Wilms tumor gene peptide-based immunotherapy for patients with overt leukemia from myelodysplastic syndrome (MDS) or MDS with myelofibrosis

The Wilms tumor gene, WT1, is overexpressed not only in leukemias and myelodysplastic syndrome (MDS) but also in various types of solid tumors, including lung and breast cancer, and the WT1 protein is a tumor antigen for these malignancies. In clinical trials of WT1 peptide-based cancer immunotherapy, patients with overt leukemia from MDS or MDS with myelofibrosis were injected intradermally with 0.3 mg of an HLA-A*2402-restricted, 9-mer WT1 peptide emulsified with Montanide ISA51 adjuvant. Only a single dose of WT1 vaccination resulted in an increase in WT1-specific cytotoxic T-lymphocytes, which was followed by a rapid reduction in leukemic blast cells. Severe leukopenia and local erythema at the injection sites of WT1 peptide were observed as adverse effects. These results have provided us with the first clinical evidence suggesting that WT1 peptide-based immunotherapy is an attractive treatment for patients with leukemias or MDS.     

Cause of death and excess mortality in patients with lower-risk myelodysplastic syndromes (MDS): A report from the European MDS registry

Information on causes of death (CoDs) and the impact of myelodysplastic syndromes (MDS) on survival in patients with lower-risk MDS (LR-MDS) is limited. A better understanding of the relationship between disease characteristics, clinical interventions and CoDs may improve outcomes of patients with LR-MDS. We prospectively collected data on patients with LR-MDS in the European MDS registry from 2008 to 2019. Clinical, laboratory and CoDs data were obtained. To examine MDS-specific survival, relative survival (RS) was estimated using national life tables. Of 2396 evaluated subjects, 900 died (median overall survival [OS]: 4.7 years; median follow-up: 3.5 years). The most common CoDs were acute myeloid leukaemia/MDS (20.1%), infection (17.8%) and cardiovascular disease (CVD; 9.8%). Patients with isolated del(5q) and with red cell transfusion needed during the disease course, had a higher risk of fatal CVD. The 5-year OS was 47.3% and the 5-year RS was 59.6%, indicating that most patients died due to their underlying MDS. Older patients (aged >80 years) and the lowest-risk patients were more likely to die from competing causes. This study shows that MDS and its related complications play crucial role in the outcome of patients with LR-MDS.     

Individual outcome prediction for myelodysplastic syndrome (MDS) and secondary acute myeloid leukemia from MDS after allogeneic hematopoietic cell transplantation

We integrated molecular data with available prognostic factors in patients undergoing allogeneic hematopoietic cell transplantation (alloHCT) for myelodysplastic syndrome (MDS) or secondary acute myeloid leukemia (sAML) from MDS to evaluate their impact on prognosis. Three hundred four patients were sequenced for mutations in 54 genes. We used a Cox multivariate model and competing risk analysis with internal and cross validation to identify factors prognostic of overall survival (OS), cumulative incidence of relapse (CIR), and non-relapse mortality (NRM). In multivariate analysis, mutated NRAS, U2AF1, IDH2, and TP53 and/or a complex karyotype were significant prognostic markers for OS besides age above 60 years, remission status, IPSS-R cytogenetic risk, HCT-CI > 2 and female donor sex. Mutated NRAS, IDH1, EZH2, and TP53 and/or a complex karyotype were genetic aberrations with prognostic impact on CIR. No molecular markers were associated with the risk of NRM. The inclusion of molecular information results in better risk prediction models for OS and CIR when assessed by the Akaike information criterion. Internal cross validation confirmed the robustness of our comprehensive risk model. In summary, we propose to combine molecular, cytogenetic, and patient- and transplantation-associated risk factors into a comprehensive risk model to provide personalized predictions of outcome after alloHCT.     

Extended cytogenetic follow-up of patients with myelodysplastic syndrome (MDS)

The prognostic significance of clonal karyotype status in myelodysplastic syndrome (MDS) is assessed after an extended follow-up period of 5 years. There are three karyotype, single abnormalities or multiple abnormalities at the time of referral. However, there is no correlation between the size of the abnormal clone and prognosis. Karyotype status has independent prognostic significance in 'high risk' MDS so that patients with a refractory anaemia with excess of blasts (RAEB)/RAEB in transformation (RAEB-t) and a normal karyotype survive significantly longer than those with an abnormal karyotype (P < 0.001) and do not differ significantly from patients with refractory anaemia (RA). Significant differences in survival according to karyotype status are also seen in patients with chronic myelomonocytic leukaemia (P < 0.001) but not in those with primary acquired sideroblastic anaemia and RA. Among patients studied sequentially, those who retained a normal karyotype survived significantly longer than those who developed an abnormality on follow-up (P < 0.001). The risk of leukaemic transformation was also increased in patients who presented with or subsequently developed a clonal karyotype abnormality compared with those who remained normal (P < 0.05).     

Cytogenetic studies in 69 patients with myelodysplastic syndromes (MDS)

Cytogenetic studies were performed in 69 patients with myelodysplastic syndromes classified according to the FAB proposals. Overall incidence of chromosomal anomalies was 48% with 5q-, +8, 12p-,-7/7q- being the aberrations most often found. The 12p- chromosome showed a close correlation with a prior exposure to mutagenic agents and CMML. Although there were no group-specific cytogenetic anomalies, FAB classification strongly influenced their incidence. They were lower (36%) in RA/RA-S than in RAEB/RAEB-T/CMML (53%). Chromosomal anomalies were significantly more often found in patients with a prior exposure to carcinogenic agents (80%) than in unexposed patients (33%). The presence of chromosomal anomalies did not predict a higher risk of leukemic transformation.     

Exisulind induces apoptosis in advanced myelodysplastic syndrome (MDS) and acute myeloid leukaemia/MDS

The influence of Exisulind on the viability and apoptosis of CD34(+) stem cells from patients with advanced myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML)/MDS was investigated. In eight out of 10 patient samples Exisulind reduced the fraction of viable cells by inducing apoptosis. We found evidence that Exisulind-mediated apoptosis depends on c-Jun NH(2)-terminal kinase (JNK) activation. Addition of a specific JNK-inhibitor to Exisulind-treated advanced MDS and AML/MDS cells partly abrogated apoptosis. We propose that Exisulind is tested in clinical phase I/II trials for the treatment of advanced MDS and AML/MDS.     

Efficacy and safety of CHG regimen (low-dose cytarabine,homoharringtonine with G-CSF priming) as induction chemotherapy for elderly patients with high-risk MDS or AML transformed from MDS

Background  

To evaluate the efficacy and toxicity of CHG regimen (low-dose cytarabine, homoharringtonine with G-CSF priming) as an induction chemotherapy for elderly patients with high-risk MDS or acute myeloid leukemia transformed from MDS (MDS–AML).     

Allogeneic transplantation for myelodysplastic syndrome (MDS)

Haematopoietic stem cell transplantation (HSCT) remains the only curative option for patients with myelodysplastic syndrome (MDS). Developing conditioning regimens with low toxicity, at the same time as preserving an effective graft versus tumour response, is pivotal to expanding the scope for allogeneic transplantation in older patients with MDS. With the introduction of reduced intensity conditioned regimens, transplant centres worldwide are able to offer allogeneic HSCT to a much larger cohort of patients. Graft versus host disease (GvHD) remains a significant cause of morbidity and mortality, however with the use of T-cell depletion, centres have been able to utilise volunteer unrelated donors with an increasing degree of HLA disparity. The graft versus dysplasia effect resulting from allogeneic HSCT and the infusion of donor leukocytes has led to a greater understanding of the immunological mechanisms that govern outcome following transplantation in MDS.     

Azacitidine for treatment of patients with myelodysplastic syndromes (MDS): practical recommendations of the German MDS Study Group

Myelodysplastic syndromes (MDS) are a group of common bone marrow disorders characterized by ineffective hematopoiesis, peripheral cytopenias, and a substantial risk of progression to acute myeloid leukemia (AML). For many years, the main treatment option for MDS was best supportive care which alleviates symptoms, but has no effect on the natural course of the disease. Recently, demethylating agents have become available as a promising new treatment for patients with MDS. In two randomized clinical trials, the demethylating agent azacitidine has demonstrated a reduced risk of transformation to AML, improvement of peripheral blood values, an improved quality of life, and a definite survival advantage compared to conventional care regimens for patients with International Prognostic Scoring System score of intermediate-2 or high-risk MDS. This review aims to provide practical recommendations for the use of azacitidine and the management of its side effects in patients with MDS, assuring safe administration and best efficacy of treatment.     

Legionella pneumophila community-acquired pneumonia (CAP) in a post-splenectomy patient with myelodysplastic syndrome (MDS)

Legionnaire's disease is a cause of community-acquired pneumonia (CAP) in normal hosts, but those with impaired cell-mediated immunity (CMI) and T-lymphocyte function are particularly predisposed to Legionella species CAP. Myelodysplastic syndrome (MDS) is a disorder of the elderly that is associated with impaired CMI. Cases of MDS or Legionella species CAP are rare. Splenectomized patients primarily have impaired humoral immunity and B-lymphocyte function, and, to a lesser extent, some decrease in CMI. For this reason, Legionnaire's disease has rarely been reported in splenectomized patients. We believe this to be the first reported case of Legionella pneumophila CAP in an asplenic patient with MDS.