Krystyna Jagoda

Status of minimal residual disease after induction predicts outcome in both standard and high-risk Ph-negative adult acute lymphoblastic leukaemia. The Polish Adult Leukemia Group ALL 4-2002 MRD Study

The treatment of adults with Philadelphia‐negative acute lymphoblastic leukaemia (ALL) depends on the presence of risk factors including age, white blood cell count, immunophenotype and time to complete remission. In recent years, status of minimal residual disease (MRD) has been postulated as an additional risk criterion. This study prospectively evaluated the significance of MRD. Patients were treated with a uniform Polish Adult Leukemia Group (PALG) 4‐2002 protocol. MRD status was assessed after induction and consolidation by multiparametric flow cytometry. Out of 132 patients included (age, 17–60 years), 116 patients were suitable for analysis. MRD level ≥0·1% of bone marrow cells after induction was found to be a strong and independent predictor for relapse in the whole study population (P < 0·0001), as well as in the standard risk (SR, P = 0·0003) and high‐risk (P = 0·008) groups. The impact of MRD after consolidation on outcome was not significant. The combination of MRD status with conventional risk stratification system identified a subgroup of patients allocated to the SR group with MRD <0·1% after induction who had a very low risk of relapse of 9% at 3 years as opposed to 71% in the remaining subjects (P = 0·001). We conclude that MRD evaluation after induction should be considered with conventional risk criteria for treatment decisions in adult ALL.

G-CSF Administered in Time-sequenced Setting During Remission Induction and Consolidation Therapy of Adult Acute Lymphoblastic Leukemia has Beneficial Influence on Early Recovery and Possibly Improves Long-term Outcome: A Randomized Multicenter Study

Sixty-four untreated adult acute lymphoblastic leukemia (ALL) patients were randomized to receive chemotherapy alone, n =31 or chemotherapy and granulocyte colony stimulating factor (G-CSF), n =33. During induction patients received G-CSF for 5 days between four weekly Epirubicin+Vcr administrations, starting 36 h after each application and finishing 48 h before the next one with the intention to possibly generate a cell cycle dependent protection of normal hematopoietic progenitors and to stimulate granulopoiesis. The complete remission (CR) rate equaled 94% in the G-CSF group and 87% in controls. Patients who received G-CSF, if compared to the controls, had shorter granulocytopenia during induction and consolidation, displayed a lower infection rate, completed the induction-consolidation quicker and stayed shorter in hospital during induction, p <0.001-0.04. Follow-up at 2 years revealed a rather higher probability of survival (59 vs. 27%, p =0.04 ) and a lower relapse rate (32 vs. 60%) in G-CSF arm than in controls. The beneficial influence of G-CSF administered in time-sequenced fashion on survival needs further confirmation.

Effects of incretin agonists on endothelial nitric oxide synthase expression and nitric oxide synthesis in human coronary artery endothelial cells exposed to TNFα and glycated albumin

BACKGROUND There have been a number of beneficial effects of incretin agonists on the cardiovascular system. Glycated albumin (GA) and tumor necrosis factor (TNFα) may lead to endothelial dysfunction. Due to reports of cardioprotective effects of incretin agonist, we wanted to determine if GLP-1 and exendin-4 can reverse diminished production of nitric oxide (NO) after treatment with TNFα and GA. The objective of our experiment was to study the interaction between incretin agonists and proinflammatory substances like TNFα and GA on production of NO in HCAEC. METHODS Human vascular endothelial cells from the coronary artery (HCAEC) were used. The mRNA expression and protein level of endothelial nitric oxide synthase (eNOS) and inducible (iNOS) were quantified. NO production was measured in cells using DAF-FM/DA and flow cytometry. RESULTS TNFα (10 ng/mL) decreased eNOS: mRNA by 90% and protein level by 31%. TNFα also decreased NO by 33%. GA (500 μg/mL) neither affected eNOS expression nor the protein level, but inhibited nearly all formation of NO in endothelium. GLP-1 (100 nM) and exendin-4 (1 and 10nM) decreased the amount of NO compared to control. Incubation of HCAEC with TNFα and incretin agonists did not change or moderately reduce the amount of NO compared to TNFα alone. CONCLUSIONS TNFα and GA decrease production of NO in HCAEC, presumably by inducing reactive oxygen species or eNOS uncoupling. Incretin agonists in tested concentrations in the presence of l-arginine were not able to reverse this effect and instead led to a further reduction in NO production.

The importance of the number of transplanted cells with dipeptidyl peptidase-4 expression on the haematopoietic recovery and lymphocyte reconstitution in patients with multiple myeloma after autologous haematopoietic stem-cell transplantation

Autologous haematopoietic stem cell transplantation (AHSCT) remains recommended treatment in the first remission in multiple myeloma (MM). In earlier research it has been suggested that there is an influence of the expression of dipeptidyl peptidase‐4 (CD26) on both the homing and lymphocyte reconstitution after AHSCT. The aim of the study is to investigate the influence of transplanted cells CD26+ on the haematopoietic recovery and lymphocyte reconstitution after AHSCT in MM. Forty eight patients with MM underwent AHSCT in our centre. Number of all CD26+ cells, CD26+ lymphocytes, CD26+ monocytes and CD26+ and CD34+ cells were measured in the harvested material. Number of lymphocytes subpopulations (all lymphocytes CD3+, helpers, suppressors, natural killer (NK), cytotoxic NK and lymphocytes B) were measured in peripheral blood during regeneration after AHSCT. In both flow cytometry was used. On the basis of the analysis there was, as regards regeneration of haematopoietic cells after AHSCT, it was shown that a higher number of monocytes CD26+ improves the reconstitution of helper, suppressor and NK lymphocytes. A higher number of transplanted CD26+ lymphocytes accelerates the reconstitution of NK lymphocytes, whereas a higher number of all the cells CD26+ has a positive impact on the regeneration of cytotoxic NK lymphocytes. Copyright

Impact of granulocyte colony stimulating factor administered during induction and consolidation of adults with acute lymphoblastic leukemia on survival: long-term follow-up of the Polish adult leukemia group 4-96 study.

Department of Clinical Oncology, Comprehensive Cancer Centre, Maria Sklodowska-Curie Memorial Institute Branch Gliwice, Gliwice, Poland, Department of Hematology and Bone Marrow Transplantation, Silesian Medical University, Katowice, Poland, Department of Hematology, Institute of Internal Diseases, Gdansk Medical Academy, Gdansk, Poland, Department of Hematology and Bone Marrow Transplantation, Lublin Medical Academy, Lublin, Poland, Department of Hematology, Oncology and Internal Medicine, Warsaw Medical University, Warsaw, Poland, Department of Hematology, Lodz Medical University, Lodz, Poland, Department of Internal Diseases, Institute of Haematology and Blood Transfusion, Warsaw, Poland, Department of Hematology, Institute of Haematology and Blood Transfusion, Warsaw, Poland, and Department of Hematology, Collegium Medicum, Jagiellonian University, Krakow, Poland

Could cytogenetics and minimal residual disease replace conventional risk criteria in adults with Ph-negative acute lymphoblastic leukaemia?

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Early assessment of donor CD34 + positive cells chimerism after allogeneic stem cell transplantation in acute myeloid leukemia/myelodysplastic syndrome patients – pilot study

Introduction. In high-risk acute myeloid leukaemia/myelodysplastic syndrome patients, relapse remains the major cause of treatment failure after allogeneic stem cell transplantation (alloSCT). The investigation of lineage-specific chimerism has become an important tool in the management of patients during the post-transplant period. Aim. Early assessment of lineage specific chimerism in patients who underwent allogeneic hematopoietic stem cell transplantation. Material and methods. 55 patients with acute myeloid leukemia and myelodysplastic syndrome who underwent alloSCT were included in the study. Flow cytometric analysis and cell sorting was performed in bone marrow collected at day 30 after alloSCT. For the purpose of this study we analyzed sorted immature progenitor cells (CD34+CD19-) using STR method. Results. All patients who relapsed presented with lower donor chimerism in CD34+ positive cells in comparison to the group of patients in remission of the underlying disease. Median value of chimerism in CD34+ positive cells in the group of patients who relapsed was 14.5% (range 0-51%), whereas in patients who remained in remission of the underlying disease, chimerism in CD34+ never fell below 97% (median 100%, range 97-100%). All relapses occurred during the first year after alloSCT. Median time to relapse was 107 days (range 28-323). Conclusions. Early assessment of chimerism in CD34+ cells sorted out of bone marrow is a sensitive technique to detect residual or reoccurring disease after allogeneic SCT. The assessment of donor chimerism in CD34+ cells in day +30 after alloSCT seems to be relevant in post-transplant care of high risk patients.

Związek polimorfizmów genu CTLA-4 dawcy komórek hematopoetycznych z ryzykiem wystąpienia choroby przeszczep-przeciw-gospodarzowi u biorców allogenicznego przeszczepienia komórek hematopoetycznych

I. Frydecka *, L. Karabon , M. Markiewicz , A. Tomkiewicz , A. Jedynak , E. Pawlak , K. Jagoda , A. Szteblich , S. Kyrcz-Krzemien 3 1 Instytut Immunologii i Terapii Doświadczalnej PAN, Wroclaw, Polska Uniwersytet Medyczny we Wroclawiu, Katedra i Klinika Urologii i Onkologii Urologicznej, Wroclaw, Polska Śląski Uniwersytet Medyczny, Klinika Hematologii i Transplantacji Szpiku, Katowice, Polska *Autor prezentujący i do korespondencji. Adres email: frydecka@am.wroc.pl