The role of NF-κB and Smac/DIABLO proteins in the treatment response and survival of acute myeloid leukemia patients.

INTRODUCTION: The misbalance between a family of inhibitor of apoptosis proteins (IAP), regulated by the nuclear factor kappa B (NF-κB) and their natural antagonist second mitochondrial-derived activator of caspases/direct IAP binding protein with low pI (Smac/DIABLO) are important to biology of acute myeloid leukemia (AML). MATERIAL AND METHODS: The aim of the study was to assess NF-κB and Smac/DIABLO proteins expression in blasts of 109 newly diagnosed AML patients using the multicolor flow cytometry and evaluate their influence on AML patients outcome. RESULTS: Expression of NF-κB and of Smac/DIABLO proteins were found in 95% and 98% of the patients, respectively. A negative correlation between Smac/DIABLO and NF-κB was observed. Age < 60 years old as well as higher Smac/DIABLO expression were associated with a higher probability of complete response achievement in the multivariate analysis. Longer overall survival (OS) in the univariate and multivariate analyses was influenced by age < 60 years old, a favorable or intermediate-risk karyotype and high Smac/DIABLO expression. Additionally, in the survival analysis of the subgroups, the patients aged < 60 years old, with high Smac/DIABLO expression, lower NF-κB expression and < 50% of bone marrow blasts who were treated with standard treatment had better OS. CONCLUSIONS: Lower NF-κB and higher Smac/DIABLO expression may influence AML patients outcome.

Early induction intensification with cladribine, cytarabine, and mitoxantrone (CLAM) in AML patients treated with the DAC induction regimen: a prospective, non-randomized, phase II study of the Polish Adult Leukemia Group (PALG).

We present the results of a prospective, non-randomized phase 2 trial in which 253 AML patients (pts) under 60 years old received DAC (Daunorubicin + AraC + Cladribine) as first induction followed by CLAM (Cladribine + AraC + Mitoxantrone) as early second induction on day 16 based on bone marrow (BM) blasts on day 14 (D14). The CR/CRi rate after a single course of DAC was 83% for pts with D14 BM blasts less than 10%. Forty-six pts had >10% BM blasts on D14, of whom 35 received CLAM with rates of CR/CRi 60% and early death (ED) 23%. The remaining 11 pts were not fit to receive CLAM, with rates of CR/CRi 28%, PR 18%, and ED 18%. Median OS was 7.2 versus 7.5 months, respectively. The overall CR/CRi rate was 77% after the first induction, with final CR/CRi rate 80% after DAC reinduction for pts who achieved PR with initial DAC course. CLAM used as early second induction might improve CR/CRi rates for younger AML pts with poor early response to DAC induction, but may be associated with higher mortality.

Prognostic value of inhibitor of apoptosis protein family expression in patients with acute myeloid leukemia.

The inhibitor of apoptosis protein (IAP) family acts as an inhibitor of apoptosis pathways. The potential prognostic value of the expression of selected IAP family members, XIAP, cIAP-1, cIAP-2 and survivin protein, was evaluated with regard to treatment response and survival of 56 newly diagnosed adult patients with acute myeloid leukemia (AML). The presence of these IAP members influenced the achievement of a complete response (CR). In addition, overall survival (OS) was influenced by low survivin expression in univariate and multivariate analysis (p = 0.014 and p = 0.013, respectively). A strong correlation was observed between members of the IAP family (XIAP and cIAP-1, XIAP and cIAP-2, cIAP-1 and cIAP-2, p < 0.001 for all comparisons), while Smac/DIABLO demonstrated an inverse correlation with XIAP, cIAP-1 and cIAP-2 (p < 0.001 for all comparisons). Further studies should be undertaken to better demonstrate the mode of action of IAP members, as well as their prognostic and therapeutic potentials.

Angiopoietins in haematopoietic stem cell mobilisation in patients with haematological malignancies.

BACKGROUND: The bone marrow niche contains different types of cells including osteoblasts and endothelial progenitors, all of which interact and take part in the process of mobilisation. The aim of our study was to evaluate the levels of cytokines (osteopontin and angiopoietins 1 and 2) active in the bone marrow niche during the mobilisation of haematopoietic stem cells for autologous transplantation. MATERIALS AND METHODS: Forty-eight patients (24 females, 24 males), median age 56.5 years, entered the study. The group consisted of patients with multiple myeloma (n=34), lymphoma (n=13) and acute myeloid leukaemia (n=1). Blood samples were collected before chemotherapy and on the day of the first apheresis. Cytokines were evaluated by enzyme-linked immunosorbent assays. Additionally, circulating endothelial cells were assessed by flow cytometry. RESULTS: The median concentration of angiopoietin 1 at the time of apheresis was lower than that at baseline (2.7 vs 7.8 ng/mL, p<0.001). In contrast, the median level of angiopoietin 2 increased during the mobilisation procedure (3.6 vs 2.8 ng/mL, p=0.001). The patients were divided according to the number of days of granulocyte colony-stimulating factor treatment before the first apheresis into "early" (median) mobilisers. The group of "early mobilisers" had higher baseline angiopoietin 1 levels (median=11.6 ng/mL) than those of the "late mobilisers" (median=6.0 ng/mL, p=0.05). An adverse correlation was observed between duration of granulocyte colony-stimulating factor treatment and baseline angiopoietin 1 level. Baseline angiopoietin 1 levels correlated with numbers of circulating endothelial cells. Low angiopoietin 2 level increased the chance of poor mobilisation. CONCLUSIONS: The angiogenic processes can influence the timing of mobilisation. Angiopoietins 1 and 2 need further evaluation in the context of mobilisation.