Carlos Solano

Invasive fungal infections after allogeneic peripheral blood stem cell transplantation: incidence and risk factors in 395 patients

Summary. We have analysed the incidence and risk factors for the occurrence of invasive fungal infections (IFI) among 395 recipients of an allogeneic peripheral blood stem cell transplantation (PBSCT) from a human leucocyte antigen (HLA)‐identical sibling. IFI (n = 50) occurred in 46 patients, giving an overall probability of 14%. There were 12 cases of invasive candidiasis (3%), with only one death. Non‐Candida IFI occurred in 37 patients (12% probability), mostly invasive aspergillosis (n = 32). In multivariate analysis the only two significant variables associated with a higher risk of developing a non‐Candida IFI were the development of moderate‐to‐severe graft‐versus‐host disease (GvHD, P < 0·0001; OR 4·6) and having received steroid prophylaxis for GvHD (P = 0·04; OR 2·1). In multivariate analysis the variables associated with a lower overall survival after PBSCT were development of a non‐Candida IFI (P < 0·0001; OR 5·6), non‐early disease phase (P = 0·0001; OR 1·9), steroid prophylaxis (P = 0·02; OR 1·4), moderate‐to‐severe GvHD (P = 0·01; OR 1·6) and cytomegalovirus infection post transplant (P = 0·001; OR 1·8). Our results show that non‐Candida IFI (in particular aspergillosis) was an important cause of infectious morbidity and mortality after an HLA‐identical sibling PBSCT, while invasive candidiasis was rare. Use of steroid prophylaxis and, in particular, the development of moderate‐to‐severe GvHD post transplant were risk factors for non‐Candida IFI. Prophylactic strategies for these infections should thus take into account these risk factors.

Antilymphocyte Globulin for Prevention of Chronic Graft-versus-Host Disease

BACKGROUND Chronic graft-versus-host disease (GVHD) is the leading cause of later illness and death after allogeneic hematopoietic stem-cell transplantation. We hypothesized that the inclusion of antihuman T-lymphocyte immune globulin (ATG) in a myeloablative conditioning regimen for patients with acute leukemia would result in a significant reduction in chronic GVHD 2 years after allogeneic peripheral-blood stem-cell transplantation from an HLA-identical sibling. METHODS We conducted a prospective, multicenter, open-label, randomized phase 3 study of ATG as part of a conditioning regimen. A total of 168 patients were enrolled at 27 centers. Patients were randomly assigned in a 1:1 ratio to receive ATG or not receive ATG, with stratification according to center and risk of disease. RESULTS After a median follow-up of 24 months, the cumulative incidence of chronic GVHD was 32.2% (95% confidence interval [CI], 22.1 to 46.7) in the ATG group and 68.7% (95% CI, 58.4 to 80.7) in the non-ATG group (P<0.001). The rate of 2-year relapse-free survival was similar in the ATG group and the non-ATG group (59.4% [95% CI, 47.8 to 69.2] and 64.6% [95% CI, 50.9 to 75.3], respectively; P=0.21), as was the rate of overall survival (74.1% [95% CI, 62.7 to 82.5] and 77.9% [95% CI, 66.1 to 86.1], respectively; P=0.46). There were no significant between-group differences in the rates of relapse, infectious complications, acute GVHD, or adverse events. The rate of a composite end point of chronic GVHD-free and relapse-free survival at 2 years was significantly higher in the ATG group than in the non-ATG group (36.6% vs. 16.8%, P=0.005). CONCLUSIONS The inclusion of ATG resulted in a significantly lower rate of chronic GVHD after allogeneic transplantation than the rate without ATG. The survival rate was similar in the two groups, but the rate of a composite end point of chronic GVHD-free survival and relapse-free survival was higher with ATG. (Funded by the Neovii Biotech and the European Society for Blood and Marrow Transplantation; ClinicalTrials.gov number, NCT00678275.).

Voriconazole versus itraconazole for antifungal prophylaxis following allogeneic haematopoietic stem-cell transplantation

Antifungal prophylaxis for allogeneic haematopoietic stem‐cell transplant (alloHCT) recipients should prevent invasive mould and yeast infections (IFIs) and be well tolerated. This prospective, randomized, open‐label, multicentre study compared the efficacy and safety of voriconazole (234 patients) versus itraconazole (255 patients) in alloHCT recipients. The primary composite endpoint, success of prophylaxis, incorporated ability to tolerate study drug for ≥100 d (with ≤14 d interruption) with survival to day 180 without proven/probable IFI. Success of prophylaxis was significantly higher with voriconazole than itraconazole (48·7% vs. 33·2%, P < 0·01); more voriconazole patients tolerated prophylaxis for 100 d (53·6% vs. 39·0%, P < 0·01; median total duration 96 vs. 68 d). The most common (>10%) treatment‐related adverse events were vomiting (16·6%), nausea (15·8%) and diarrhoea (10·4%) for itraconazole, and hepatotoxicity/liver function abnormality (12·9%) for voriconazole. More itraconazole patients received other systemic antifungals (41·9% vs. 29·9%, P < 0·01). There was no difference in incidence of proven/probable IFI (1·3% vs. 2·1%) or survival to day 180 (81·9% vs. 80·9%) for voriconazole and itraconazole respectively. Voriconazole was superior to itraconazole as antifungal prophylaxis after alloHCT, based on differences in the primary composite endpoint. Voriconazole could be given for significantly longer durations, with less need for other systemic antifungals.

Allogeneic peripheral blood stem cell transplantation with reduced-intensity conditioning: results of a prospective multicentre study

Reduced‐intensity conditioning (RIC) regimens for allogeneic haematopoietic stem cell transplantation (SCT) have been shown to lead to engraftment of donor stem cells without the severe extra‐haematological toxicities of traditional myeloablative transplants. Between December 1998 and December 2000, 76 patients underwent a RIC peripheral blood SCT in a prospective multicentre study. The median age was 53 years, and 57 patients were beyond the early phase of their disease. The conditioning regimens consisted of fludarabine (150 mg/m2) plus melphalan (140 mg/m2) or busulphan (10 mg/kg). Graft‐versus‐host disease (GVHD) prophylaxis consisted of cyclosporin A plus short‐course methotrexate. The preparative regimens were well tolerated. All patients experienced severe pancytopenia, but haematological recovery was prompt in all but two cases (early deaths). The 100‐d probability of developing grade II–IV acute GVHD was 32% (10% grade III–IV), and the 1‐year probability of developing chronic extensive GVHD was 43%. Early complete donor chimaerism was observed in 52/68 patients, and 16 evaluable patients were in complete chimaerism 1 year post transplant. With a median follow‐up of 283 d (355 in 48 survivors), the 1‐year probability of transplant‐related mortality was 20%, and the 1‐year overall and progression‐free survivals were 60% and 55% respectively. In conclusion, RIC regimens lead to low early toxicity after allografting, with stable donor haematopoietic engraftment, with an apparent low risk of acute GVHD. Chronic GVHD, however, develops in a significant proportion of patients.

Quantification of DNA in Plasma by an Automated Real-Time PCR Assay (Cytomegalovirus PCR Kit) for Surveillance of Active Cytomegalovirus Infection and Guidance of Preemptive Therapy for Allogeneic Hematopoietic Stem Cell Transplant Recipients

ABSTRACT The performance of a plasma real-time PCR (cytomegalovirus [CMV] PCR kit; Abbott Diagnostics) was compared with that of the antigenemia assay for the surveillance of active CMV infection in 42 allogeneic hematopoietic stem cell transplantation (Allo-SCT) recipients. A total of 1,156 samples were analyzed by the two assays. Concordance between the two assays was 82.2%. Plasma DNA levels correlated with the number of pp65-positive cells, particularly prior to the initiation of preemptive therapy. Fifty-seven episodes of active CMV infection were detected in 37 patients: 18 were defined solely by the PCR assay and four were defined on the basis of the antigenemia assay. Either a cutoff of 288 CMV DNA copies/ml or a 2.42-log10 increase of DNAemia levels between two consecutive PCR positive samples was an optimal value to discriminate between patients requiring preemptive therapy and those not requiring therapy on the basis of the antigenemia results. The real-time PCR assay allowed an earlier diagnosis of active CMV infection and was a more reliable marker of successful clearance of CMV from the blood. Analysis of the kinetics of DNAemia levels at a median of 7 days posttreatment allowed the prediction of the response to CMV therapy. Two patients developed CMV colitis. The PCR assay tested positive both before the onset of symptoms and during the disease period. The plasma real-time PCR from Abbott is more suitable than the antigenemia assay for monitoring active CMV infection in Allo-SCT recipients and may be used for guiding preemptive therapy in this clinical setting.

Single-unit umbilical cord blood transplantation from unrelated donors in patients with hematological malignancy using busulfan, thiotepa, fludarabine and ATG as myeloablative conditioning regimen

Attempts to optimize outcomes in cord blood transplantation (CBT) by using new conditioning regimens and standardization of cord blood unit selection are warranted. In all, 88 patients (18 children and 70 adults) with hematological malignancy from nine Spanish institutions underwent a single-unit CBT after an i.v. BU-based myeloablative conditioning regimen. All evaluable patients except one engrafted. The overall cumulative incidence (CI) of myeloid engraftment was 94% at a median time of 19 days. In multivariate analysis, nonadvanced disease stage was the only factor with a favorable impact on myeloid engraftment. The CI of acute GVHD grades II–IV and chronic extensive GVHD were 24% each. The CI of nonrelapse mortality at 100 days, 180 days and 5 years was 14, 23 and 44%, respectively. The 5-year CI of relapse was 18%, whereas disease-free survival (DFS) was 46%, 39% and 11% for patients transplanted in early, intermediate and advanced stages of the disease, respectively. Our study shows high rates of engraftment with fast neutrophil recovery in patients undergoing single-unit CBT using a BU-based conditioning regimen. Long-term DFS can be achieved in a substantial number of patients with high-risk hematological malignancies, particularly when transplanted in an early stage of the disease.

Comparison between once a day vs twice a day G-CSF for mobilization of peripheral blood progenitor cells (PBPC) in normal donors for allogeneic PBPC transplantation

Despite the wide use of G-CSF for mobilization of PBPC the best dose and schedule of G-CSF has not been definitively established. In this study we have compared three different schedules of G-CSF for mobilization of PBPC in normal donors including a single daily dose of 10 μg/kg/day for 5 days (21 donors) and doses of 6 (21 donors) or 8 μg/kg/12 h (6 donors) for 5 days. We demonstrate that G-CSF at doses of 6 and 8 μg/kg/12 h mobilizes significantly more CD34+ cells/ml of blood (83.3 ± 6.7 and 121 ± 6.9, respectively) than 10 μg/kg/day (71.6 ± 6.5). Mobilization with 6 or 8 μg/kg/12 h of G-CSF was also associated with collection of significantly more CD34+ cells in comparison with 10 μg/kg/24 h (2.24 ± 1.2 and 2.46 ± 1.22 vs 1.15 ± 0.8 CD34+ cells/kg of donor/blood volume). PBPC collection was associated with a significant decrease in platelet count which was not significantly different between the three groups. Ten days after the last PBPC collection platelet counts were within normal limits while there was a decrease in WBC and ANC. We conclude that G-CSF administered every 12 h at doses of 6 μg/kg provides better CD34+ cell yield than 10 μg/kg once a day in normal donors which may translate into a decrease in the number of aphereses required to obtain enough numbers of CD34+ cells for allogeneic PBPC transplant.

Chronic graft-versus-host disease after allogeneic peripheral blood progenitor cell or bone marrow transplantation from matched related donors. A case-control study

We retrospectively compared the incidence and clinical characteristics of cGVHD in 37 allo-PBT recipients transplanted between July 1994 and October 1996 and 37 historical control allo-BMT recipients in a case- control study. All patients received a first unmanipulated transplant, graft from an HLA-identical sibling donor, with CsA-MTX GVHD prophylaxis and survived more than 100 days after transplant. PBT and BMT groups were well matched for age, grade of acute GVHD, male patients grafted from female donors, and phase of disease. The median CD34+ and CD3+ cell numbers infused in the PBT group were 5.2 × 106/kg and 307 × 106/kg, respectively. The median time to an ANC greater than 0.5 × 109/l was 16 days (range 11–22) after PBT and 22 days (range 14–36) after BMT (P < 0.001). the median time to a platelet count greater than 20 × 109/l was 15 days (range 6–43) after PBT and 28 days (range 12–68) after BMT (P < 0.001). median follow-up was 12.3 months (range 5.4–30.3) and 58.7 months (range 4–122.3), for patients receiving pbt and bmt, respectively. seventeen out of 37 (46%) pbt recipients, vs nine out of 37 (24%) BM recipients developed cGVHD. Actuarial probability of cGVHD at 1 year was 59% (95% CI, 39–79) in the PBT group vs 27% (95% CI, 12–42) in the BM group (P = 0.01). Cumulative incidence estimate of cGVHD was 51% and 25%, for patients receiving PBT and BMT respectively (P = 0.03). Clinical characteristics of cGVHD and response to therapy were similar in both groups, except for a higher incidence of de novo cGVHD in the PBT group. Our results suggest that as compared with BMT, PBT may result in an increased incidence of cGVHD.

Disparity for the minor histocompatibility antigen HA-1 is associated with an increased risk of acute graft-versus-host disease (GvHD) but it does not affect chronic GvHD incidence, disease-free survival or overall survival after allogeneic human leucocyte antigen-identical sibling donor transplantation

Disparity for the minor histocompatibility antigen HA‐1 between patient and donor has been associated with an increased risk of acute graft‐versus‐host disease (GvHD) after allogeneic human leucocyte antigen (HLA)‐identical sibling donor stem cell transplantation (SCT). However, no data concerning the impact of such disparity on chronic GvHD, relapse or overall survival are available. A retrospective multicentre study was performed on 215 HLA‐A2‐positive patients who received an HLA‐identical sibling SCT, in order to determine the differences in acute and chronic GvHD incidence on the basis of the presence or absence of the HA‐1 antigen mismatch. Disease‐free survival and overall survival were also analysed. We detected 34 patient–donor pairs mismatched for HA‐1 antigen (15·8%). Grades II–IV acute GvHD occurred in 51·6% of the HA‐1‐mismatched pairs compared with 37·1% of the non‐mismatched. The multivariate logistic regression model showed statistical significance (P: 0·035, OR: 2·96, 95% CI: 1·07–8·14). No differences were observed between the two groups for grades III–IV acute GvHD, chronic GvHD, disease‐free survival or overall survival. These results confirmed the association between HA‐1 mismatch and risk of mild acute GvHD, but HA‐1 mismatch was not associated with an increased incidence of chronic GvHD and did not affect relapse or overall survival.

Comparison of outcomes after single or double cord blood transplantation in adults with acute leukemia using different types of myeloablative conditioning regimen, a retrospective study on behalf of Eurocord and the Acute Leukemia Working Party of EBMT

We report outcomes after single (s) and double (d) umbilical cord blood transplantation (UCBT) after myeloablative conditioning (MAC) regimen for 239 patients transplanted for acute leukemia in first complete remission (CR1). All sUCBT patients received a total nucleated cell dose >2.5 × 107/kg. Conditioning regimen for sUCBT was total body irradiation (TBI)12 Gy- or busulfan (BU)-based±fludarabine (Flu) (n=68, group 1), thiotepa+BU+Flu (TBF) (n=88, group 2), and for dUCBT it was TBI12 Gy+cyclophosphamide±Flu (n=83, group 3). dUCBT recipients were younger, received higher cell dose and less frequently antithymocyte globulin. In multivariate analysis, we found similar neutrophil recovery among the three groups; however, acute graft-versus-host disease II–IV was higher in dUCBT compared with others. Non-relapse mortality and relapse incidence were not statistically different among the three groups. Leukemia-free survival was 30% for sUCBT using TBI- or BU-based MAC compared with 48% for sUCBT TBF and 48% for dUCBT (P=0.02 and P=0.03, respectively), and it was not statistically different between sUCBT with TBF and dUCBT. In conclusion, use of sUCBT with adequate cell dose (>2.5 × 107/kg) and a specific conditioning regimen in the MAC setting results in similar outcomes as dUCBT. The choice of TBF conditioning regimen for sUCBT may improve results, and whether this regimen may be effective in dUCBT should be further analyzed.