•This ESMO Clinical Practice Guideline provides key recommendations for managing myelodysplastic syndromes.•It covers diagnosis, classification, staging and risk assessment of myelodysplastic ...syndromes.•Treatment recommendations for lower- and higher-risk myelodysplastic syndromes are also provided.•All recommendations were compiled by a multidisciplinary group of experts.•Recommendations are based on available scientific data and the authors' expert opinions.
Attempts to optimize outcomes in cord blood transplantation (CBT) by using new conditioning regimens and standardization of cord blood unit selection are warranted. In all, 88 patients (18 children ...and 70 adults) with hematological malignancy from nine Spanish institutions underwent a single-unit CBT after an i.v. BU-based myeloablative conditioning regimen. All evaluable patients except one engrafted. The overall cumulative incidence (CI) of myeloid engraftment was 94% at a median time of 19 days. In multivariate analysis, nonadvanced disease stage was the only factor with a favorable impact on myeloid engraftment. The CI of acute GVHD grades II-IV and chronic extensive GVHD were 24% each. The CI of nonrelapse mortality at 100 days, 180 days and 5 years was 14, 23 and 44%, respectively. The 5-year CI of relapse was 18%, whereas disease-free survival (DFS) was 46%, 39% and 11% for patients transplanted in early, intermediate and advanced stages of the disease, respectively. Our study shows high rates of engraftment with fast neutrophil recovery in patients undergoing single-unit CBT using a BU-based conditioning regimen. Long-term DFS can be achieved in a substantial number of patients with high-risk hematological malignancies, particularly when transplanted in an early stage of the disease.
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.
We analyzed the incidence, clinicopathological features, risk factors and prognosis of patients with EBV-associated post-transplant lymphoproliferative disorder (EBV-PTLD) in 288 adults undergoing ...umbilical cord blood transplantation (UCBT) at a single institution. Twelve patients developed proven EBV-PTLD at a median time of 73 days (range, 36-812). Three-year cumulative incidence (CI) of EBV-PTLD was 4.3% (95% CI: 1.9-6.7). All patients presented with extranodal involvement. Most frequently affected sites were the liver, spleen, central nervous system (CNS), Waldeyer's ring and BM in 7, 6, 4, 3 and 3 patients, respectively. One patient had polymorphic and 11 had monomorphic EBV-PTLD (7 diffuse large B-cell lymphomas not otherwise specified, 4 plasmablastic lymphomas). We confirmed donor origin and EBV infection in all histological samples. EBV-PTLD was the cause of death in 11 patients at a median time of 23 days (range, 1-84). The 3-year CI of EBV-PTLD was 12.9% (95% CI: 3.2-22.5) and 2.6% (95% CI: 0.5-4.7) for patients receiving reduced-intensity conditioning (RIC) and myeloablative conditioning, respectively (P<0.0001). In conclusion, adults with EBV-PTLD after UCBT showed frequent visceral and CNS involvement. The prognosis was poor despite routine viral monitoring and early intervention. An increased risk of EBV-PTLD was noted among recipients of RIC regimens.
Outcomes after unmanipulated haploidentical stem cell transplantation (Haplo) and after unrelated cord blood transplantation (UCBT) are encouraging and have become alternative options to treat ...patients with high-risk acute leukemia without human leukocyte antigen (HLA) matched donor. We compared outcomes after UCBT and Haplo in adults with de novo acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Median follow-up was 24 months. Analysis was performed separately for patients with AML, n=918 (Haplo=360, UCBT=558) and ALL, n=528 (Haplo=158 and UCBT=370). UCBT was associated with delayed engraftment and higher graft failure in both AML and ALL recipients. In multivariate analysis, UCBT was associated with lower incidence of chronic graft-vs-host disease both in the AML group (hazard ratio (HR)=0.63, P=0.008) and in the ALL group (HR=0.58, P=0.01). Not statistically significant differences were observed between Haplo and UCBT for relapse incidence (HR=0.95, P=0.76 for AML and HR=0.82, P=0.31 for ALL), non-relapse mortality (HR=1.16, P=0.47 for AML and HR=1.23, P=0.23 for ALL) and leukemia-free survival (HR 0.78, P=0.78 for AML and HR=1.00, P=0.84 for ALL). There were no statistically differences on main outcomes after unmanipulated Haplo and UCBT, and both approaches are valid for acute leukemia patients lacking a HLA matched donor. Both strategies expand the donor pool for patients in need.
We describe incidence, clinical features, serological data, response to therapy and outcome of autoimmune cytopenias (ACs), including autoimmune hemolytic anemia (AIHA) and autoimmune ...thrombocytopenia (AIT) in a series of 281 consecutive adults with hematological malignancies that received single-unit umbilical cord blood transplantation (UCBT) at a single institution. AIHA was diagnosed in 15 patients at a median time of 181 days (range, 25-543), 12 of them had cold antibodies (IgM). The 3-year cumulative incidence (CI) of AIHA was 5.4% (CI 95% 2.7-8.1). Concomitant infections at the time of AIHA were present in 10 patients. Five out of nine patients that received corticosteroids achieved either a PR or a CR, whereas six out of eight patients that received rituximab responded. Four patients developed AIT giving a 3-year CI of 1.4% (CI 95% 0-2.8), concomitant infections were present in three of them. Multivariable analysis showed that development of chronic GVHD (relative risk (RR) 4; 95% CI 1.1-13.7; P=0.03) and diagnosis of CML (RR 4.3; 95% CI 1.5-12.7; P=0.008) were associated with an increased risk of AC. In conclusion, AIHA and AIT are relevant and clinically significant complications in UCBT recipients, especially among those that develop chronic GVHD. Response to therapy is sub-optimal, and rituximab should be considered as a therapeutic option, in this setting were most patients had cold AIHA and a serological profile similar to that seen in cold agglutinin disease.
Studies that analyze the epidemiology and risk factors for invasive fungal disease (IFD) after engraftment in alloSCT are few in number. This single-center retrospective study included 404 alloSCT ...adult recipients surviving >40 days who engrafted and were discharged without prior IFD. All patients who received ⩾20 mg/day of prednisone were assigned to primary oral prophylaxis (itraconazole or low-dose voriconazole). The primary end point was the cumulative incidence (CI) of probable/proven IFD using the European Organization for Research and Treatment of Cancer and Mycoses Study Group (EORTC/MSG) criteria. The independent prognostic factors after multivariate analyses were used to construct a post-engraftment IFD risk score. The 1-year CI of IFD was 11%. The non-relapse mortality was 40% in those developing IFD and 16% in those who did not. The intent-to-treat analysis showed that 17% of patients abandoned the assigned prophylaxis. Age >40 years, ⩾1 previous SCT, pre-engraftment neutropenia >15 days, extensive chronic GVHD and CMV reactivation were independent risk factors. The post-engraftment IFD score stratified patients into low risk (0-1 factor, CI 0.7%), intermediate risk (2 factors, CI 9.9%) and high risk (3-5 factors, CI 24.7%) (P<0.0001). The antifungal prophylaxis strategy failed to prevent post-engraftment IFD in 11% of alloSCT. Our risk score could be useful to implement risk-adapted strategies using antifungal prophylaxis after engraftment.
Pneumonia in foals caused by the bacterium Rhodococcus equi has a worldwide distribution and is a common cause of disease and death for foals. The purpose of this narrative review was to summarise ...recent developments pertaining to the epidemiology, immune responses, treatment, and prevention of rhodococcal pneumonia of foals. Screening tests have been used to implement earlier detection and treatment of foals with presumed subclinical R. equi pneumonia to reduce mortality and severity of disease. Unfortunately, this practice has been linked to the emergence of antimicrobial‐resistant R. equi in North America. Correlates of protective immunity for R. equi infections of foals remain elusive, but recent evidence indicates that innate immune responses are important both for mediating killing and orchestrating adaptive immune responses. A macrolide antimicrobial in combination with rifampin remains the recommended treatment for foals with R. equi pneumonia. Great need exists to identify which antimicrobial combination is most effective for treating foals with R. equi pneumonia and to limit emergence of antimicrobial‐resistant strains. In the absence of an effective vaccine against R. equi, passive immunisation remains the only commercially available method for effectively reducing the incidence of R. equi pneumonia. Because passive immunisation is expensive, labour‐intensive and carries risks for foals, great need exists to develop alternative approaches for passive and active immunisation.
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