Thorsten Graef

Cyclosporine A and Mycophenolate Mofetil vs Cyclosporine A and Methotrexate for graft-versus-host disease prophylaxis after stem cell transplantation from HLA-identical siblings

Summary:The combination of Cyclosporin A (CSA) and Methotrexate (MTX) is considered to be the standard regimen for the prevention of graft-versus-host disease (GVHD) after stem cell transplantation (SCT) from HLA-identical siblings. Mycophenolate Mofetil (MMF) has been widely used for GVHD prophylaxis after nonmyeloablative SCT, but experience following myeloablative therapy is still limited. We retrospectively compared CSA/MTX and CSA/MMF in 93 patients (median age 35 years, range 17–59 years, male subjects 48, female subjects 45) with acute myeloid leukemia (n=33), myelodysplastic syndrome (MDS) (n=3), acute lymphoblastic leukemia (ALL) (n=20) or chronic myeloid leukemia (n=37) who received CSA/MMF (n=26) or CSA/MTX (n=67) as GVHD prophylaxis following high-dose therapy and allogeneic SCT from HLA-identical siblings. No statistically significant differences were found in overall survival, relapse rate, treatment-related mortality and acute or chronic GVHD. Time to myeloid recovery was significantly shorter in patients who received CSA/MMF. We conclude that the combination of CSA/MMF appears equivalent to CSA/MTX for GVHD prophylaxis in patients receiving conventional-intensity SCT from HLA-identical siblings.

Single-agent thalidomide for treatment of first relapse following high-dose chemotherapy in patients with multiple myeloma.

Single-agent thalidomide for treatment of first relapse following high-dose chemotherapy in patients with multiple myeloma

Transplantation of allogeneic CD34+-selected cells followed by early T-cell add-backs: favorable results in acute and chronic myeloid leukemia.

BACKGROUND The aim of this study was to investigate preservation of anti-leukemic activity and protection from opportunistic infections after transplantation of allogeneic + cells in patients with hematologic malignancies and bad prognosis. Methods Thirty-three patients [median age 42 years, range 23-55 years, diagnosis AML/myelodysplastic syndrome (MDS) 14, ALL nine, CML seven and multiple myeloma (MM) three] received myeloablative conditioning followed by infusion of selected CD34+ cells from matched unrelated donors (31) or HLA-identical siblings (two). Early donor lymphocyte infusions (DLI; 0.5 and 1.0 x 10(6) CD3+ cells/kg) were given while patients were on immunosuppressive therapy. RESULTS Ninety-seven per cent of patients engrafted and 24 of 29 patients surviving more than 30 days received at least one pre-emptive DLI. Three patients (10%) developed acute (a)GvHD (two grade I-II, one grade III-IV) spontaneously, and 16 patients (67%) developed aGvHD after DLI (12 grade I-II, four grade III-IV). Eight of 24 evaluable patients developed chronic (c)GvHD (33%, six limited, two extensive). After a median follow-up of 590 days (range 138-1610 days) 18 patients were alive (55%), 16 in complete remission (CR), one in hematologic and one in molecular relapse. Seven patients died after relapse (21%) and eight died from transplantation-related causes (24%). Patients with myeloid malignancies had a significantly better survival than patients with ALL or MM (74%+/-10 vs. 30%+/-13, P<0.05). DISCUSSION Early pre-emptive low-dose DLI following transplantation of selected CD34+ cells from unrelated donors after myeloablative conditioning is feasible and effective without undue toxicity, especially in patients with myeloid malignancies.

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.