Christian Steidl

New insights into the prognostic impact of the karyotype in MDS and correlation with subtypes: evidence from a core dataset of 2124 patients

We have generated a large, unique database that includes morphologic, clinical, cytogenetic, and follow-up data from 2124 patients with myelodysplastic syndromes (MDSs) at 4 institutions in Austria and 4 in Germany. Cytogenetic analyses were successfully performed in 2072 (97.6%) patients, revealing clonal abnormalities in 1084 (52.3%) patients. Numeric and structural chromosomal abnormalities were documented for each patient and subdivided further according to the number of additional abnormalities. Thus, 684 different cytogenetic categories were identified. The impact of the karyotype on the natural course of the disease was studied in 1286 patients treated with supportive care only. Median survival was 53.4 months for patients with normal karyotypes (n = 612) and 8.7 months for those with complex anomalies (n = 166). A total of 13 rare abnormalities were identified with good (+1/+1q, t(1q), t(7q), del(9q), del(12p), chromosome 15 anomalies, t(17q), monosomy 21, trisomy 21, and -X), intermediate (del(11q), chromosome 19 anomalies), or poor (t(5q)) prognostic impact, respectively. The prognostic relevance of additional abnormalities varied considerably depending on the chromosomes affected. For all World Health Organization (WHO) and French-American-British (FAB) classification system subtypes, the karyotype provided additional prognostic information. Our analyses offer new insights into the prognostic significance of rare chromosomal abnormalities and specific karyotypic combinations in MDS.

Results of a phase 2 study of valproic acid alone or in combination with all-trans retinoic acid in 75 patients with myelodysplastic syndrome and relapsed or refractory acute myeloid leukemia

Valproic acid (VPA) inhibits histone deacetylase activity and induces differentiation of acute myeloid leukemia (AML) blasts in vitro. We observed clinical responses to VPA in patients with myelodysplastic syndrome (MDS) and AML. Here, we report follow-up data on 75 patients. Of these, 66 were started on VPA monotherapy, with later addition of all-trans retinoic acid (ATRA) in patients who did not respond or relapsed. Nine patients were treated with VPA + ATRA from the start. Median treatment duration was 4 months for VPA and 2 months for ATRA. Hematological improvement, according to international working group criteria for MDS, was observed in 18 patients (24%). Median response duration was 4 months. ATRA exerted no additional effect in patients receiving the combination from the start or benefited primary VPA nonresponders. However, of ten VPA responders who relapsed, four achieved a second response after addition of ATRA. Response rates were strongly dependent on disease type according to WHO classification. We found a response rate of 52% in MDS patients with a normal blast count (refractory sideroblastic anemia, refractory cytopenia with multilineage dysplasia, and refractory sideroblastic cytopenia with multilineage dysplasia). The response rate was 6% in refractory anemia with excess blasts (I + II), 16% in AML, and 0% in chronic myelomonocytic leukemia. Bone marrow blast count was the only variable that predicted responses. We conclude that VPA is clinically useful in low-risk MDS. For patients with high-risk MDS, VPA may be combined with chemotherapy or demethylating drugs. If patients relapse after an initial response to VPA, ATRA has the potential to induce a prolonged second response.

Distinct gene expression pattern of malignant hematopoietic stem and progenitor cells in polycythemia vera

Abstract: Polycythemia vera (PV) is a chronic myeloproliferative disorder with an expansion of multipotent hematopoietic progenitor cells. Although it is known that hematopoietic progenitors in PV are erythropoietin independent and hypersensitive to several cytokines, the molecular oncogenic mechanisms in PV are largely unknown. In this study, we examined gene expression profiles of CD34+ cells from bone marrow of patients with de novo PV and from healthy volunteers to identify molecular changes associated with the malignant growth of hematopoietic stem and progenitor cells in this myeloproliferative disorder. Using cDNA arrays, we found significant differences (P < .01) in the expression of 107 genes. Proapoptotic genes (CASP2, CASP3, DAPK1, ALG2) were expressed at lower levels in PV‐CD34+ cells, reflecting a lower apoptotic activity. Fibrosis‐stimulating growth factors (transforming growth factor β1, transforming growth factor β2, bone morphogenetic protein 2, and endothelial growth factor) were expressed at significantly higher levels in PV‐CD34+ cells. Furthermore, PV‐CD34+ cells overexpressed several receptors, protein kinases, and proteasome subunits, which might be targets for directed therapeutic approaches. It is interesting that three retinoid receptors were overexpressed in PV‐CD34+ cells—retinoic acid receptor β (RARβ), retinoid X receptor β (RXRβ), and cellular retinoic acid binding protein 2 (CRABP2). Using methylcellulose colony‐forming assays, we found that the formation of erythroid colonies derived from PV hematopoietic progenitors was inhibited by all‐trans‐retinoic acid (ATRA), a natural ligand of those receptors, in a dose‐dependent manner, showing a maximum inhibition of 89% at 10 μM; the growth of myelomonocytic colonies was not significantly affected. These data suggest that the use of ATRA could be of therapeutic benefit for patients with PV.

Cytogenetics of MDS

Cytogenetic aberrations are major markers in pathogenesis, diagnosis, and prognosis of patients with myelodysplastic syndromes (MDS). Their relevance for an individualized therapy in selected patients with MDS is increasing. Using conventional chromosomal banding analysis, aberrations are detectable in about 50% of patients. The application of additional methods like fluorescence in situ hybridization (FISH)-techniques improves the detection rate and diagnostic accuracy. In spite of the cytogenetic heterogeneity of MDS patients, the prognostic impact of the most frequent chromosomal changes is known and the understanding of rare abnormalities, independent clones, and double and complex aberrations is increasing. Future research will also focus on karyotype evolution, as it could give notice of disease progression and thus affect therapy decisions. International cooperations facilitate to unravel the remaining challenges for cytogenetics in MDS.