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There is an increasing interest on the effectiveness of azacitidine for the treatment of higher-risk myelodysplastic syndromes (MDS) outside clinical trials. We recently reported the lack of effect of this drug in an unselected population of 821 patients.1 In response to our work, Dinmohamed et al.2 have performed a similar retrospective analysis of a cohort including 121 patients with higher-risk MDS included in the Dutch registry and treated with either chemotherapy, azacitidine or best supportive care (BSC). Both studies are aimed to analyze the potential effect of the different treatment alternatives on overall survival (OS) in large population-based registries of higher-risk MDS patients. A common finding in both series is the lack of a survival advantage of azacitidine compared with intensive chemotherapy.

This cooperative study assessed prognostic factors for overall survival (OS) and risk of transformation to acute myeloid leukemia (AML) in 541 patients with de novo myelodysplastic syndrome (MDS) and deletion 5q. Additional chromosomal abnormalities were strongly related to different patients' characteristics. In multivariate analysis, the most important predictors of both OS and AML transformation risk were number of chromosomal abnormalities (P

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=94) or acute lymphoblastic leukemia (n=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=21) or mismatched (n=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=0.09 and P=0.13, respectively). Sixty-nine donor–patient pairs were HLA-A, -B or -C KIR-ligand incompatible and 149 compatible. KIR-ligand-incompatible UCBT showed improved LFS (hazards ratio=2.05, P=0.0016) and overall survival (OS) (hazards ratio=2.0, P=0.004) and decreased RI (hazards ratio=0.53, P=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=0.012), and 5 versus 36% (P=0.005), respectively). UCBT for acute leukemia in CR from KIR-ligand-incompatible donors is associated with decreased RI and improved LFS and OS. Supplementary information The online version of this article (doi:10.1038/leu.2008.365) contains supplementary material, which is available to authorized users.

The benefit of azacitidine treatment in survival of high risk myelodysplastic syndromes (MDS) patients compared to conventional care treatment (CCT) has not been established outside clinical trials. To assess its effectiveness, we compared overall survival between azacitidine and conventional treatment (CCT) in high-risk MDS patients, excluding those undergoing stem cell transplantation, submitted to the Spanish MDS registry from 2000 to 2013. Several Cox regression and competing risk models, considering azacitidine as a time-dependent covariate, were used to assess survival and AML progression. Among 821 patients included, 251 received azacitidine. Median survival was 13.4 (11.8–16) months for azacitidine-treated patients and 12.2 (11–14.1) for patients under CCT (P=0.41). In a multivariate model, age, IPSS and LDH were predictors of OS whereas azacitidine was not (adjusted odds ratio 1.08, 95% confidence interval 0.86–1.35, P=0.49). However, in patients with chromosome 7 abnormalities, a trend towards a better survival was observed in azacitidine-treated patients (median survival 13.3 [11–18] months) compared to CCT (median survival 8.6 [5–10.4] months, P=0.08). In conclusion, our data show that, in spite of a widespread use of azacitidine, there is a lack of improvement in survival over the years. Identification of predicting factors of response and survival is mandatory., Bernal, T., Martínez-Camblor, P., Sánchez-García, J., De Paz, R., Luño, E., Nomdedeu, B., Ardanaz, M.T., Pedro, C., Amigo, M.L., Xicoy, B., Del Cañizo, C., Tormo, M., Bargay, J., Valcárcel, D., Brunet, S., Benlloch, L., Sanz, G., On behalf of The Spanish Group on Myelodysplastic Syndromes and PETHEMA Foundation, Spanish Society of Hematology

We report outcomes after single (s) and double (d) umbilical cord blood transplantation (UCBT) after myeloablative conditioning (MAC) regimen for 239 patients transplanted for acute leukemia in first complete remission (CR1). All sUCBT patients received a total nucleated cell dose >2.5 x 10(7)/kg. Conditioning regimen for sUCBT was total body irradiation (TBI) 12 Gy-or busulfan (BU)based +/- fludarabine (Flu) (n = 68, group 1), thiotepa + BU + Flu (TBF) (n = 88, group 2), and for dUCBT it was TBI12 Gycyclophosphamide +/- Flu (n = 83, group 3). dUCBT recipients were younger, received higher cell dose and less frequently antithymocyte globulin. In multivariate analysis, we found similar neutrophil recovery among the three groups; however, acute graft-versus-host disease II-IV was higher in dUCBT compared with others. Non-relapse mortality and relapse incidence were not statistically different among the three groups. Leukemia-free survival was 30% for sUCBT using TBI-or BU-based MAC compared with 48% for sUCBT TBF and 48% for dUCBT (P = 0.02 and P = 0.03, respectively), and it was not statistically different between sUCBT with TBF and dUCBT. In conclusion, use of sUCBT with adequate cell dose (42.5 +/- 107/kg) and a specific conditioning regimen in the MAC setting results in similar outcomes as dUCBT. The choice of TBF conditioning regimen for sUCBT may improve results, and whether this regimen may be effective in dUCBT should be further analyzed.

Activation of the Wnt signaling pathway has been implicated recently in the pathogenesis of leukemia. We studied the function of epigenetic regulation of the Wnt pathway and its prognostic relevance in acute myelogenous leukemia (AML). We used a methylation-specific polymerase chain reaction approach to analyze the promoter methylation status of a panel of Wnt antagonists including sFRP1, sFRP2, sFRP4, sFRP5, DKK1 and DKK3. Aberrant methylation of Wnt antagonists was detected in four AML cell lines and in up to 64% of AML marrow samples. Treatment of the cell lines with 5-aza-2'-deoxycytidine induced reexpression of methylated Wnt antagonists and inactivation of the Wnt pathway by downregulating the Wnt pathway genes cyclin D1, TCF1 and LEF1 and reducing nuclear localization of beta-catenin. In a subgroup of patients 60 years and younger with newly diagnosed AML and intermediate-risk cytogenetics, abnormal methylation of Wnt antagonists was associated with decreased 4-year relapse-free survival (28 vs 61%, respectively, P=0.03). Our results indicate a function of the epigenetic regulation of the Wnt pathway in predicting relapse in a subgroup of AML patients.

Predicting survival for myeloid leukemia after HLA-identical sibling donor allogeneic stem cell transplantation

Umbilical cord blood (UCB) has emerged as an appealing alternative source of hematopoietic stem cells for unrelated donor transplantation. Shorter time to transplant and an improved chance of finding a suitable graft are evident advantages over bone marrow transplantation from unrelated donors. The majority of UCB transplants from unrelated donors have been performed in children, but the number in adults has been growing steadily in recent years. We review herein the reported experience with that source of hematopoietic stem cells in adults with hematological malignancies. The available data support the use of UCB transplantation from unrelated donors for young adults with hematological malignancies and no appropriate bone marrow donor, especially for those requiring urgent transplantation.

In the majority of patients the distinction between myelodysplastic syndromes (MDSs) and chronic myeloprololiferative disorders is made relatively easily by assessment of clinical, laboratory and morphological characteristics of the peripheral blood and bone marrow. However, the existence of uni- or mulitlineage dysplasia and hyperplastic myelopoiesis in the same patient is well recognized and classified by the World Health Organization (WHO) as myelodysplastic/myeloproliferative disease, unclassifiable.1 Within this group is a provisional entry referred to as refractory anaemia with ringed sideroblasts associated with marked thrombocytosis (platelets >600 109/l) (RARS-T).1