Simone Cesaro

Extracorporeal photochemotherapy for paediatric patients with graft‐versus‐host disease after haematopoietic stem cell transplantation

Summary. This study aimed to ascertain whether extracorporeal photochemotherapy (ECP) is an effective treatment for paediatric patients with refractory graft‐versus‐host disease (GVHD). From January 1992 to December 2000, 77 children (median age 8·6 years) with either acute (n = 33) or chronic (n = 44) GVHD, resistant to conventional immunosuppressive therapy, were treated with ECP in four Italian paediatric hospitals. After ECP, acute GVHD involving skin, liver and gut responded completely in 76%, 60% and 75% of patients respectively. The 5‐year overall survival was 69% for responding patients vs 12% for non‐responders (P = 0·001). Among the 44 children with chronic GVHD, 15 (44%) showed a complete response and 10 (29%) a significant improvement after ECP. The 5‐year overall survival was 96% for responders vs 58% for non‐responders (P = 0·04). Our results suggest that ECP is an effective treatment that may be useful in paediatric patients with either acute or chronic GVHD who have failed to respond to standard immunosuppressive therapy.

The EBMT activity survey: 1990-2010

A total of 654 centers from 48 countries were contacted for the 2010 survey. In all, 634 centers reported a total of 33 362 hematopoietic SCT (HSCT) with 30 012 patients receiving their first transplant (12 276 allogeneic (41%) and 17 736 autologous (59%)). Main indications were leukemias: 9355 (31%; 93% allogeneic), lymphoid neoplasias specifically Non Hodgkin’s lymphoma, Hodgkin’s lymphoma and plasma cell disorders: 17 362 (58%; 12% allogeneic), solid tumors: 1585 (5%; 6% allogeneic) and non-malignant disorders: 1609 (6%; 88% allogeneic). There were more unrelated donors than HLA-identical sibling donors (53% versus 41%); the proportion of peripheral blood as stem cell source was 99% for autologous and 71% for allogeneic HSCT. Cord blood was primarily used in allogeneic transplants (6% of total) with three autologous cord blood HSCT being reported. The number of transplants has increased by 19% since 2005 (allogeneic 37% and autologous 9%) and continued to increase by about 1100 HSCT per year since 2000. Patterns of increase were distinct and different. The data show the development of transplantation in Europe since 1990, with the number of patients receiving a HSCT increasing from 4200 to over 30 000 annually. The most impressive trend seen is the steady increase of unrelated donor transplantation, in parallel to the availability of unrelated donors through donor registries.

Fourth European Conference on Infections in Leukaemia (ECIL-4): guidelines for diagnosis, prevention, and treatment of invasive fungal diseases in paediatric patients with cancer or allogeneic haemopoietic stem-cell transplantation

Invasive opportunistic fungal diseases (IFDs) are important causes of morbidity and mortality in paediatric patients with cancer and those who have had an allogeneic haemopoietic stem-cell transplantation (HSCT). Apart from differences in underlying disorders and comorbidities relative to those of adults, IFDs in infants, children, and adolescents are unique with respect to their epidemiology, the usefulness of diagnostic methods, the pharmacology and dosing of antifungal agents, and the absence of interventional phase 3 clinical trials for guidance of evidence-based decisions. To better define the state of knowledge on IFDs in paediatric patients with cancer and allogeneic HSCT and to improve IFD diagnosis, prevention, and management, the Fourth European Conference on Infections in Leukaemia (ECIL-4) in 2011 convened a group that reviewed the scientific literature on IFDs and graded the available quality of evidence according to the Infectious Diseases Society of America grading system. The final considerations and recommendations of the group are summarised in this manuscript.

Fludarabine, cyclophosphamide and anti-thymocyte globulin for alternative donor transplants in acquired severe aplastic anemia: a report from the EBMT-SAA Working Party

Summary:We have developed a reduced-intensity conditioning regimen for patients with severe aplastic anemia (SAA) undergoing alternative donor transplants, which includes fludarabine (120 mg/m2), cyclophosphamide (1200 mg/m2) and antithymocyte globulin (7.5 mg/kg). Graft-versus-host disease (GvHD) prophylaxis consisted of cyclosporine and methotrexate. We have enrolled 38 SAA patients in this trial: median age of 14 (3–37) years, transplanted from unrelated (n=33) or family mismatched (n=5) donors, with unmanipulated marrow (n=36) or peripheral blood (n=2). Seven patients (18%) had evidence of graft failure, 11% developed grade II–III acute GvHD and 27% developed chronic GvHD. The actuarial 2-year survival is 73%, with a median follow-up of 621 days. Younger patients (⩽14 years) had a lower risk of rejection (5%) and improved actuarial survival (84%). Causes of death were infections (n=3), graft failure (n=2), Epstein–Barr virus lymphoma (n=2) and hemorrhage (n=2). In conclusion, the actuarial 2-year survival is encouraging in young SAA patients receiving a radiation-free conditioning regimen. The significant risk of graft failure in patients 15 years or older may require modification of the conditioning regimen in adults.

Clinical, genetic, and cellular analysis of 49 osteopetrotic patients: implications for diagnosis and treatment

Background: Osteopetrosis, a genetic disease characterised by osteoclast failure, is classified into three forms: infantile malignant autosomal recessive osteopetrosis (ARO), intermediate autosomal recessive osteopetrosis (IRO), and autosomal dominant osteopetrosis (ADO). Methods: We studied 49 patients, 21 with ARO, one with IRO, and 27 with type II ADO (ADO II). Results: Most ARO patients bore known or novel (one case) ATP6i (TCIRG1) gene mutations. Six ADO II patients had no mutations in ClCN7, the only so far recognised gene implicated, suggesting involvement of yet unknown genes. Identical ClCN7 mutations produced differing phenotypes with variable degrees of severity. In ADO II, serum tartrate resistant acid phosphatase was always elevated. Bone alkaline phosphatase (BALP) was generally low, but osteocalcin was high, suggesting perturbed osteoblast differentiation or function. In contrast, BALP was high in ARO patients. Elevated osteoclast surface/bone surface was noted in biopsies from most ARO patients. Cases with high osteoclasts also showed increased osteoblast surface/bone surface. ARO osteoclasts were morphologically normal, with unaltered formation rates, intracellular pH handling, and response to acidification. Their resorption activity was greatly reduced, but not abolished. In control osteoclasts, all resorption activity was abolished by combined inhibition of proton pumping and sodium/proton antiport. Conclusions: These findings provide a rationale for novel therapies targeting pH handling mechanisms in osteoclasts and their microenvironment.

Defibrotide for prophylaxis of hepatic veno-occlusive disease in paediatric haemopoietic stem-cell transplantation: an open-label, phase 3, randomised controlled trial

BACKGROUND Hepatic veno-occlusive disease is a leading cause of morbidity and mortality after haemopoietic stem-cell transplantation (HSCT). We aimed to assess whether defibrotide can reduce the incidence of veno-occlusive disease in this setting. METHODS In our phase 3 open-label, randomised controlled trial, we enrolled patients at 28 European university hospitals or academic medical centres. Eligible patients were younger than 18 years, had undergone myeloablative conditioning before allogeneic or autologous HSCT, and had one or more risk factor for veno-occlusive disease based on modified Seattle criteria. We centrally assigned eligible participants on the basis of a computer-generated randomisation sequence (1:1), stratified by centre and presence of osteopetrosis, to receive intravenous defibrotide prophylaxis (treatment group) or not (control group). The primary endpoint was incidence of veno-occlusive disease by 30 days after HSCT, adjudicated by a masked, independent review committee, in eligible patients who consented to randomisation (intention-to-treat population), and was assessed with a competing risk approach. Patients in either group who developed veno-occlusive disease received defibrotide for treatment. We assessed adverse events to 180 days after HSCT in all patients who received allocated prophylaxis. This trial is registered with ClinicalTrials.gov, number NCT00272948. FINDINGS Between Jan 25, 2006, and Jan 29, 2009, we enrolled 356 eligible patients to the intention-to-treat population. 22 (12%) of 180 patients randomly allocated to the defibrotide group had veno-occlusive disease by 30 days after HSCT compared with 35 (20%) of 176 controls (risk difference -7·7%, 95% CI -15·3 to -0·1; Z test for competing risk analysis p=0·0488; log-rank test p=0·0507). 154 (87%) of 177 patients in the defibrotide group had adverse events by day 180 compared with 155 (88%) of 176 controls. INTERPRETATION Defibrotide prophylaxis seems to reduce incidence of veno-occlusive disease and is well tolerated. Thus, such prophylaxis could present a useful clinical option for this serious complication of HSCT. FUNDING Gentium SpA, European Group for Blood and Marrow Transplantation.

Hematopoietic SCT in Europe 2013: Recent trends in the use of alternative donors showing more haploidentical donors but fewer cord blood transplants

A record number of 39 209 HSCT in 34 809 patients (14 950 allogeneic (43%) and 19 859 autologous (57%)) were reported by 658 centers in 48 countries to the 2013 survey. Trends include: more growth in allogeneic than in autologous HSCT, increasing use of sibling and unrelated donors and a pronounced increase in haploidentical family donors when compared with cord blood donors for those patients without a matched related or unrelated donor. Main indications were leukemias, 11 190 (32%; 96% allogeneic); lymphoid neoplasias, 19 958 (57%; 11% allogeneic); solid tumors, 1543 (4%; 4% allogeneic); and nonmalignant disorders, 1975 (6%; 91% allogeneic). In patients without a matched sibling or unrelated donor, alternative donors are used. Since 2010 there has been a marked increase of 96% in the number of transplants performed from haploidentical relatives (802 in 2010 to 1571 in 2013), whereas the number of unrelated cord blood transplants has slightly decreased (789 in 2010 to 666 in 2013). The use of donor type varies greatly throughout Europe.

Fludarabine, cyclophosphamide, antithymocyte globulin, with or without low dose total body irradiation, for alternative donor transplants, in acquired severe aplastic anemia: a retrospective study from the EBMT-SAA working party

Background We analyzed the outcome of 100 patients with acquired severe aplastic anemia undergoing an alternative donor transplant, after immune suppressive therapy had failed. Design and Methods As a conditioning regimen, patients received either a combination of fludarabine, cyclophosphamide, and antithymocyte globulin (n=52, median age 13 years) or this combination with the addition of low dose (2 Gy) total body irradiation (n=48, median age 27 years). Results With a median follow-up of 1665 and 765 days, the actuarial 5-year survival was 73% for the group that received fludarabine, cyclophosphamide, and antithymocyte globulin and 79% for the group given the conditioning regimen including total body irradiation. Acute graft-versus-host disease grade III–IV was seen in 18% and 7% of the groups, respectively. Graft failure was seen in 17 patients with an overall cumulative incidence of 17% in patients receiving conditioning with or without total body irradiation: 9 of these 17 patients survive in the long-term. The most significant predictor of survival was the interval between diagnosis and transplantation, with 5-year survival rates of 87% and 55% for patients grafted within 2 years of diagnosis and more than 2 years after diagnosis, respectively (P=0.0004). Major causes of death were graft failure (n=7), post-transplant-lymphoproliferative-disease (n=4) and graft-versus-host disease (n=4). Conclusions This study confirms positive results of alternative donor transplants in patients with severe aplastic anemia, the best outcomes being achieved in patients grafted within 2 years of diagnosis. Prevention of rejection and Epstein-Barr virus reactivation may further improve these results.

Human polyomavirus BK (BKV) load and haemorrhagic cystitis in bone marrow transplantation patients

Several observations suggest an association between long-lasting haemorrhagic cystitis (HC) in bone marrow transplantation (BMT) recipients and human polyomavirus BK (BKV) reactivation, but no conclusive evidence has been obtained so far. The amount of BKV measured in the urine of BMT patients during an episode of HC was compared with that detected in the urine of BMT patients without HC and of immunocompetent individuals in order to better assess the association of BKV reactivation with HC. For this purpose a quantitative competitive PCR was developed. The application of this assay to clinical samples allowed us to distinguish asymptomatic reactivation both in healthy individuals and in immunocompromised patients from reactivation associated with HC, in almost all cases. Low levels, below the sensitivity of the quantitative assay, were shown in asymptomatic healthy individuals and in about 50% of immunocompromised patients. A significantly higher viral load than in the urine of asymptomatic immunocompromised patients was detected in the urine of patients with HC. These data strengthen the hypothesis that BKV reactivation can cause, together with other factors, the majority of late HC in BMT recipients as well as in patients treated for acute refractory lymphoblastic leukemia.

Fungal Infections in Children With Cancer A Prospective, Multicenter Surveillance Study

Background: Data on epidemiology and survival after fungal infections in patients with cancer are primarily based on studies in adults, whereas few data are available on children. Methods: A prospective, multicenter, 2-year surveillance of fungal infections in children receiving antineoplastic treatment was performed in 15 Italian centers. For each case, defined by means of EORTC-IFIG/NIAID-MSG, information was collected on age, phase of treatment, presence of neutropenia or lymphocytopenia, administration of antifungal drugs and survival. Results: Ninety-six episodes (42 proven [19 fungemias, 23 deep tissue infections], 17 probable and 37 possible invasive mycoses) were reported. Most of them (73%) followed aggressive chemotherapy, 21% allogeneic hematopoietic stem cell transplantation and only 6% moderately aggressive treatment. Neutropenia was present in 77% of the episodes, and it had a longer duration before deep tissue mycosis as compared with fungemia (P = 0.020). Lymphocytopenia was present in 75% of the episodes observed in nonneutropenic patients. As compared with children with fungemia, patients with probable invasive mycoses had a 25.7-fold increased risk of death, whereas it was 7.7-fold greater in children with possible invasive mycoses and 5-fold higher in those with proven deep tissue infection (P = 0.004). The risk of death was also 3.8-fold higher in patients already receiving antifungals at the time of diagnosis of infection as compared with those not receiving antimycotic drugs. Conclusions: In children with cancer, aggressive antineoplastic treatment, severe and longlasting neutropenia and lymphocytopenia are associated with fungal infections. These features as the clinical pictures are similar to those reported in adults, but in children, the overall and the infection-specific (fungemia or mycosis with deep tissue infection) mortalities are lower.