: Immune reconstitution may be delayed after CD34‐selected compared with unmanipulated autologous peripheral blood stem cell transplantation (PBSCT), resulting in a theoretically increased risk of ...infections. In a case–control matched study we compared the incidence of infection in 25 recipients of CD34‐selected PBSC (CD34 group) and 75 recipients of unmanipulated PBSC (PBSC group) transplants. The population included 52 males and 48 females suffering from non‐Hodgkin's lymphoma (n = 32), Hodgkin's disease (n = 8), multiple myeloma (n = 40) or breast cancer (n = 20). Neutrophil engraftment was comparable in the two groups. The actuarial incidence of infection was similar in the two groups (56% vs. 49% at day 30, and 70% vs. 64% at 1 yr respectively). The proportion of patients with 1, 2 or 3 infections, the number of infectious event per patient (1.32 vs. 1.04; NS), the number of infections before day 15 or 30, between days 31 and 100 or after day 100, the risk of varicella‐zoster virus or cytomegalovirus infection or disease, or the use of antibiotic or antifungal therapy, were not increased in the CD34 compared with the PBSC group. The main agents responsible for infection were bacteria, particularly gram‐positive cocci, in both groups. Bacteremia accounted for 33% of all infectious events in the CD34 group vs. 16% in the PBSC group (P < 0.05). Fungal infections were rare. In conclusion, our results do not support the notion that CD34‐selection of the graft is associated with an increased rate of infection after autologous PBSC transplantation. The role of extended infection prophylaxis should be evaluated.
Primary antifungal prophylaxis in leukaemia patients Maertens, Johan A; Frère, Pascale; Lass-Flörl, Cornelia ...
European journal of cancer supplements,
07/2007, Letnik:
5, Številka:
2
Journal Article, Conference Proceeding
Recenzirano
Abstract These recommendations have been developed by an expert panel following an evidence-based search of the literature assessing the role of primary antifungal prophylaxis in patients with acute ...leukaemia or stem cell transplantation. We present results from a questionnaire on the current practice among experts in Europe, show results of the literature search and provide the panel’s recommendations.
Relapse remains the major cause of failure after high-dose chemotherapy and autologous peripheral blood stem cell transplantation (PBSCT). As tumor contamination of the graft may contribute to this, ...CD34 selection has been used as an attempt to decrease the relapse rate. However, immune reconstitution may be delayed with CD34 selection due to the removal of T cells, natural killer (NK) cells and monocytes. The result could be an increased incidence of infectious complications. Some small series of patients have reported a higher incidence of infections, and in particular of viral infections, but others have not. Therefore, we compared the incidence of infection in 25 recipients of CD34-selected PBSC (CD34 group) and 75 case-matched recipients of unmanipulated PBSC (PBSC group) transplants. There were 52 males and 48 females with an average age of 52±11 yrs. They included 32 patients with non-Hodgkin's lymphoma, 8 with Hodgkin's disease, 40 with multiple myeloma and 20 with breast cancer, with 42 in first-line therapy and 58 in relapse, receiving their 1st (N=63) or 2nd (N=37) transplant. The number of CD34 cells infused as well as speed of engraftment were comparable in the two groups. There were no significant increase in the CD34 compared to the PBSC group for: actuarial incidence of infection (56 vs 49% at day 30, 70 vs 64% at 1 yr); proportion of patients with at least 1 (68 vs 68%), 2 (24 vs 17%) or 3 (0 vs 3%) infections; number of infectious events per patient before (1.32 vs 1.04) or after (0.59 vs 0.71) disease progression, before day 30 (0.84 vs 0.64), within days 31–100 (0.00 vs 0.09, p<0.01) or after day 100 (0.48 vs 0.31); risk of VZV (27 vs 30% at 5 yr) or CMV infection (8 vs 6%) or disease (0 vs 3%); use of antibiotics (8 vs 5 days) or antifungal therapy (0 vs 0%) or days with fever (1 vs 1 day) in the initial hospitalisation. However, bacteremias tended to be more frequent in the CD34 group (0.44 vs 0.20 episode/patient). Bacteria accounted for the majority of infections in both groups (64 vs 72%). Infection was the main or a contributing cause of death in 0% and 20% of patients in the CD34 group compared to 1% and 10% in the PBSC group (NS). In conclusion, our results indicate only a trend towards an increased risk of infection after CD34-selected autologous PBSCT. The role of extended infection prophylaxis should be evaluated.
In order to assess the effect of Pegfilgrastim on the duration of neutropenia and clinical outcome of patients after autologous peripheral blood stem cell (PBSC) transplantation, we compared 20 ...consecutive patients with lymphoma or multiple myeloma receiving a single 6-mg dose of Pegfilgrastim on day 1 posttransplant to an historical control group of 60 patients receiving daily Filgrastim 5 μg/kg starting on day 1 posttransplant. The duration of neutropenia was similar in the Pegfilgrastim group compared with the control group. There were no differences in time to neutrophil, erythroid, or platelet engraftment nor in the incidence of fever and infections. The duration of antibiotic therapy, transfusion support, and time to hospital discharge were similar in the two groups. However, after initial hematopoietic reconstitution, we observed significantly higher values of lymphocytes (e.g., 1660 ± 1000 versus 970 ± 460 on day 80,
p = 0.0002), neutrophils (e.g., 3880 ± 2030 versus 2420 ± 1500 on day 25,
p = 0.0004), reticulocytes (e.g., 148,160 ± 90,590 versus 87,140 ± 65,920 on day 25,
p < 0.0001), and platelets (e.g., 210,700 ± 116,090 versus 150,240 ± 58,230 on day 55,
p = 0.0052) up to day 100 in the Pegfilgrastim group compared with the Filgrastim group. These observations had no impact on clinical outcome of the patients after day 30 due to the low incidence of infectious events after engraftment in autologous PBSC transplantation. We conclude that the effect of Pegfilgrastim administrated on day 1 posttransplant is comparable to that of daily Filgrastim on initial hematopoietic reconstitution. The possibly superior effect of Pegfilgrastim on cell counts we observed after initial engraftment should be further tested in a prospective randomized trial.
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.
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.
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).
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.
In order to assess the effect of Pegfilgrastim on the duration of neutropenia and clinical outcome of patients after autologous peripheral blood stem cell transplantation (PBSCT), we compared 20 ...consecutive patients with lymphoma or multiple myeloma receiving a single 6 mg dose of Pegfilgrastim on day 1 posttransplant to a historical control group of 60 patients receiving daily Filgrastim 5 μg/kg starting on day 1 posttransplant. There were 54 M and 26 F, 30 patients with lymphoma and 50 with myeloma, 26 in CR and 54 not in CR. Mean age was 55±10 yrs and 25 had already received a previous autologous transplant. The two groups were matched for disease and disease status, transplant number, age and sex. Cell dose infused tended to be higher in the Pegfilgrastim group (7.16±3.82 vs 10.03±6.25 x106 CD34+ cells/kg, p=0.0575). There were no differences (p>0.05) in time to 0.5 (8 vs 9 days) or 1 (9 vs 9 days) x109/L neutrophils; to 1 % reticulocytes (13 vs 15 days) or 9 (12 vs 14 days) or 10 (30 vs 25 days) g/dL Hb; to 20 (9 vs 9 days) or 100 (20 vs 31 days) x 109/L platelets. The number of days with fever (2.7±2.3 vs 2.3±2.4 days), incidence of infections (all infections; bacteremia; bacterial, fungal or viral infections; FUO), duration of antibiotic therapy (8.7±5.9 vs 8.4±5.9 days), RBC (1.1±1.6 vs 0.9±1.6) and platelet (1.0±1.7 vs 1.2±1.8) transfusions, and time to hospital discharge (14.5±5.3 vs 15.4±5.8 days) were similar in the Pegfilgrastim compared to the Filgrastim group. However, after initial hematopoietic recovery, several differences between the groups became apparent, with the group always showing higher counts compared to the Filgrastim group (p values <0.05 to <0.001). Neutrophils remained significantly higher in the Pegfilgrastim group between days 14–30, lymphocytes between days 56–90, monocytes between days 21–24, reticulocytes between days 17–42 and platelets between days 35–90, respectively. These differences had no impact on clinical outcome after day 30 due to the low incidence of infectious events after engraftment. We conclude that Pegfilgrastim administrated on day 1 posttransplant facilitates early hematopoietic reconstitution comparable to daily Filgrastim. However, despite a trend towards fewer CD34+ cells transplanted, the Pegfilgrastim group enjoyed higher trilineage cell counts for some time after initial engraftment. This should be further tested in prospective randomized trials.
Background: In a previous pilot study, we demonstrated that CD8-depletion of the graft apparently reduced the severity of AGvHD without impairing the GvL effect after peripheral blood stem cell ...(PBSC) transplantation with a nonmyeloablative conditioning (NMSCT).
Aim of the study: To evaluate the effect of CD8-depletion on graft rejection, AGvHD and CGvHD, and relapse.
Patients: 53 patients were randomised between CD8-depletion (group 1) (n=25) and no manipulation (group 2) (n=28). Two patients in the CD8 group were excluded for poor CD34+ cell count collected. Diagnoses were: AML (n=3), CML-AP (n=2), MDS (n=14), MPD (n=3), CLL (n=5), NHL (n=14), MM (n=8) and RCC (n=2). Median age was 57 (range 36–69) yrs. After conditioning with 2 Gy TBI with (n=39) or without (n=12) fludarabine, patients received PBSC from family (n=21) or unrelated (n=30) HLA-matched donors. CD8-depletion was carried out using the Eligix system and GvHD prophylaxis consisted in CyA and MMF.
Results: CD8 depletion removed 96% of CD8+ cells so that the number of CD8+ cells infused was 6.8 vs 136.8 x108 cells/Kg in group 2 (p<0.0001). AGvHD of any grade was observed in 13 (56%) patients in group 1 and 17 (61%) in group 2 (NS); it was grade 3–4 in 1 (4%) and 5 (18%) patients in groups 1 and 2, respectively (NS). Limited and extensive CGvHD developed in 3 and 1 patients in group 1 and in 7 and 2 patients in group 2, respectively (NS). Nine patients in group 1 and 12 in group 2 received unmanipulated DLI for poor chimerism or disease progression. Eight (3 initial and 5 late) graft failures were observed in group 1 and one (late) in group 2. Full donor chimerism was achieved in 57% (group 1) and 50% (group 2) at day 100, and in 73% (group 1) and 59% (group 2) (NS) at 1 yr. The 2-yr OS and PFS rates are 55% and 43 % in group 1 vs 59% and 46% in group 2, respectively (NS). Four (17%) patients died of their disease in group 1 vs 3 (11%) in group 2 (NS). Two patients died of severe AGvHD in group 2 vs none in group 1.
Conclusion: In vitro CD8-depletion results in higher rates of graft failure after NMSCT. The incidence of acute and chronic GvHD is not reduced but there is a trend towards reduced severity of AGvHD. Relapse and survival rates are not changed by this strategy.
Hematopoietic stem cell transplantation with a non-myeloablative conditioning (NMSCT) could theoretically be associated with a reduced risk of infection because it causes less mucosal damage or ...severe neutropenia compared to standard myeloablative allogeneic transplantation. Previous studies have sometimes indicated a reduced incidence of infection after NMSCT but other reports have not. We analyzed the incidence and risk factors (Cox model) of infection in 62 patients (16 F and 46 M, aged 54±11 yrs) undergoing NMSCT with a conditioning regimen of low-dose TBI±fludarabine and immunosuppression with CsA+MMF (Seattle protocol). We compared them to 119 recipients (72 peripheral blood (PBSCT) and 47 bone marrow (BMT) transplants) of a conventional HCT. The proportion of NMSCT patients with repeated infections (at least 1, 2, 3 or 4 infections) was significantly lower than in the 2 other groups, but the difference was confined to the first 30 days post-transplant (34% vs 89% and 74%, p<0.001). In NMSCT recipients, donor other than sibling (p<0.0001), older age (p=0.0024), a diagnosis of MDS (p=0.0123), early disease (p=0.0233) and male gender (p=0.0441) were significant risk factors. The incidence of bacteremia was lower (55% vs 70% and 66% at 1 yr, p=0.0264), but the total number of bacteremic episodes (0.9, 1.2 and 1.0 per patient) did not differ in the NMSCT compared to the PBSCT and BMT groups. However, in the first 30 days post-transplant, 4–6 times fewer episodes were encountered in the NMSCT group (p<0.0001). In the NMSCT group, donor other than sibling (p<0.0001), older age (p=0.0126), a diagnosis of leukemia (p=0.0099) and conditioning without fludarabine (p=0.0022), but not neutropenia, were significant risk factors. The incidence of infections other than bacteremia was quite comparable in the 3 groups, but with a significant delay in the NMSCT group (p=0.0002) in which only corticosteroid usage was associated with an increased risk (p=0.0066). The vast majority of infections were bacterial (less frequent in the NMSCT group in the first 30 days), but the rates of fungal or VZV infections were similar in the 3 groups. No case of CMV reactivation or disease occurred among the low risk (donor and recipient seronegative), very few in the intermediate risk (donor alone seropositive), but many in the high risk category (recipient seropositive) and similarly so in the 3 groups. Among NMSCT patients, the risk of CMV infection increased with high risk category (p<0.0001), older age (p=0.0002), donor other than sibling (p=0.0003) and a diagnosis of lymphoma (p=0.0035). Infection was the primary cause of death in 10% or less of the patients, but it contributed to death in 24%, 41% and 27% of the NMSCT, PBSCT and BMT patients, respectively (NS). We conclude that the risk of infection after NMSCT is significantly smaller than after standard allogeneic transplants within 30 days posttransplant, but very similar thereafter.
The role of conditioning intensity on occurrence of thrombotic microangiopathy (TMA) after allogeneic hematopoietic cell transplantation (HCT) has remained unclear thus far. Here, we retrospectively ...compared the incidence of TMA in patients given allogeneic hematopoietic stem cells after either nonmyeloablative (n=176) or high-dose (n=111) conditioning. The 1-year cumulative incidence of TMA was 13% in nonmyeloablative recipients versus 15% in high-dose conditioning recipients (P=0.5). In multivariate Cox analysis, occurrence of grade 3-4 acute graft-versus-host disease (GVHD) (hazard ratio (HR)=2.3, P<0.001), older age (HR=1.01, P=0.045), and unrelated donors (HR=1.6, P=0.01) were each associated with a higher risk of TMA, whereas nonmyeloablative conditioning was associated with a lower risk of TMA (HR=0.6, P=0.01). We conclude that acute GVHD, age, donor type, and conditioning intensity might have a role in the physiopathology of TMA after allogeneic HCT.
We have previously shown that CD8 depletion or CD34 selection of peripheral blood stem cells (PBSC) reduced the incidence of acute graft-versus-host disease (GvHD) after nonmyeloablative stem-cell ...transplantation (NMSCT). In this study, we analyze the effect of CD8 depletion or CD34 selection of the graft on early T-cell reconstitution.
Nonmyeloablative conditioning regimen consisted in 2 Gy total-body irradiation (TBI) alone, 2 Gy TBI and fludarabine, or cyclophosphamide and fludarabine. Patients 1 to 18 received unmanipulated PBSC, patients 19 to 29 CD8-depleted PBSC, and patients 30 to 35 CD34-selected PBSC.
T-cell counts, and particularly CD4+ and CD4CD45RA+ counts, remained low the first 6 months after nonmyeloablative stem-cell transplantation (NMSCT) in all patients. CD34 selection (P<0.0001) but not CD8 depletion of PBSC significantly decreased T-cell chimerism. Donor T-cell count was similar in unmanipulated compared with CD8-depleted PBSC recipients but was significantly lower in CD34-selected PBSC recipients (P=0.0012). T cells of recipient origin remained stable over time in unmanipulated and CD8-depleted PBSC patients but expanded in some CD34-selected PBSC recipients between day 28 and 100 after transplant. Moreover, whereas CD8 depletion only decreased CD8+ counts (P<0.047), CD34 selection reduced CD3+(P<0.001), CD8+(P<0.016), CD4+ (P<0.001), and CD4+CD45RA+ (P<0.001) cell counts. T-cell repertoire was restricted in all patients on day 100 after hematopoietic stem-cell transplantation but was even more limited after CD34 selection (P=0.002).
Despite of the persistence of a significant number of T cells of recipient origin, T-cell counts were low the first 6 months after NMSCT. Moreover, contrary with CD8 depletion of the graft that only affects CD8+ lymphocyte counts, CD34 selection dramatically decreased both CD8 and CD4 counts.
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