Mature erythrocyte indices: new markers of iron availability.

in Haematologica (2005), 90(4), 549-51

This study was aimed at evaluating mature erythrocyte indices as new markers of iron status. Contrarily to those in the whole red blood cell (RBC) population, mature erythrocyte parameters are valid ... [more ▼]

This study was aimed at evaluating mature erythrocyte indices as new markers of iron status. Contrarily to those in the whole red blood cell (RBC) population, mature erythrocyte parameters are valid markers of iron status that remain independent of erythropoietic activity. When reticulocytosis is low, these parameters are similar to whole RBC parameters. [less ▲]

Endogenous erythropoietin in the anemia of chronic disorders

in Weiss, W.; Gordeuk, V. R.; Hershko, C. (Eds.) Anemia of chronic disease (2005)

Modulation of homing properties of primitive progenitor cells generated by ex vivo expansion.

in Haematologica (2005), 90(4), 445-51

BACKGROUND AND OBJECTIVES: The maintenance of adequate interactions with the bone marrow (BM) microenvironment is critical to ensure efficient homing of ex vivo-expanded hematopoietic cells. This study ... [more ▼]

BACKGROUND AND OBJECTIVES: The maintenance of adequate interactions with the bone marrow (BM) microenvironment is critical to ensure efficient homing of ex vivo-expanded hematopoietic cells. This study was intended to assess adhesion and migration properties of long-term culture-initiating cells (LTC-IC) harvested after self-renewal division in ex vivo culture and to determine their susceptibility to growth-inhibitory signals mediated by adhesion to BM stromal ligands. DESIGN AND METHODS: We used cell tracking to isolate primitive LTC-IC that had accomplished 1 or 2 divisions ex vivo. Adhesion, migration and growth inhibition of divided LTC-IC were determined in the presence of purified BM ligands, and compared to the properties of uncultured LTC-IC. RESULTS: As compared to undivided LTC-IC, adhesion and migration mediated by very late antigen (VLA)-4 integrin across both vascular cell adhesion molecule-1 (VCAM-1) and fibronectin (Fn) were downregulated in post-mitotic LTC-IC. Conversely, binding and motility via VLA-5 across Fn were stimulated. No changes occurred in LTC-IC interactions with intercellular adhesion molecule-1 (ICAM-1) or with E- or P-selectin. Proliferation of uncultured LTC-IC was inhibited by VLA-4-mediated binding to VCAM-1 and the CS-1 domain of Fn, as well as binding to P-selectin. Growth of ex vivo-generated LTC-IC became unresponsive to these 3 ligands but was suppressed through VLA-5 engagement by the cell binding domain of Fn. INTERPRETATION AND CONCLUSIONS: The generation of LTC-IC in expansion culture is associated with functional alterations of adhesion receptors, modulating not only binding and migration in the BM but also responsiveness to adhesion-mediated growth inhibitory signals. Such changes may limit homing and engraftment of expanded primitive stem/progenitor cells. [less ▲]

Bacteremia after hematopoietic stem cell transplantation: incidence and predictive value of surveillance cultures.

in Bone Marrow Transplantation (2004), 33(7), 745-9

We studied 622 transplants undertaken between 1982 and 2001 to: (1) determine the incidence, timing and etiology of bacteremias, and (2) examine the ability of routine surveillance cultures to predict ... [more ▼]

We studied 622 transplants undertaken between 1982 and 2001 to: (1) determine the incidence, timing and etiology of bacteremias, and (2) examine the ability of routine surveillance cultures to predict bacteremias. A total of 404 episodes (0.65 episode per patient) occurred in 248 patients, due to coagulase-negative staphylococci (n=171, 42%), Gram-negative bacteria (n=129, 32%), streptococci (n=48, 12%), other Gram-positive bacteria (n=33, 8%), anaerobes (n=9, 2%) and fungi (n=14, 3%). Bacteremias were more frequent in allogeneic (0.96 episode/patient) compared to autologous (0.44) transplants (P<0.0001). The overall incidence decreased from 0.92 episode/patient until 1990 to 0.66 in 1991-1996 and 0.55 in 1997-2001 (P<0.0001), but this was only observed in autologous transplants. Among them, 212 (53%) occurred before hospital discharge and 192 (47%) thereafter. This proportion was lower for coagulase-negative staphylococci, other Gram-positive bacteria and Gram-negative bacteria compared to other agents (P=0.001). In 50% of the cases, the agent responsible for the bacteremic episode was present in routine surveillance cultures previously. In conclusion: (1) bacteremias remain a frequent complication, particularly in allogeneic transplantation, even long after hospital discharge; (2) routine surveillance cultures can predict bacteremias in 50% of the cases, but the practical impact of this observation is limited in view of the costs. [less ▲]

Haematopoetic stem cell transplantation for refractory autoimmune cytopenia.

in British Journal of Haematology (2004), 125(6), 749-55

This study describes the outcome of patients receiving haematopoietic stem cell transplantation (HSCT) to treat severe refractory autoimmune cytopenia. The registry of the European Group of Blood and ... [more ▼]

This study describes the outcome of patients receiving haematopoietic stem cell transplantation (HSCT) to treat severe refractory autoimmune cytopenia. The registry of the European Group of Blood and Marrow Transplantation holds data on 36 patients receiving 38 transplants, the first transplant was autologous for 27 and allogeneic for nine patients. Patients had autoimmune haemolytic anaemia (autologous: 5; allogeneic: 2), Evans's syndrome (autologous: 2; allogeneic: 5); immune thrombocytopenia (autologous: 12), pure red cell aplasia (autologous: 4; allogeneic: 1), pure white cell aplasia (autologous: 1; allogeneic 1), or thrombotic thrombocytopenic purpura (autologous: 3). Patients had longstanding disease having failed multiple prior treatments. Among 26 evaluable patients mobilized for autologous HSCT, three died of treatment-related causes, one died of disease progression, seven were non-responders, six patients had transient responses and nine had continuous partial or complete remission. Of the seven evaluable patients receiving allogeneic HSCT, one died of treatment-related complications, one with transient response died of progressive disease and five had a continuous response. Autologous and allogeneic HSCT may induce a response in a subset of patients with autoimmune cytopenia of long duration albeit at the price of considerable toxicity. [less ▲]

The tyrosine kinase inhibitor Imatinib increases irradiation toxicity but does not impair engraftment of human CD34+ cells into NOD/SCIDB2mNull mice

Poster (2004)

Phase III randomized study comparing 5 or 10 microg per kg per day of filgrastim for mobilization of peripheral blood progenitor cells with chemotherapy, followed by intensification and autologous transplantation in patients with nonmyeloid malignancies.

in Transfusion (2003), 43(1), 50-7

BACKGROUND: It is not known whether increasing the dose of filgrastim after mobilizing chemotherapy improves collection of peripheral blood progenitor cells (PBPC) and leads to faster hematopoietic ... [more ▼]

BACKGROUND: It is not known whether increasing the dose of filgrastim after mobilizing chemotherapy improves collection of peripheral blood progenitor cells (PBPC) and leads to faster hematopoietic engraftment after autologous transplantation. STUDY DESIGN AND METHODS: A randomized, open-label, multicenter trial was carried out in patients with breast cancer, multiple myeloma, and lymphoma, in which patients were randomized to receive 5 or 10 microg per kg per day of filgrastim after standard chemotherapy to mobilize PBPCs. After high-dose chemotherapy, the components from the first two leukapheresis procedures were returned, and all patients received 5 microg per kg day of filgrastim after transplantation. RESULTS: A total of 131 patients were randomized, of whom 128 were mobilized (Group A, 5 microg/kg, n = 66; Group B, 10 microg/kg, n = 62) and 112 were transplanted. Only six patients were not transplanted because of insufficient CD34+ cell numbers. The median number of CD34+ cells collected in the first two leukapheresis procedures tended to be higher in Group B than in Group A (12.0 vs. 7.2 x 10(6)/kg, NS), but after transplantation there was no significant difference in median times to platelet (9 days in both groups) or neutrophil (8 days in both groups) engraftment or the number of platelet transfusions (three in both groups). A subsequent subgroup analysis separating patients transplanted after first- or second-line chemotherapy also showed no measurable impact of filgrastim dose on the median CD34+ cell yield or on platelet engraftment in either subgroup. CONCLUSION: PBPC mobilization with chemotherapy and 5 microg per kg of filgrastim is very efficient, and 10 microg per kg of filgrastim does not provide additional clinical benefit. [less ▲]

Early detection of relapse by whole-body positron emission tomography in the follow-up of patients with Hodgkin's disease.

in Annals of Oncology (2003), 14(1), 123-30

BACKGROUND: Relapse after treatment of Hodgkin's disease (HD) is usually identified as a result of the investigation of symptoms. We undertook this study to examine the value of whole-body positron ... [more ▼]

BACKGROUND: Relapse after treatment of Hodgkin's disease (HD) is usually identified as a result of the investigation of symptoms. We undertook this study to examine the value of whole-body positron emission tomography (PET) for the detection of preclinical relapse. PATIENTS AND METHODS: Thirty-six patients underwent 2-[fluorine-18]fluoro-2-deoxy-D-glucose ((18)F-FDG) PET at the end of treatment and than every 4-6 months for 2-3 years after the end of polychemotherapy and/or radiotherapy. In those cases of abnormal (18)F-FDG accumulation a confirmatory study was performed 4-6 weeks later. RESULTS: One patient had residual tumor and four patients relapsed during a follow-up of 5-24 months. All five events were correctly identified early by (18)F-FDG PET. Residual tumor or relapse was never first diagnosed based on clinical examination, laboratory findings or computed tomography (CT) studies. Two patients presented B symptoms and the three others were asymptomatic at the time of residual disease or relapse. Confirmation of residual disease or relapse was obtained by biopsy in four patients 1, 1, 5 and 9 months after PET and by unequivocal clinical symptoms and CT studies in one patient 3 months after PET. False-positive (18)F-FDG PET studies incorrectly suggested possible relapse in six other patients, but the confirmatory PET was always negative. Our study also provides important information about physiological (18)F-FDG uptake in the thymus. CONCLUSIONS: Our data suggest the potential of (18)F-FDG PET to detect preclinical relapse in patients with HD. This could help identify patients requiring salvage chemotherapy at the time of minimal disease rather than at the time of clinically overt relapse. Further studies are warranted to determine the impact of PET on treatment management and outcome. In fact, the aim of follow-up procedures is not only to detect preclinical relapse but mainly to obtain better results by starting salvage treatment earlier. A cost-benefit analysis will also be necessary before (18)F-FDG PET can be used routinely in the follow-up of patients with HD. [less ▲]

Minitransplants: allogeneic stem cell transplantation with reduced toxicity.

in Acta Clinica Belgica (2003), 58(1), 37-45

Allogeneic hematopoietic stem cell transplantation (HSCT) is used for the treatment of selected hematological malignancies. Its curative potential is based on two very different mechanisms, involving the ... [more ▼]

Allogeneic hematopoietic stem cell transplantation (HSCT) is used for the treatment of selected hematological malignancies. Its curative potential is based on two very different mechanisms, involving the conditioning regimen and the graft-versus-host reactions, respectively. The high-dose chemo-radiotherapy conditioning regimen is aimed at destroying tumor cells, ablating the host immune system (to prevent rejection) and eliminating the host bone marrow (to "make space" for donor stem cells). However, the definitive eradication of tumor cells is also largely mediated by an immune-mediated destruction of malignant cells by donor lymphocytes termed graft-versus-leukemia (GVL) or graft-versus-tumor (GVT) effect. However, because of its toxicity, conventional allogeneic HSCT is restricted to younger (< 55 years) and fitter patients. These observations led several groups to set up new (less toxic) transplant protocols based on a two step approach: first the use of immunosuppressive (but nonmyeloablative) conditioning regimens providing sufficient immunosuppression to achieve engraftment of allogeneic hematopoietic stem cells and, in a second step, destruction of malignant cells by the GVL effect. These transplants are called nonmyeloablative HSCT or reduced-conditioning HSCT or minitransplants. Preliminary results show that minitransplants are feasible with a relatively low transplant-related mortality (TRM) even in patients up to 70 years. In addition, strong anti-tumor responses are observed in several hematological malignancies as well as in some patients with renal cell carcinoma. As the benefits of minitransplants over alternative forms of treatment remain to be demonstrated, this strategy should be restricted to patients included in clinical trials. [less ▲]

Recombinant human erythropoietin therapy is very effective after an autologous peripheral blood stem cell transplant when started soon after engraftment.

in Clinical Cancer Research : An Official Journal of the American Association for Cancer Research (2003), 9(15), 5566-72

PURPOSE: Previous trials of recombinant human erythropoietin (rHuEpo) therapy after autologous hematopoietic stem cell transplantation have administered very high doses of i.v. rHuEpo starting on day 1 ... [more ▼]

PURPOSE: Previous trials of recombinant human erythropoietin (rHuEpo) therapy after autologous hematopoietic stem cell transplantation have administered very high doses of i.v. rHuEpo starting on day 1 and continuing for 1-2 months until erythroid engraftment and have shown no benefit of rHuEpo therapy. We sought to establish a more effective use of rHuEpo in this setting. EXPERIMENTAL DESIGN: In this report, we show in a first cohort of 45 lymphoma or myeloma patients undergoing peripheral blood stem cell transplant (control group) that endogenous erythropoietin levels are high for the degree of anemia during the first 3 weeks after transplant but become adequate or slightly decreased thereafter. We thus enrolled 41 consecutive similar patients in a trial of rHuEpo therapy at a dose of 500 units/kg/week started on day 30 after the transplant. RESULTS: The 12-week probability of achieving hemoglobin (Hb) levels of 13 g/dl was 87% in rHuEpo-treated patients versus 14% in controls (P = 0.0001). Mean Hb levels were significantly higher in the rHuEpo group than in the control group from day 42 through day 150 after transplant (Ps of <0.05 to <0.001). Two of 41 patients in the rHuEpo group versus 12 of 45 patients in the control group had Hb levels of <9 g/dl between day 42 and day 100 after the transplant (P = 0.0078). CONCLUSIONS: Anemia after autologous peripheral blood stem cell transplant is exquisitely sensitive to rHuEpo when therapy is started soon after engraftment. This is the first convincing report showing that rHuEpo is effective in this setting. Our data set the stage for a more rational use of rHuEpo after autologous hematopoietic stem cell transplantation and should renew interest in erythropoietin therapy in this setting. Prospective, randomized trials should investigate the impact of rHuEpo therapy on transfusion requirements and quality of life. [less ▲]