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These recommendations have been developed by an expert panel following an evidencebased 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.

After allogeneic hematopoietic stem cell transplantation with nonmyeloablative conditioning (NMHCT), many patients experience prolonged anemia and require red blood cell (RBC) transfusions. We enrolled 60 consecutive patients undergoing NMHCT in a phase II trial to determine the optimal utilization of recombinant human erythropoietin (rHuEPO) therapy in this setting.The first 14 NMHCT recipients did not receive rHuEPO (control group). Nineteen patients were scheduled to start rHuEPO on day 0 (EPO group 2) and 27 patients on day 28 after the transplant (EPO group 1). RHuEPO was administered subcutaneously once weekly at a dose of 500 U/kg/wk with the aim of achieving hemoglobin (Hb) levels of 13 g/dL. The 3 groups were well balanced for major characteristics.During the first month (p0.0001) as well as days 30 to 100 (p0.0001) and days 100 to 180 (p0.0001), Hb values were higher in patients receiving rHuEPO compared to those not receiving it. However, transfusion requirements were significantly decreased only in the first month in EPO group 2 (p = 0.0169). T-cell chimerism above 60% on day 42 was the best predictor of Hb response (p0.0001) or Hb correction (p = 0.0217), but myeloid chimerism above 90% also predicted for Hb response (p = 0.0069). Hb response was also decreased in patients receiving CD8-depleted grafts and increased in the few patients not receiving TBI, but only in univariate analysis.Anemia after NMHCT is sensitive to rHuEPO therapy, but less so than after conventional allogeneic HCT. RHuEPO decreases transfusion requirements only in the first 30 days posttransplant. T-cell chimerism below 60% on day 42 impaired Hb response, suggesting possible inhibition of donor erythropoiesis by residual recipient lymphocytes. A prospective randomized trial should be performed with rHuEPO starting on the day of transplantation to assess its clinical benefit in terms of transfusion requirements and quality of life.

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

Non-myeloablative transplantation with CD8-depleted or unmanipulated peripheral blood stem cells: a phase II randomized trial

We report a patient with multiple myeloma who suffered from hyperammonemia after a second stem cell autograft. This syndrome is not well known but is associated with a high mortality rate. Considering the possibility of this diagnosis in patients developing confusion and neurological degradation with respiratory alkalosis after intensive chemotherapy, could allow earlier treatment and perhaps improved survival. Possible mechanisms and potential therapies are discussed. With rapid recognition and treatment of the syndrome, the patient fully recovered. One and a half years later, she is still alive and well, on interferon for persisting myeloma.

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

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

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 (P0.0001) 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 (P0.047), CD34 selection reduced CD3+(P0.001), CD8+(P0.016), CD4+ (P0.001), and CD4+CD45RA+ (P0.001) 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.

We investigate the feasibility of CD34-selected peripheral blood stem cell (PBSC) transplantation followed by pre-emptive CD8-depleted donor lymphocyte infusions (DLI) after a minimal conditioning regimen. Six patients with advanced hematological malignancies ineligible for a conventional myeloablative transplant (n=5) or metastatic renal cell carcinoma (n=1), and with an HLA-identical (n=4) or alternative (n=2) donor were included. The nonmyeloablative conditioning regimen consisted in 2 Gy TBI alone (n=4), 2 Gy TBI and fludarabine (RCC patient, n=1) or cyclophosphamide and fludarabine (patient who had previously received 12 Gy TBI, n=1). Post transplant immunosuppression was carried out with cyclosporin (CyA) and mycophenolate mofetil (MMF). Initial engraftment was achieved in all patients. One out of six patients (17%) experienced grade > or =2 acute GVHD only after abrupt cyclosporin discontinuation and alpha interferon therapy for life-threatening tumor progression. T-cell chimerism was 23% (19-30) on day 28, 32% (10-35) on day 100, 78% (49-95) on day 180 and 99.5% (99-100) on day 365. Three out of four patients who had measurable disease before the transplant experienced a complete response. We conclude that CD34-selected NMSCT followed by CD8-depleted DLI is feasible and preserves engraftment and apparently also the graft-versus-leukemia (GVL) effect. Further studies are needed to confirm this encouraging preliminary report.

We evaluated the ability of recombinant human erythropoietin (rHuEpo) therapy, given before high-dose therapy (HDT), to allow autologous peripheral blood stem cell transplantation (PBSCT) without red blood cell (RBC) transfusions. Eleven multiple myeloma patients underwent tandem HDT and autologous PBSC, receiving 500 U/kg/week rHuEpo from d 30 after initial transplant. Haemoglobin levels were 9.5 +/- 1.1 g/dl and 12.5 +/- 0.9 g/dl at the first and second transplant respectively (P < 0.001). RBC transfusions were required for 10/11 patients for the first transplant versus 1/11 for the second (P < 0.001). To conclude, a short course of rHuEpo therapy before HDT facilitates the performance of an autologous transplant without RBC transfusions.

To decrease the incidence of graft-versus-host disease (GVHD) observed after nonmyeloablative stem cell transplantation (NMSCT), we studied the feasibility of CD8-depleted or CD34-selected NMSCT followed by CD8-depleted preemptive donor lymphocyte infusion (DLI) given in incremental doses on days 40 and 80. Fourteen patients with high-risk malignancies and an HLA-identical sibling (n = 8) or alternative donor (n = 6) but ineligible for a conventional transplant were included. Nonmyeloablative conditioning regimen consisted in 2 Gy total body irradiation (TBI) alone, 2 Gy TBI and fludarabine (previously untreated patients) or cyclophosphamide and fludarabine (patients who had previously receivedor =12 Gy TBI). Patients 1-4 (controls) received unmanipulated peripheral blood stem cells (PBSC) and DLI and patients 5-14 CD8-depleted or CD34-selected PBSC followed by CD8-depleted DLI. Post-transplant immunosuppression was carried out with cyclosporine A (CsA) and mycophenolate mofetil (MMF). Initial engraftment was seen in all patients, but 1 patient (7%) later rejected her graft. The actuarial 180-day incidence of grades II-IV acute GVHD was 75% for patients 1-4 versus 0% for patients 5-14 (p = 0.0019). Five of 14 patients were in complete remission (CR) 180 days after the transplant and 6/14 had partial responses. The 1-year survival rate was 69%, and nonrelapse and relapse mortality rates were 16 and 18%, respectively. We conclude that CD8-depleted or CD34-selected NMSCT followed by CD8-depleted DLI is feasible and considerably decreases the incidence of acute GVHD while preserving engraftment and apparently also the graft-versus-leukemia (GVL) effect. Further studies are needed to confirm this encouraging preliminary report.

Simultaneous reactivation of distinct Herpesviridae with development of clinical manifestations is exceptional. We report a 48-year-old woman suffering from idiopathic thrombocytopenic purpura. As the disease remained refractory to corticosteroids, immunoglobulins and splenectomy, a cure of vinblastine was administered. An atypical stomatitis developed few days later. Immunohistochemistry on a Tzanck smear and a biopsy evidenced a Herpes simplex virus type 1 (HSV-1) infection. The patient presented simultaneously a single necrotic lesion on the abdomen. Immunohistochemistry on a skin biopsy revealed the presence of the varicella-zoster virus (VZV) gE, gB and IE63 proteins. Intravenous aciclovir was initiated. The present case of simultaneous clinical infections by HSV-I and VZV underlines the importance of complementary viral identification testing in the event of unusual clinical presentations.

Background : We previously reported a retrospective study suggesting that erythropoietin therapy starting on day 28 after autologous HCT was highly effective to improve Hb levels and that i.v. iron might improve response in patients with low transferrin saturation (Baron et al., Clin Cancer Res 2003). This prompted us to conduct a multicenter prospective randomized study analyzing the impact of darbepoetin alfa with or without i.v. iron on erythroid recovery after autologous HCT. Patients and Methods : 127 autologous HCT recipients with lymphoid malignancies were randomized 1:2:2 between no treatment (group 1, n=25), darbepoetin alfa (Aranesp®) 300 μg QOW starting on day 28 after HCT for a total of 7 doses (group 2, n=52), or the same regimen of darbepoetin alfa plus i.v. iron sucrose (Venofer®) 200 mg on days 28, 42 and 56 after HCT (group 3, n=50). Once the target Hb (13 g/dL) was attained, the dose of darbepoetin alfa was reduced to 150 μg, while it was withheld when Hb was ≥ 14 g/dL. Primary endpoints included proportion of complete correctors (i.e. patients reaching Hb □ 13 g/dL) before day 126 post-transplant and median time to achieve Hb correction in each arm. Data were analyzed following the intention-to-treat principle. The proportion of complete correctors by day 126 in each group was compared using the Fisher’s exact test, and median times to reach 13 g/dL in each group were compared using the logrank test. Results : The proportion of complete correctors was 24% in group 1, 81% in group 2 (P Conclusions : This is the first prospective randomized trial demonstrating that darbepoetin alfa is safe and highly effective to ensure full erythroid reconstitution after autologous HCT when started on day 28 posttransplant. I.v. iron sucrose tended (not statistically significant) to further fasten erythroid recovery with a lower dose of darbepoetin alfa required. Future studies in this setting should aim at further investigating the impact i.v. iron might have on improving response in patients with low transferrin saturation. Figure 1. Figure 1.

Background. Low donor T-cell chimerism levels after allogeneic hematopoietic cell transplantation (HCT) with nonmyeloablative conditioning have been associated with high risks of both graft rejection and relapse/progression (Baron et al., Blood2004, vol 104, p2254 and Baron et al., J Clin Oncol2005, vol 23, p1993). In a preclinical canine model, DLI preceded by 2 Gy TBI converted mixed to full donor chimerism after nonmyeloablative conditioning (Taranova et al., Blood2003, vol 102, 256a). Here, we investigated the ability of donor lymphocyte infusion (DLI) preceeded (n=15; TBI/DLI group) or not (n=15; DLI (“historical”) group) by 2 Gy TBI (given a few hours before DLI) to increase donor T-cell chimerism levels in patients with low donor T-cell chimerism levels after HCT. Methods. Conditioning regimen for HCT consisted of 2 Gy TBI with (n=15) or without (n=11) added fludarabine. 20 patients received PBSC from related, and 6 PBSC from HLA-matched unrelated donors. Peripheral blood stem cells (PBSC) were unmanipulated in 15 patients, and CD8-depleted in the 11 remaining patients. Indication for TBI/DLI included < 50% donor T-cell chimerism or decrement of donor T-cell chimerism by 20% (or 10% if below 60%). Depending of patient-donor relationship, DLIs were given at a dose of 1 to 10 × 107 T-cells/kg (median 2 × 107 T-cells/kg), 42 to 725 days (median 68.5 days) following HCT. Prophylactic postgrafting immunosuppression was pursued after DLI in all but one patients. Results. Before DLI, donor T-cell chimerism levels ranged from 15 to 77% (median 44%) in the DLI group, versus from 24 to 66% (median 47%) in the TBI/DLI group (P=0.66). Two months after DLI, donor T-cell chimerism levels ranged from 15 to 93% (median 53%) in the DLI group (P=0.10 in comparison to before DLI), versus from 20 to 98% (median 56%) in the TBI/DLI group (P=0.04 in comparison to before DLI) (Figure 1). In addition, 0 of 15 patients in the DLI group versus 5 of 15 patients in the TBI/DLI group had > 25% increased T-cell chimerism levels 2 months after DLI (P=0.04). Highest T-cell chimerism levels after DLI ranged from 15 to 99% (median 71%) in the DLI group, versus from 43 to 100% (median 96%) in the TBI/DLI group (P=0.06). Further, 2 of 15 patients in the DLI group, versus 0 of 15 patients in the TBI/DLI group experienced graft rejection. In the DLI group, 3 patients developed grade II–IV acute GVHD (2 grade II and 1 grade IV), while 1 patient in the TBI/DLI group experienced grade II acute GVHD. TBI/DLI was followed by grade IV hematologic toxicities in most patients, but most of them remained treated in the outpatient clinic. One-year overall survival was 67% in the DLI group versus 73% in the TBI/DLI group (NS). Conclusions. DLI increased donor T-cell chimerism levels in a number of patients when preceeded by low dose TBI. However, hematological toxicity of TBI/DLI was relatively high, with most patients requiring several RBC and Plt transfusions. Further studies are needed to assess its impact on HCT outcomes. Figure Figure

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 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.

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