Donor killer cell immunoglobulin-like receptor (KIR)-ligand incompatibility is associated with decreased relapse incidence (RI) and improved leukemia-free survival (LFS) after haploidentical and HLA-mismatched unrelated hematopoietic stem cell transplantation. We assessed outcomes of 218 patients with acute myeloid leukemia (AML n ¼ 94) or acute lymphoblastic leukemia (n ¼ 124) in complete remission (CR) who had received a single-unit unrelated cord blood transplant (UCBT) from a KIR-ligand-compatible or -incompatible donor. Grafts were HLA-A, -B or -DRB1 matched (n ¼ 21) or mismatched (n ¼ 197). Patients and donors were categorized according to their degree of KIR-ligand compatibility in the graft-versus-host direction by determining whether or not they expressed HLA-C group 1 or 2, HLA-Bw4 or HLA-A3/-A11. Both HLA-C/-B KIR-ligand-and HLA-A-A3/-A11 KIR-ligand-incompatible UCBT showed a trend to improved LFS (P ¼ 0.09 and P ¼ 0.13, respectively). Sixty-nine donor-patient pairs were HLA-A, -B or -C KIR-ligand incompatible and 149 compatible. KIR-ligandincompatible UCBT showed improved LFS (hazards ratio ¼ 2.05, P ¼ 0.0016) and overall survival (OS) (hazards ratio ¼ 2.0, P ¼ 0.004) and decreased RI (hazards ratio ¼ 0.53, P ¼ 0.05). These results were more evident for AML transplant recipients (2-year LFS and RI with or without KIR-ligand incompatibility 73 versus 38% (P ¼ 0.012), and 5 versus 36% (P ¼ 0.005), respectively). UCBT for acute leukemia in CR from KIR-ligandincompatible donors is associated with decreased RI and improved LFS and OS.

UCBT is a viable treatment for adults with advanced lymphoid malignancies. Chemosensitive disease, use of low-dose TBI, and higher cell dose were factors associated with significantly better outcome.

The online version of this article has a Supplementary Appendix. BackgroundParoxysmal nocturnal hemoglobinuria (PNH) is associated with an increased risk of thrombosis through unknown mechanisms. Design and MethodsWe studied 23 patients with PNH, before and after five and 11 weeks of treatment with eculizumab. We examined markers of thrombin generation and reactional fibrinolysis (prothrombin fragment 1+2 (F1+2), D-dimers, and plasmin antiplasmin complexes (P-AP), and endothelial dysfunction tissue plasminogen activator (t-PA), plasminogen activator inhibitor (PAI-1), soluble thrombomodulin (sTM), intercellular adhesion molecule 1 (sICAM-1), vascular cell adhesion molecule (sVCAM-1), endothelial microparticles (EMPs), and tissue factor pathway inhibitor (TFPI). ResultsAt baseline, vWF, sVCAM-1, the EMP count, and F1+2 and D-dimer levels were significantly elevated in the patients, including those with no history of clinical thrombosis. Treatment with eculizumab was associated with significant decreases in plasma markers of coagulation activation (F1+2, P=0.012, and D-dimers, P=0.01), and reactional fibrinolysis (P-AP, P=0.0002). Eculizumab treatment also significantly reduced plasma markers of endothelial cell activation (t-PA, P=0.0005, sVCAM-1, P<0.0001, and vWF, P=0.0047) and total (P=0.0008) and free (P=0.0013) TFPI plasma levels. ConclusionsOur results suggest a new understanding of the contribution of endothelial cell activation to the pathogenesis of thrombosis in PNH. The terminal complement inhibitor, eculizumab, induced a significant and sustained decrease in the activation of both the plasma hemostatic system and the vascular endothelium, likely contributing to the protective effect of eculizumab on thrombosis in this setting.Key words: paroxysmal nocturnal hemoglobinuria, thrombosis, eculizumab. hemoglobinuria receiving eculizumab. Haematologica. 2010;95:574-581. doi:10.3324/haematol.2009 This is an open-access paper. Citation: Helley D, Peffault de Latour R, Porcher R, Rodrigues CA, Galy-Fauroux I, Matheron J, Duval A, Schved J-F, Fischer A-M, and Socié G on behalf of the French Society of Hematology. Evaluation of hemostasis and endothelial function in patients with paroxysmal nocturnal Evaluation of hemostasis and endothelial function in patients with paroxysmal nocturnal hemoglobinuria receiving eculizumab

The availability of living donors allows transplant teams to indicate living donor liver transplantation (LDLT) early in the course of liver disease before the occurrence of life-threatening complications. Late referral to transplant centers is still a problem and can compromise the success of the procedure. The aim of this study was to examine the perioperative factors associated with patient and graft survival for 430 consecutive pediatric LDLT procedures at Sirio-Libanes Hospital/A. C. Camargo Hospital (Sã o Paulo, Brazil) between October 1995 and April 2011. The studied pretransplant variables included the following: recipient age and body weight, Pediatric End-Stage Liver Disease score, z score for height/age, bilirubin, albumin, international normalized ratio, hemoglobin, sodium, presence of ascites, and previous surgery. The analyzed technical aspects included the graft-to-recipient weight ratio and the use of vascular grafts for portal vein reconstruction. In addition, the occurrence of hepatic artery thrombosis (HAT), portal vein thrombosis (PVT), and biliary complications was also analyzed. The liver grafts included 348 left lateral segments, 5 monosegments, 51 left lobes, and 9 right lobes. In a univariate analysis, an age < 12 months, a low body weight ( 10 kg), malnutrition, hyperbilirubinemia, and HAT were associated with decreased patient and graft survival after LDLT. In a multivariate analysis, a body weight 10 kg and HAT were significantly associated with decreased patient and graft survival. The use of vascular grafts significantly increased the occurrence of PVT. In conclusion, a low body weight ( 10 kg) and the occurrence of HAT independently determined worse patient and graft survival in this large cohort of pediatric LDLT patients.

ResumoHemoglobinúria paroxística noturna (HPN) é uma anemia hemolítica crônica adquirida rara, de curso clínico extremamente variável. Apresenta-se frequentemente com infecções recorrentes, neutropenia e trombocitopenia, e surge em associação com outras doenças hematológicas, especialmente com síndromes de falência medular, como anemia aplásica e síndrome mielodisplásica. É considerada ainda um tipo de trombofilia adquirida, apresentando-se com tromboses venosas variadas, com especial predileção por trombose de veias hepáticas e intra-abdominais, sua maior causa de mortalidade. A tríade anemia hemolítica, pancitopenia e trombose faz da HPN uma síndrome clínica única, que deixou de ser encarada como simples anemia hemolítica adquirida para ser considerada um defeito mutacional clonal da célula-tronco hematopoética (CTH). A mutação ocorre no gene da fosfaditilinositolglicana classe-A, e resulta no bloqueio precoce da síntese de âncoras de glicosilfosfaditilinositol (GPI), responsáveis por manter aderidas à membrana plasmática dezenas de proteínas com funções específicas. A falência em sintetizar GPI madura gera redução de todas as proteínas de superfície normalmente ancoradas por ela. Dentre elas estão o CD55 e o CD59, que controlam a ativação da cascata do complemento. Assim, na HPN há aumento da susceptibilidade de eritrócitos ao complemento, gerando hemólise. Revisa-se aqui sua fisiopatologia, curso clínico, os tratamentos disponíveis com ênfase para o transplante de células-tronco hematopoéticas alogênicas e para o eculizumab, um anticorpo monoclonal humanizado que bloqueia a ativação do complemento terminal no nível C5 e previne a formação do complexo de ataque à membrana, a primeira droga a demonstrar eficácia no tratamento da HPN. uniterMoS: Resultado de tratamento. Hemoglobinúria paroxística. Revisão. Sintomas clínicos.

Venous thromboembolism (VTE) is a serious and potentially fatal disorder, which is often associated with a significant impact on the quality of life and on the clinical outcome of cancer patients. The pathophysiology of the association between thrombosis and cancer is complex: malignancy is associated with a baseline hypercoagulable state due to many factors including release of inflammatory cytokines, activation of the clotting system, expression of hemostatic proteins on tumor cells, inhibition of natural anticoagulants, and impaired fibrinolysis. Several risk factors, related to the patient, the disease, and the therapeutic interventions, have been identified as contributing to the occurrence of VTE. There is convincing evidence to recommend the use of heparins or fondaparinux for prevention of VTE in selected cancer patients, and, especially in some particular types of malignancies and cancer treatments. Management of VTE in patients with cancer is more challenging and bleeding complications associated with the use of anticoagulants are significantly higher in cancer patients than in those without malignancy. Important issues that need to be considered in all cases are interference with anticancer therapy, inconvenience of treatment, and impact on quality of life.

Chronic lymphocytic leukemia is characterized by clonal proliferation and progressive accumulation of B-cell lymphocytes that typically express CD19+, CD5+ and CD23+. The lymphocytes usually infiltrate the bone marrow, peripheral blood, lymph nodes, and spleen. The diagnosis is established by immunophenotyping circulating B-lymphocytes, and prognosis is defined by two staging systems (Rai and Binet) established by physical examination and blood counts, as well as by several biological and genetic markers. In this update, we present the recommendations from the Brazilian Group of Chronic Lymphocytic Leukemia for the diagnosis and treatment of chronic lymphocytic leukemia. The following recommendations are based on an extensive literature review with the aim of contributing to more uniform patient care in Brazil and possibly in other countries with a similar social–economic profile.

We have reported encouraging results of unrelated cord blood transplantation for patients with lymphoid malignancies. Whether those outcomes are comparable to matched unrelated donor transplants remains to be defined. We studied 645 adult patients with mature lymphoid malignancies who received an allogeneic unrelated donor transplant using umbilical cord blood (n=104) or mobilized peripheral blood stem cells (n=541) after a reduced-intensity conditioning regimen. Unrelated cord blood recipients had more refractory disease. Median follow-up time was 30 months. Neutrophil engraftment (81% vs. 97%, respectively; P<0.0001) and chronic graft-versus-host disease (26% vs. 52%; P=0.0005) were less frequent after unrelated cord blood than after matched unrelated donor, whereas no differences were observed in grade II-IV acute graft-versus-host disease (29% vs. 32%), non-relapse mortality (29% vs. 28%), and relapse or progression (28% vs. 35%) at 36 months. There were also no significant differences in 2-year progression-free survival (43% vs. 58%, respectively) and overall survival (36% vs. 51%) at 36 months. In a multivariate analysis, no differences were observed in the outcomes between the two stem cell sources except for a higher risk of neutrophil engraftment (hazard ratio=2.12; P<0.0001) and chronic graft-versus-host disease (hazard ratio 2.10; P=0.0002) after matched unrelated donor transplant. In conclusion, there was no difference in final outcomes after transplantation between umbilical cord blood and matched unrelated donor transplant. Umbilical cord blood is a valuable alternative for patients with lymphoid malignancies lacking an HLA-matched donor, being associated with lower risk of chronic graft-versus-host disease.Alternative donor hematopoietic stem cell transplantation for mature lymphoid malignancies after reduced-intensity conditioning regimen: similar outcomes with umbilical cord blood and unrelated donor peripheral blood ABSTRACT © F e r r a t a S t o r t i F o u n d a t i o nand has relatively lower risk of GVHD considering the degree of HLA-mismatch, it is associated with slower hematopoietic recovery and higher risk of graft failure. 28-34We reported encouraging outcomes in 104 patients with mature lymphoid malignancies receiving an umbilical cord blood transplant (UCB) after myeloablative or RIC conditioning regimens.35 Progression-free survival (PFS) was improved in patients with chemosensitive disease, those who have received higher cell doses, or low-dose total body irradiation (TBI) in the preparative regimen.However, there are no data published so far comparing outcomes between UCB and conventional matched unrelated donor transplants (MUD) after RIC for the treatment of mature lymphoid malignancies. Thus, we report here a retrospective analysis comparing outcomes of adults with mature lymphoid malignancies who received a MUD or a UCB reported to the EBMT and Eurocord registries Methods Data collectionEurocord and EBMT databases provided data on both UCB and MUD. Centers not associated with...