Pascale Frere

Comparison of thrombotic microangiopathy after allogeneic hematopoietic cell transplantation with high-dose or nonmyeloablative conditioning.

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.

Infections after allogeneic hematopoietic stem cell transplantation with a nonmyeloablative conditioning regimen.

Hematopoietic cell transplantation (HCT) following nonmyeloablative conditioning (NMSCT) may be associated with a reduced risk of infection compared to standard allogeneic HCT. We retrospectively analyzed incidence and risk factors of infection in 62 patients undergoing NMSCT with low-dose TBI +/− fludarabine and postgrafting CsA and MMF. The proportion of patients with any infection was 77%, but the majority of infectious events occurred beyond day 30. Donor other than sibling, older age, early disease and male gender were significant risk factors. The incidence of bacteremia was 55% at 1 year and the number of bacteremic episodes was 0.9 per patient (0.08 before day 30). The risk of bacteremia increased with older age and the use of a donor other than an HLA-identical sibling, but not with neutropenia. The incidence of infections other than bacteremia correlated with the use of corticosteroids. The risk of CMV infection increased with high-risk CMV serology, and risk of CMV disease with high-risk CMV serology, older age, first transplantation and a diagnosis of lymphoma. In conclusion, after NMSCT, infections are not frequent in the first 30 days post transplant but careful long-term monitoring is necessary thereafter.

T-CELL RECONSTITUTION AFTER UNMANIPULATED, CD8- DEPLETED OR CD34-SELECTED NONMYELOABLATIVE PERIPHERAL BLOOD STEM-CELL TRANSPLANTATION

Background. 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. Methods. 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. Results. 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). Conclusions. 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.

Nonmyeloablative stem cell transplantation with CD8-depleted or CD34-selected peripheral blood stem cells.

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 received > or =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.

Infections after CD34-selected or unmanipulated autologous hematopoietic stem cell transplantation

Abstract:  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‐Hodgkins lymphoma (n = 32), Hodgkins 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.

Changing pattern of bacterial susceptibility to antibiotics in hematopoietic stem cell transplant recipients.

Adequate infection prophylaxis and empirical antibiotic therapy are of critical importance after hematopoietic stem cell transplantation (HSCT). We examined the evolution of bacterial susceptibility to antibiotics in 492 patients (198 allografts and 294 autografts) transplanted between 1982 and 1999 and evaluated whether ciprofloxacin prophylaxis and an empirical antibiotic regimen (glycopeptide + third-generation cephalosporin) were still valid. We collected all susceptibility tests performed during the initial hospitalization on blood cultures as well as routine surveillance cultures and analyzed susceptibility to ciprofloxacin and to major antibiotics used in our unit. Gram-positive cocci rapidly became resistant to ciprofloxacin (susceptibility around 70% in 1990 to less than 20% in 1998) but sensitivity to glycopeptides remained unaltered. There was a rapid decline in the number of patients colonized with Gram-negative bacilli in the early years of ciprofloxacin prophylaxis. However, susceptibility to ciprofloxacin fell sharply from around 90% in 1990 to around 30% in 1999. In parallel, susceptibility to ceftazidime also decreased to less than 80% in recent years. Piperacillin (± tazobactam) did not show any variation over time and its efficacy remained too low (about 60%). Imipenem as well as recently introduced cefepim and meropenem showed stable and excellent profiles (>90% susceptibility). In conclusion: (1) quinolone prophylaxis has now lost most of its value; (2) the choice of a third-generation cephalosporin for empirical antibiotic therapy may no longer be the best because of the emergence of Gram-negative strains resistant to β-lactamases, such as Enterobacter sp. More appropriate regimens of empirical antibiotic therapy in HSCT recipients may be based on the use of a carbapenem or fourth-generation cephalosporin.

Hyperammonemia after high-dose chemotherapy and stem cell transplantation.

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. Bone Marrow Transplantation (2000) 26, 343–345.

Tandem high-dose therapy (HDT) for multiple myeloma: recombinant human erythropoietin therapy given between first and second HDT allows second peripheral blood stem cell transplantation without red blood cell transfusion.

Summary. 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.

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

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

Low T-cell chimerism is not followed by graft rejection after nonmyeloablative stem cell transplantation (NMSCT) with CD34-selected PBSC.

Summary: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 ⩾2 acute GVHD only after abrupt cyclosporin discontinuation and α 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.