo-HSCT, this could therefore be a potentially promising therapeutic approach.

A prognostic score for acute graft-versus-host disease based on biomarkers: a multicentre study

Graft-versus-host disease (GVHD) is the major cause of non-relapse mortality after allogeneic haemopoietic stem-cell transplantation (SCT). The severity of symptoms at the onset of GVHD does not accurately define risk, and thus most patients are treated alike with high dose systemic corticosteroids. We aimed to define clinically meaningful risk strata for patients with newly diagnosed acute GVHD using plasma biomarkers. Between April 13, 2000, and May 7, 2013, we prospectively collected plasma from 492 SCT patients with newly diagnosed acute GVHD and randomly assigned (2:1) using a random number generator, conditional on the final two datasets having the same median day of onset, into training (n=328) and test (n=164) sets. We used the concentrations of three recently validated biomarkers (TNFR1, ST2, and Reg3α) to create an algorithm that computed the probability of non-relapse mortality 6 months after GVHD onset for individual patients in the training set alone. We rank ordered the probabilities and identified thresholds that created three distinct non-relapse mortality scores. We evaluated the algorithm in the test set, and again in an independent validation set of an additional 300 patients who underwent stem cell transplant and were enrolled on multicentre clinical trials of primary therapy for acute GVHD. In all three datasets (training, test, and validation), the cumulative incidence of 6-month non-relapse mortality significantly increased as the Ann Arbor GVHD score increased. In the multicentre validation set, scores were 8% (95% CI 3-16) for score 1, 27% (20-34) for score 2, and 46% (33-58) for score 3 (p<0·0001). Conversely, the response to primary GVHD treatment within 28 days decreased as the GVHD score increased 86% for score 1, 67% for score 2, and 46% for score 3 in the multicentre validation set, p<0·0001). Biomarker-based scores can be used to guide risk-adapted therapy at the onset of acute GVHD. High risk patients with a score of 3 are candidates for intensive primary therapy, while low risk patients with a score of 1 are candidates for rapid tapers of systemic steroid therapy. The National Cancer Institute, the National Heart, Lung, and Blood Institute, the National Institute of Allergy and Infectious Diseases, the Doris Duke Charitable Fund, the American Cancer Society, and the Judith Devries Fund.

Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study

Adults with relapsed or refractory B-precursor acute lymphoblastic leukaemia have an unfavourable prognosis. Blinatumomab is a bispecific T-cell engager antibody construct targeting CD19, an antigen consistently expressed on B-lineage acute lymphoblastic leukaemia cells. We aimed to confirm the activity and safety profile of blinatumomab for acute lymphoblastic leukaemia. In a multicentre, single-arm, open-label phase 2 study, we enrolled adult patients with Philadelphia-chromosome-negative, primary refractory or relapsed (first relapse within 12 months of first remission, relapse within 12 months after allogeneic haemopoietic stem-cell transplantation [HSCT], or no response to or relapse after first salvage therapy or beyond) leukaemia. Patients received blinatumomab (9 μg/day for the first 7 days and 28 μg/day thereafter) by continuous intravenous infusion over 4 weeks every 6 weeks (up to five cycles), per protocol. The primary endpoint was complete remission (CR) or CR with partial haematological recovery of peripheral blood counts (CRh) within the first two cycles. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, number NCT01466179. Between Jan 13, 2012, and Oct 10, 2013, 189 patients were enrolled and treated with blinatumomab. After two cycles, 81 (43%, 95% CI 36-50) patients had achieved a CR or CRh: 63 (33%) patients had a CR and 18 (10%) patients had a CRh. 32 (40%) of patients who achieved CR/CRh underwent subsequent allogeneic HSCT. The most frequent grade 3 or worse adverse events were febrile neutropenia (48 patients, 25%), neutropenia (30 patients, 16%), and anaemia (27 patients, 14%). Three (2%) patients had grade 3 cytokine release syndrome. Neurologic events of worst grade 3 or 4 occurred in 20 (11%) and four (2%) patients, respectively. Three deaths (due to sepsis, Escherichia coli sepsis, and Candida infection) were thought to be treatment-related by the investigators. Single-agent blinatumomab showed antileukaemia activity in adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia characterised by negative prognostic factors. Further assessment of blinatumomab treatment earlier in the course of the disease and in combination with other treatment approaches is warranted. Amgen.