Summary:This trial was designed to compare foscarnet with ganciclovir as pre-emptive therapy for CMV infection in patients undergoing allogeneic hemopoietic stem cell transplant (HSCT). Thirty-nine patients were randomized to receive foscarnet 90 mg/kg every 12 h (n = 20) or ganciclovir 5 mg/kg every 12 h (n = 19) for 15 days at the time of development of CMVAg-emia. Primary-end points of the study were (1) outcome of CMVAg-emia; (2) progression to CMV disease; and (3) side-effects of treatment. The secondary end-point was transplant-related mortality (TRM). The two groups were comparable for diagnosis, status of disease, donor type, acute graft-versus-host (aGVHD) prophylaxis, interval between HSCT and CMVAg-emia and number of CMVAg positive cells; the donor and recipient age were borderline older in the foscarnet group. Increments of serum creatinine in the foscarnet group, and cytopenia in the ganciclovir group were controlled by reducing the administered dose: in the first 15 days of therapy 9/20 foscarnet and 10/19 ganciclovir patients had a dose reduction greater than 20% (P = 0.43). Clearance of CMVAg-emia was faster in the foscarnet group although with borderline statistical significance. Failures of treatment occurred in 3/20 patients in foscarnet group vs 8/19 patients in ganciclovir group (P = 0.06): causes of failure were the need for combination therapy to control antigenemia (1/20 vs 5/19), and reactivation during treatment for 2 vs 3 patients, respectively. CMV disease was diagnosed in 1 vs 2 patients (P = 0.5) who subsequently died. The actuarial 1-year TRM was 25 vs 12%, respectively (P = 0.3). This study suggests that foscarnet and ganciclovir are both effective for pre-emptive therapy of CMVAg-emia, although the number of failures would seem to be slightly higher in the ganciclovir patients. Side-effects are seen in both groups and can be managed with appropriate dose reduction.
Apoptosis has been implicated in the pathogenesis of marrow failure in MDS and the coexistence of marrow hypercellularity along with blood cytopenias was seen as evidence of extreme cell death of mainly mature cells in the marrow (ineffective hematopoiesis). We investigated apoptosis in 53 patients with MDS, by using single-step DNA extraction and gel electrophoresis and then by separating fresh marrow mononuclear cells in CD34+ and CD34 − populations and in situ single cell evaluation of the process. We also studied the expression of apoptosis-related genes, in total and separated mononuclear marrow cells and correlated the findings with clinical and laboratory characteristics. Patients with apoptosis had increased marrow cellularity, longer overall survival and a longer period for transformation to AML. In 'good' prognosis MDS patients, total mononuclear marrow cells, as well as isolated populations of CD34+ and CD34 − cells showed significant degrees of apoptosis; in 'poor' prognosis cases, however, apoptosis was evident only in a large percentage of CD34 + marrow cells and not in total or CD34 − cells. Absence of expression of both c-myc and p53 in total marrow cells was associated with significant degrees of apoptosis and in isolated CD34+ and CD34 − marrow cells the phenomenon was inversely correlated with the level of bcl-2 expression. In conclusion, marrow apoptosis is detected in both CD34+ and CD34 − cells in early MDS and seems to be restricted to CD34+ cells in advanced MDS cases.
Summary:that survival of CML patients after marrow transplantation from unrelated or sibling donors is currently similar, provided the former are well matched. The This is a report on 60 consecutive patients with chronic myeloid leukemia (CML) who received an allogeneic increased incidence of GVHD in MUD patients is possibly compensated by a lower risk of relapse. bone marrow transplant (BMT) in this Unit. Donors were HLA-identical siblings (SIB) (n ؍ 36) or unrelated Keywords: chronic myeloid leukemia; unrelated donor transplants donors (MUD) (n ؍ 24) matched by serology for HLA A and B and by molecular biology for HLA DR. All patients were prepared with cyclophosphamide 120 mg/kg and fractionated total body irradiation 10-Allogeneic bone marrow transplantation (BMT) is one of 12 Gy. GVHD prophylaxis consisted of cyclosporin A the therapeutic options for patients with chronic myeloid (CsA) starting on day ؊7 and short-course methotrexleukemia (CML), and is capable of inducing long-term ate. Bone marrow was unmanipulated in all cases. Cytodisease-free survival in over half of patients, when performegalovirus prophylaxis consisted of acyclovir for SIBs med in the early stages of the disease. deficiency, graft versus host disease (GVHD) and cytome-P ؍ 0.002), had younger donors (31 vs 39; P ؍ 0.001), galovirus infections (CMV) are all major causes of failure, had a longer interval between diagnosis and BMT (1459 particularly in CML patients and lead to a transplant-related vs 263 days; P Ͻ 0.001) and received a smaller number mortality (TRM) of 20-50%. 3 To investigate possible difof nucleated cells at transplant (3.3 vs 4.4 ؋ 10 8 /kg; ferences between CML and acute myeloid leukemia P ؍ 0.003). More MUDs had advanced disease (AML), we analyzed 213 patients undergoing unmanipul-(50 vs 17%, P ؍ 0.005). The median day to 0.5 ؋ 10 9 /l ated allogeneic BMT with the same conditioning regimen, neutrophils was similar in both groups (18 days for SIBs from an HLA-identical sibling: CML patients had signifivs 17 days for MUDs; P ؍ 0.06); the median platelet cantly slower neutrophil (P = 0.0001) and platelet count on days ؉30, ؉50, ؉100 was significantly engraftment (P = 0.002) 5 and delayed immune reconsti-(P Ͻ 0.01) higher in SIB than in MUD patients tution (P = 0.0001) as indicated by lower absolute CD4 (122 vs 38, 113 vs 50 and 97 vs 45 ؋ 10 9 /l, respectively). counts: CML patients had significantly greater TRM as Acute GVHD was scored as absent-mild, moderate, or compared to AML patients (39 vs 16%, P = 0.002) severe, in 36, 58 and 6% of SIBs vs 25, 42 and 33% in (unpublished). We therefore observed a greater TRM asso-MUD patients (P ؍ 0.01). Chronic GVHD was compaciated with delayed graft function in patients with CML, rable (P ؍ 0.1). The actuarial risk of CMV antigenemia possibly due to the fact that CML patients may be more at 1 year was 60% in both groups. There were six deaths immune competent when compared to acute leukemias, not in SIB patients (two leukemia, two infections, one having recei...
Summary.To determine if reducing the intensity of the mobilizing chemotherapy protocol used would alter the number and/or quality of the progenitors mobilized in patients with chronic myelogenous leukaemia (CML), we undertook a pilot study. 36 consecutive CML patients previously treated only with hydroxyurea were given mobilization therapy within 12 months of diagnosis. 17 patients were treated by the ICE protocol and 19 patients received the mini-ICE protocol. The leukapheresis product collected from 22/36 patients (62%) was entirely Ph-negative. The cytogenetic results between ICE and mini-ICE-treated protocols were not significant, although the reduction in median days of hospitalization required for the mini-ICE versus the ICE protocol was highly significant (P < 0·0001). There was no significant difference in the yield of CD34 þ cells and CFU-GM collected. No patient in the mini-ICE protocol experienced high-grade oral mucositis and GI toxicity whereas three such cases occurred with the ICE protocol. No patient died of the mobilization procedure in either group.
Summary.We carried out studies to quantify Ph-negative progenitors both in steady state and during regeneration after chemotherapy and G-CSF in 23 newly diagnosed chronic myeloid leukaemia (CML) patients (group A) and in 14 individuals more than a year from diagnosis (nine in chronic and five in accelerated phase, group B). In steadystate bone marrow, Ph-negative long-term culture initiating cells (LTC-IC) and Ph-negative colony-forming-cells (CFC) were detected in 18/23 and 14/23 patients of group A versus 3/14 and 3/14 patients of group B (P < 0·001 and P < 0·02, respectively). The absolute number of mobilized Ph-negative progenitors was markedly higher in group A versus group B (P < 0·02 for LTC-IC, P < 0·003 for CFC). 12/16 newly diagnosed patients mobilized Ph-negative LTC-IC only and the yield was in the range of normal allogeneic donors. Overall the frequency of Ph-negative LTC-IC in the bone marrow predicted the yield of Ph-negative LTC-IC mobilized into peripheral blood (P < 0·001). The bone marrow frequency of Ph-positive LTC-IC was considerably lower than the normal counterpart. Taken together, these findings suggest that normal progenitors are relatively well preserved in newly diagnosed CML patients, but tend to rapidly decline with time. This observation helps in the understanding of the pathogenesis of CML and has potential implications for autografting. The optimal time for a successful collection of Ph-negative circulating progenitors would appear to be soon after diagnosis.
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