All-trans retinoic acid in association with low dose cytosine arabinoside in the treatment of acute myeoid leukemia in elderly patients.

All-trans retinoic acid (ATRA) has shown a synergistic activity in combination with cytosine arabinoside in vitro in the treatment of acute myeloid leukaemia (AML). In this paper we report the results of treatment with low dose cytosine arabinoside (LDAC) with or without ATRA in 28 patients with acute myeloid leukaemia aged over 60 years: 14 patients received only LDAC and the other 14 LDAC + ATRA. The patients of the 2 groups showed similar clinical features: in 10 patients AML developed after a myelodysplastic form and 4 patients presented a previous malignancy. All the patients received subcutaneous (sc) LDAC (15 mg twice a day for 14 days) and in 14 patients oral ATRA (45 mg/sqm in the same days) was added to LDAC; the courses were repeated every 4 weeks from diagnosis to relapse. The treatment was well tolerated and the patients could self-administer sc LDAC and oral ATRA at home. No statistically significant differences were observed in complete remission rate (21% vs. 50%, respectively) and resistant rate (57% vs. 29%), but the patients treated with the combination of the 2 drugs had a better time to treatment failure (15 weeks vs. 30 weeks, respectively) (P = 0.045) and a longer survival (37 weeks vs. 66 weeks) (P = 0.019). Our experience, although with a low number of patients, confirms the efficacy of ATRA in combination with sc LDAC in the treatment of AML in elderly patients.

Hepatocyte growth factor favors monocyte differentiation into regulatory interleukin (IL)-10++IL-12low/neg accessory cells with dendritic-cell features.

Several hematopoietic growth factors, including interleukin-10 (IL-10) and transforming growth factor-beta1 (TGF-beta1), promote the differentiation of tolerogenic dendritic cells (DCs). Hepatocyte growth factor (HGF) is a pleiotropic cytokine whose effects on human DC differentiation and function have not been investigated. Monocytes cultured with HGF (HGFMo) differentiated into accessory cells with DC-like morphology, released low amounts of IL-12p70 and up-regulated IL-10 both at the mRNA and at the protein level. Upon activation with HGFMo, allogeneic CD4+CD25- T cells expressed the T regulatory (Treg)-associated transcription factor FoxP3, proliferated poorly, and released high levels of IL-10. Interestingly, blockade of surface immunoglobulin-like transcript 3 (ILT3) on HGFMo or neutralization of secreted IL-10 translated into partial restoration of T-cell proliferation. Secondary stimulation of HGFMo-primed CD4+ T cells with immunogenic DCs differentiated with granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-4 from monocytes of the same donor resulted in measurable T-cell proliferation. HGFMo-primed CD4+ T cells significantly inhibited the proliferation of naive CD4+CD25- T cells in a cell-contact-dependent manner. Finally, DNA microarray analysis revealed a unique gene-expression profile of HGF-activated monocytes. Collectively, our findings point to a novel role for HGF in the regulation of monocyte/DC functions that might be exploited therapeutically.

Glutathione S-transferase P1 genotype and prognosis in Hodgkin's lymphoma.

PURPOSE: Glutathione S-transferase P1 (GSTP1) is a member of the GST enzyme superfamily that is important for the detoxification of several cytotoxic drugs and their by-products. A single nucleotide polymorphism results in the substitution of isoleucine (Ile) to valine (Val) at codon 105, causing a metabolically less active variant of the enzyme. We assessed the impact of the GSTP1 codon 105 genotype on treatment outcome in patients with Hodgkin's lymphoma. EXPERIMENTAL DESIGN: The Ile(105)Val polymorphism in the GSTP1 gene was analyzed using a PCR-RFLP technique. Ninety-seven patients with Hodgkin's lymphoma were included and associations with patient characteristics and treatment outcome were analyzed. RESULTS: The GSTP1 Ile(105)Val polymorphism was associated in a dose-dependent fashion with an improved failure-free survival in patients with Hodgkin's lymphoma (P = 0.02). The probability of 5-year survival for patients homozygous for the (105)Val/(105)Val GSTP1 genotype was 100%, for heterozygous patients 74% (95% confidence interval, 56-85), and for patients homozygous for the (105)Ile/(105)Ile genotype 43% (95% confidence interval, 23-61). The Cox multivariate analysis showed that GSTP1 codon 105 genotype was an independent prognostic factor. CONCLUSIONS: The GSTP1 genotype predicts clinical outcome in patients with Hodgkin's lymphoma.

Efficacy of a modified Stanford V regimen in patients with advanced Hodgkin's lymphoma.

We report treatment results obtained with a modified Stanford V regimen in 32 patients with advanced Hodgkin's lymphoma (stage II bulky disease, III, IV). Treatment results were not superior to those achieved with conventional treatment (ABVD) in terms of complete remission and survival rates (progression-free survival and overall survival at 3 years: 66% and 91%, respectively).

The expression pattern of c-mpl in megakaryocytes correlates with thrombotic risk in essential thrombocythemia.

Using immunohistochemistry, we investigated the expression of c-mpl in bone marrow megakaryocytes of 88 patients with essential thrombocythemia (ET), 6 patients with secondary thrombocytosis (ST), and 20 patients with lymphoma (controls). Considering both the pattern of expression and the staining intensity, we identified a uniform and a heterogeneous pattern of c-mpl expression. The uniform pattern was found in all the controls, all the patients with ST, and 28 of the patients with ET, with a strong staining intensity observed in most megakaryocytes (> 80%). In contrast, c-mpl expression was heterogeneous in 60 patients with ET, 18 of whom (30%) presented with thrombosis at diagnosis, a significant difference from patients with a uniform c-mpl pattern (2 of 28; 7%; P =.026). In particular, the overrepresentation of thrombotic complications in patients with a heterogeneous c-mpl expression pattern was found mainly among patients with a significant percentage (10% to 40%) of weakly stained or c-mpl-negative megakaryocytes (heterogeneous-weak pattern; 13 of 30; 43%; P =.002). Accordingly, this pattern was associated with a 6.1-fold increased risk of thrombosis compared with that of patients with a uniform c-mpl pattern. In conclusion, the presence of a heterogeneous pattern of c-mpl distribution in bone marrow megakaryocytes could be a useful diagnostic criterion in the differential diagnosis of thrombocytosis. Furthermore, detection of a significant percentage of weakly stained or c-mpl-negative megakaryocytes can identify patients with a higher risk of thrombosis.