Juergen Krauter

Rare occurrence of DNMT3A mutations in myelodysplastic syndromes

Gene mutations and epigenetic changes have been shown to play significant roles in the pathogenesis of myelodysplastic syndromes. Recently, mutations in DNMT3A were identified in 22.1% of patients with acute myeloid leukemia. In this study, we analyzed the frequency and clinical impact of DNMT3A mutations in a cohort of 193 patients with myelodysplastic syndromes. Mutations in DNMT3A were found in 2.6% of patients. The majority of mutations were heterozygous missense mutations affecting codon R882. Patients with DNMT3A mutations were found to have a higher rate of transformation to acute myeloid leukemia. When assessing the global methylation levels in patients with mutated versus unmutated DNMT3A and healthy controls no difference in global DNA methylation levels between the two groups was seen. Our data show that in patients with myelodysplastic syndromes, DNMT3A mutations occur at a low frequency and may be a risk factor for leukemia progression.

Cytoreductive treatment with clofarabine/ara‐C combined with reduced‐intensity conditioning and allogeneic stem cell transplantation in patients with high‐risk, relapsed, or refractory acute myeloid leukemia and advanced myelodysplastic syndrome

The combination of cytoreductive chemotherapy with reduced‐intensity conditioning (RIC) is a highly effective antileukemic therapy. Purpose of this retrospective analysis was to evaluate the antileukemic efficacy and toxicity of clofarabine‐based chemotherapy followed by RIC and allogeneic stem cell transplantation (SCT) for high‐risk, relapsed, or refractory acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS). From May 2007 until October 2009, a total of 27 patients underwent allogeneic SCT after treatment with clofarabine and ara‐C for 5 d and RIC (4 Gy TBI/cyclophosphamide/ATG). Prophylaxis of graft‐versus‐host disease (GvHD) consisted of cyclosporine and mycophenolate mofetil. Unmanipulated G‐CSF mobilized PBSC (n = 26) or bone marrow cells (n = 1) were transplanted from unrelated (n = 21) or matched related (n = 6) donors. Non‐hematological toxicities of this regimen mainly affected liver and skin and were all reversible. Seven patients relapsed within a median time of 5.7 months. The overall survival (OS) and relapse‐free survival rates were 56% and 52% at 2 yr, respectively. In this cohort of patients, cytoreduction with clofarabine/ara‐C (ClAraC) followed by RIC allogeneic SCT was well tolerated and showed good antileukemic efficacy even in patients with high‐risk AML or MDS, with engraftment and GvHD‐incidence comparable to other RIC regimens.

Elevated frequencies of leukemic myeloid and plasmacytoid dendritic cells in acute myeloid leukemia with the FLT3 internal tandem duplication

Some 30% of acute myeloid leukemia (AML) patients display an internal tandem duplication (ITD) mutation in the FMS-like tyrosine kinase 3 (FLT3) gene. FLT3-ITDs are known to drive hematopoietic stem cells towards FLT3 ligand independent growth, but the effects on dendritic cell (DC) differentiation during leukemogenesis are not clear. We compared the frequency of cells with immunophenotype of myeloid DC (mDC: Lin−, HLA-DR+, CD11c+, CD86+) and plasmacytoid DC (pDC: Lin−, HLA-DR+, CD123+, CD86+) in diagnostic samples of 47 FLT3-ITD− and 40 FLT3-ITD+ AML patients. The majority of ITD+ AML samples showed high frequencies of mDCs or pDCs, with significantly decreased HLA-DR expression compared with DCs detectable in ITD− AML samples. Interestingly, mDCs and pDCs sorted out from ITD+ AML samples contained the ITD insert revealing their leukemic origin and, upon ex vivo culture with cytokines, they acquired DC morphology. Notably, mDC/pDCs were detectable concurrently with single lineage mDCs and pDCs in all ITD+ AML (n = 11) and ITD− AML (n = 12) samples analyzed for mixed lineage DCs (Lin−, HLA-DR+, CD11c+, CD123+). ITD+ AML mDCs/pDCs could be only partially activated with CD40L and CpG for production of IFN-α, TNF-α, and IL-1α, which may affect the anti-leukemia immune surveillance in the course of disease progression.

Myelodysplastic syndrome with monosomy 7 after immunosuppressive therapy in Behçet's disease.

Only few cases of Behçets and hematological malignancies have been reported until now. We recently observed a 39-year-old female patient with Behçets disease developing a myelodysplastic syndrome (MDS) FAB subtype refractory anemia with excess of blasts in transformation [RAEB-t] with a monosomy 7 after being treated with cyclosporin A and chlorambucil for several years. This case is reported and the occurrence of hematological malignancies and Behçets disease is reviewed.

Prospective Validation of a Chronic GvHD-Specific Proteome Pattern (cGvHD-MS14) Post Allogeneic Hematopoietic Stem Cell Transplantation

P002 HLA-haploidentical allografting with high-dose posttransplant cyclophosphamide: clinical outcomes and immune-reconstitution A. Busca, E. Maffini, F. Ferrando, C. Dellacasa, R. Pulito, E. Saraci, L. Giaccone, M. Boccadoro, P. Omedè, B. Bruno Division of Hematology, Department of Molecular Biotechnology and Health Sciences, University of Torino, A.O.U. Città della Salute e della Scienza di Torino, Torino, Italy