ATG vs thiotepa with busulfan and cyclophosphamide in matched-related bone marrow transplantation for thalassemia.

Matched-related bone marrow transplantation (BMT) may cure >80% of low-risk children with severe thalassemia (ST). Very long-term follow-up studies have shown how the standard busulfan-cyclophosphamide (BuCy) regimen may be associated with normalization of health-related quality of life, no second malignancies in the absence of chronic graft-versus-host disease, and fertility preservation in many patients. However, because BuCy may be associated with high rejection rates, some centers incorporate thiotepa (Tt) in busulfan- or treosulfan-based regimens, a combination that may increase the risk of permanent infertility. This study retrospectively compares matched-related BMT outcomes in 2 groups of low-risk ST patients conditioned with either Tt or anti-thymocyte globulin (ATG) in addition to BuCy. A total of 81 consecutive first BMTs were performed in 5 collaborating startup BMT centers in the Indian subcontinent between January 2009 and January 2016; 30 patients were transplanted after conditioning with Tt-BuCy between January 2009 and July 2013, whereas between August 2013 and January 2016, 51 patients received ATG-BuCy. All patients were <15 years and had no hepatomegaly (liver ≤2 cm from costal margin). Actuarial overall survival in the Tt-BuCy and ATG-BuCy groups was 87% and 94% and thalassemia-free survival was 80% and 85% at a median follow-up of 37 and 17 months, respectively, with no significant differences by log-rank statistics. Substituting Tt with ATG in the standard BuCy context seems safe and effective and may decrease transplant-related mortality. Higher fertility rates are expected for patients who received ATG-BuCy.

Remission of microangiopathy in transplanted thalassemic child.

Transplant associated thrombotic microangiopathy is a severe complication of Hematopoeitic stem cell transplantation. Although there is agreement in terms of diagnostic criteria, treatment options are not clarified yet. We present a patient aged 2.6 years who developed transplant associated thrombotic microangiopathy after allogeneic bone marrow transplantation and to discuss both risk factors and possible spontaneous remission of transplant associated thrombotic microangiopathy.

Assessment of serum zinc levels of patients with thalassemia compared to their siblings.

Zinc (Zn) is essential for appropriate growth and proper immune function, both of which may be impaired in thalassemia children. Factors that can affect serum Zn levels in these patients may be related to their disease or treatment or nutritional causes. We assessed the serum Zn levels of children with thalassemia paired with a sibling. Zn levels were obtained from 30 children in Islamabad, Pakistan. Serum Zn levels and anthropometric data measures were compared among siblings. Thalassemia patients' median age was 4.5 years (range 1-10.6 years) and siblings was 7.8 years (range 1.1-17 years). The median serum Zn levels for both groups were within normal range: 100 µg/dL (10 µg/dL-297 µg/dL) for patients and 92 µg/dL (13 µg/dL-212 µg/dL) for siblings. There was no significant difference between the two groups. Patients' serum Zn values correlated positively with their corresponding siblings (r = 0.635, P < 0.001). There were no correlations between patients' Zn levels, height for age Z-scores, serum ferritin levels, chelation, or blood counts (including both total leukocyte and absolute lymphocyte counts). Patients' serum Zn values correlated with their siblings' values. In this study, patients with thalassemia do not seem to have disease-related Zn deficiency.

A prospective international cooperative information technology platform built using open-source tools for improving the access to and safety of bone marrow transplantation in low- and middle-income countries.

Jagriti Innovations developed a collaboration tool in partnership with the Cure2Children Foundation that has been used by health professionals in Italy, Pakistan, and India for the collaborative management of patients undergoing bone marrow transplantation (BMT) for thalassemia major since August 2008. This online open-access database covers data recording, analyzing, and reporting besides enabling knowledge exchange, telemedicine, capacity building, and quality assurance. As of February 2014, over 2400 patients have been registered and 112 BMTs have been performed with outcomes comparable to international standards, but at a fraction of the cost. This approach avoids medical emigration and contributes to local healthcare strengthening and competitiveness. This paper presents the experience and clinical outcomes associated with the use of this platform built using open-source tools and focusing on a locally pertinent tertiary care procedure-BMT.

International cooperation for the cure and prevention of severe hemoglobinopathies.

Thalassemia major (TM) is the most frequent life-threatening noninfectious disease of childhood in the Middle East, South Asia, and Pacific Islands where it accounts for a significant proportion of childhood mortality, morbidity, and related health care expenses. In spite of major advances in supportive care during the last decade, many patients in low-income and middle-income countries still fare poorly because of high treatment costs and lack of accessible multidisciplinary teams, not to consider the risk of blood-borne infections, primarily hepatitis C. In selected low-risk patients with a compatible sibling, TM is highly curable by bone marrow transplantation (BMT), which also improves the quality of life and is cost-effective. Starting in 2008, the Cure2Children Foundation (C2C), an Italian Non-Governmental Organization, has supported a BMT network in Pakistan, which during 2012 was extended to India. The primary aim of this project was to assess feasibility, outcomes, and costs of matched-related BMT for thalassemia in young low-risk children using a well-established and tolerable strategy. A total of 100 matched-related BMTs have been performed to date by partner institutions within this C2C-supported network; in the 50 low-risk cases with TM, over 90% disease-free survival was obtained with procedure expenses within 10,000 USD/BMT, that is, an outcome comparable to that obtained in affluent countries but with a fraction of the expenses. This cure rate was also obtained in start-up BMT centers (1 in Pakistan and 1 in India) within a structured and intensive cooperation program. Twinning and other international cooperation strategies based on shared principles and a common vision may substantially facilitate access to BMT.

Life satisfaction in young adults 10 or more years after hematopoietic stem cell transplantation for childhood malignant and nonmalignant diseases does not show significant impairment compared with healthy controls: a case-matched study.

Patients undergoing hematopoietic stem cell transplantation (HSCT) may experience physical and psychological deterioration that impairs their life satisfaction (LS). This study focused on LS in long-term survivors at 10 or more years after HSCT. Fifty-five patients (39 males, median age 25 years) undergoing allogeneic HSCT for childhood malignant (n = 52) or nonmalignant diseases (n = 3) were enrolled. A control group of 98 young adults (59 males, median age 24 years) was considered. A questionnaire with a modified Satisfaction Life Domain Scale was administered. We assessed such domains as education, employment, leisure time, social relationships, and perception of physical status with a 30-item questionnaire. To investigate the association between the domains and the probability of diminished LS, we performed a logistical procedure using the maximum likelihood method. Predictive factors of LS were adjusted for sociodemographic variables. In the multivariate analysis, the participant's level of LS was not significantly correlated with sociodemographic factors or with HSCT status. The same analysis showed a slight trend in favor of the control group (P = .06) for body perception. Our data suggest that the patients who undergo HSCT in childhood have no significant difference in long-term LS compared with healthy controls.

Glutamine-enriched nutrition does not reduce mucosal morbidity or complications after stem-cell transplantation for childhood malignancies: a prospective randomized study.

BACKGROUND: Intravenous glutamine-enriched solution seems to be effective in posttransplant period in decreasing the severity and duration of mucositis. The aim of this randomized study was to determine the benefit of glutamine supplementation both on mucosal morbidity and in posttransplant associated complications. METHODS: Children undergoing allogeneic hematopoietic stem-cell transplantation (HSCT) for malignant hematological diseases were randomly assigned to standard total parenteral nutrition (S-TPN) or glutamine-enriched (GE)-TPN solution consisting of 0.4 g/kg/day of l-alanine-glutamine dipeptide. This treatment started on the day of HSCT and ended when the patients could orally cover more than 50% of their daily energy requirements. The severity and the rate of post-HSCT mucositis were based on World Health Organization criteria. All the analyses were conducted on intention-to-treat principle. RESULTS: One hundred twenty consecutive patients (83 men; median age, 8.1 years) were enrolled. The mean duration of treatment was 23.5 and 23 days in the two treatment arms. The mean calorie intake was 1538 kcal/d in the S-TPN group and 1512 kcal/d in GE-TPN group. All patients were well nourished before and after HSCT. Mucositis occurred in 91.4% and 91.7% of patients in S-TPN and GE-TPN arm, respectively (P=0.98). Odds ratio adjusted by type of HSCT was 0.98 (95% confidence interval, 0.26-2.63). Type and duration of analgesic treatment, clinical outcome (engraftment, graft versus host disease, early morbidity, and mortality, relapse rate up to 180 days post-HSCT) were not significantly different in the two treatment arms. CONCLUSION: GE-TPN solution does not affect mucositis and outcome in well-nourished HSCT allogeneic patients.

Cardiac and pulmonary late effects do not negatively influence performance status and non-relapse mortality of children surviving five yr after autologous hematopoietic cell transplantation: report from the EBMT Paediatric Diseases and Late Effects Working Parties.

The current prospective study dealt with clinical outcome associated with pulmonary and cardiac late effects of AuHCT in children with malignancies. We prospectively evaluated 58 children, utilizing pulmonary function tests and cardiac shortening fraction, performed in pre-AuHCT phase and then annually. The overall five-yr survival was 68%. The five-yr cumulative incidence of lung and cardiac function impairment in survivors was 21% in both cases. None of the patients presented with restrictive or obstructive pulmonary pathology at the last follow-up and performance status for all survivors, ranged from 90% to 100%. The cumulative incidence of non-relapse mortality was 12.6% (range 6.3-25.3%), whereas relapse mortality was 19.7% (range 11.6-33.5). In conclusion, our study shows no significant deterioration in post-AuHCT pulmonary and cardiac function and in particular, no negative impact of lung and heart late effects on performance status and non-relapse mortality.

Allogeneic stem cell transplantation for children with acute myeloid leukemia in second complete remission.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective therapy for patients with relapsed acute myeloid leukemia. In this retrospective, multicenter study, we analyzed the outcome of 63 children (median age, 7 y; range, 0.2 to 17) who received unmanipulated allo-HSCT in second complete remission. Either a matched family donor or an unrelated donor was used in 29 (46%) and 34 (54%) patients, respectively. The stem cell source was bone marrow in 53 children (84%), peripheral blood in 7 (11%), and cord blood in 3 patients (5%). Preparative regimen included total body irradiation in 25 patients (40%). The 5-year estimates of overall survival and leukemia-free survival were 53% [95% confidence interval (CI) 39-66] and 49% (95% CI 35-63), respectively, whereas the cumulative incidence of relapse and transplant-related mortality (TRM) were 26% (95% CI 16-41) and 25% (95% CI 15-40), respectively. In multivariate analysis, the use of a matched family donor predicted a better probability of LFS [relative risk (RR) 2.29, P=0.05]. Both chronic graft-versus-host disease occurrence and age at diagnosis greater than 11 years were associated with an increased TRM (RR 8.08, P=0.04 and RR 4.38, P=0.05, respectively). These results indicate that allo-HSCT is a procedure able to rescue a significant proportion of children with acute myeloid leukemia in second complete remission, especially if an human leukocyte antigen-compatible relative is employed as donor. Both leukemia recurrence and TRM contributed to treatment failure. Optimization of donor selection and of strategies for both prophylaxis and treatment of graft-versus-host disease may improve the results of unrelated donor allo-HSCT.

Eligibility for allogeneic transplantation in very high risk childhood acute lymphoblastic leukemia: the impact of the waiting time.

The advantage of allogeneic transplant from compatible related donors versus chemotherapy in children with very-high-risk acute lymphoblastic leukemia in first complete remission was previously demonstrated in an international prospective trial. This study quantified the impact of time elapsed in first remission in the same cohort. Of 357 pediatric patients with very-high-risk acute lymphoblastic leukemia, 259 received chemotherapy, 55 transplantation from compatible related and 43 from unrelated donors. The 5-year disease-free survival was 44.2% overall and 42.5% for chemotherapy only patients. The chemotherapy conditional 5-year disease-free survival increased to 44.4%, 47.6%, 51.7%, and 60.4% in patients who maintained their first remission for at least 3, 6, 9, and 12 months respectively. The overall outcome was superior to that obtained with chemotherapy-only at any time-point. The relative advantage of transplant from compatible related donors in very-high-risk childhood acute lymphoblastic leukemia was consistent for any time elapsed in first remission.

Extracorporeal photochemotherapy for the treatment of chronic graft-versus-host disease: trend for a possible cell dose-related effect?

Extracorporeal photochemotherapy (ECP) has been progressively introduced into the treatment of both acute and chronic graft-versus-host disease (cGvHD) over the last decade. Nevertheless, its mechanisms of action, as well as the optimal treatment schedule, have not yet been defined. We retrospectively analyzed 25 patients with cGvHD unresponsive to conventional treatments who underwent ECP from 1997 until 2005. The impact of various factors (such as treated and infused nucleated cells, time from transplantation and cGvHD onset, and time from cGvHD and ECP treatment) on the probability of no response to ECP was therefore investigated. A positive response to ECP was achieved in 80% of the patients, after a median of 19 ECP treatments (with a range of 8-38). Eighteen out of the 20 patients responsive to the treatment maintained their response for a median of 30 months. We mainly focused on clinical response and yield composition. The analysis on mononuclear cell (MNC) dose suggested that an increase of MNC dose/kg b.w. (body weight) induced a decrease in the odds of treatment failure, and that, if the MNC dose infused was at least 100 x 10(6)/kg b.w. per ECP treatment, a more positive and longer-lasting response was achieved. Moreover, the mean dose of treated and infused monocytes x 10(6)/kg b.w./ECP did not account for a clear dose-related effect. These findings may eventually result in a more patient-tailored approach to ECP. Prospective multicenter trials should be designed to investigate the real impact of MNC dose on ECP responsiveness.

Risk factors and severe outcome in thrombotic microangiopathy after allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Thrombotic microangiopathy (TMA) has been described as severe complication after hematopoietic stem cell transplantation (HSCT). The principal aim of this study was to focus the incidence and the outcome of TMA in the era of more complex HSCTs. METHODS: We analyzed the role of some predicting factors for the incidence and the outcome of TMA after HSCT. We enrolled 539 consecutive patients (307 males, median age 31 years) undergoing HSCT from match or mismatch human leukocyte antigen family donor (314) or match/mismatch unrelated (195) and haploidentical donor (30) for malignant or nonmalignant diseases. TMA diagnosis was performed by homogeneous clinical and laboratory criteria. RESULTS: Sixty-four of 539 patients presented TMA (11,87%) and the five-year cumulative incidence of TMA was 14% (HR=0.13). Fifty nine of 64 patients were affected by malignant and 5/64 by non-malignant diseases. On multivariate analysis, TMA occurrence was influenced by graft versus host disease >grade II (P=0.0001), donor type (P=0.029), gender (P=0.0233), total body irradiation based conditioning regimen (P=0.0041). Three factors for TMA outcome proved to be statistically significant by multivariate analysis: age (P=0.009), donor type (P=0.0187) and TMA index (P=0.029). The TMA mortality rate was 50%. The outcome was influenced by defibrotide (P=0.02 in univariate analysis). CONCLUSIONS: The study underlines the possibility of finding out which patients are more prone to developing post-HSCT TMA, and identifies which risk factors are more frequently associated with a dismal outcome after TMA.

Distinctive characteristics of diabetes mellitus after hematopoietic cell transplantation during childhood.

We report on six patients who developed diabetes mellitus after hematopoietic cell transplantation (HCT). The prevalence in our cohort of long-term survivors after HCT performed below 18 yr of age was 3%. The median age at onset of diabetes was 22.4 yr (range 11.3-34.4). The median period between HCT and diabetes was 10.1 yr (range 5.6-22.1). Five out of the six patients received total irradiation therapy and five had other endocrinological abnormalities. The onset of diabetes in all patients was insidious and none had diabetic ketoacidosis. Body mass indexes at diabetes onset were within normal levels. The clinical and laboratory features that characterized our patients with diabetes after HCT make it difficult to classify them as having type-1 or type-2 diabetes. The relatively high prevalence of diabetes and its insidious onset in this group of patients, advocate clinicians to evaluate carefully even slight variations in fasting blood glucose, usually included in the routine biochemistry follow-up. These data also suggest that HbA1c and oral glucose-tolerance test should be added to the follow-up program of late complications if fasting blood glucose levels are slightly increased.

Treatment of acute graft-versus-host disease with prednisolone: significant survival advantage for day +5 responders and no advantage for nonresponders receiving anti-thymocyte globulin.

Newly diagnosed patients with acute graft-versus-host disease (GvHD, grades I-IV; n = 211) were given 6-methylprednisolone (6MPred) 2 mg/kg per day for 5 consecutive days; 150 patients (71%) tapered 6MPred on day +5 and were considered responders; 61 patients (29%) could not taper their steroid dose and were considered nonresponders. The cumulative incidence of transplant-related mortality (TRM) for responders and nonresponders is, respectively, 27% and 49% (P = .009), and the 5-year survival is 53% and 35% (P = .007). Nonresponders on day +5 (n = 61) were randomized to receive 6MPred 5 mg/kg per day for 10 days alone (n = 34) or in combination with rabbit anti-thymocyte globulin (ATG, 6.25 mg/kg in 10 days; n = 27). The 2 groups were balanced for clinical and GvHD characteristics. One month after randomization, 26% had a complete response; 23%, a partial response; 33%, stable GvHD; 10%, worsened; and 8%, died. There was no significant difference in response, TRM, and survival between the non-ATG and ATG group. In conclusion, 5 days of prednisolone as first-line therapy of acute GvHD identifies patients with different risk of TRM, and second-line therapy with a combination of 6MPred + ATG does not improve patient outcome, compared with 6MPred alone.

Chemotherapy versus allogeneic transplantation for very-high-risk childhood acute lymphoblastic leukaemia in first complete remission: comparison by genetic randomisation in an international prospective study.

BACKGROUND: The dismal prognosis of very-high-risk childhood acute lymphoblastic leukaemia could be improved by allogeneic haemopoietic cell transplantation. We compared this strategy with intensified chemotherapy protocols, with the aim to improve the outcome of children with very-high-risk acute lymphoblastic leukaemia in first complete remission. METHODS: A cooperative prospective study was set up in seven countries. Very-high-risk acute lymphoblastic leukaemia in first complete remission was defined by the presence of at least one of the following criteria: (1) failure to achieve complete remission after the first four-drug induction phase; (2) t(9;22) or t(4;11) clonal abnormalities; and (3) poor response to prednisone associated with T immunophenotype, white-blood-cell count of 100x10(9)/L or greater, or both. Children were allocated treatment by genetic chance, according to the availability of a compatible related donor, and assigned chemotherapy or haemopoietic-cell transplantation. The primary outcome was disease-free survival and analysis was by intention to treat. FINDINGS: Between April, 1995, and December, 2000, 357 children entered the study, of whom 280 were assigned chemotherapy and 77 related-donor haemopoietic-cell transplantation. 5-year disease-free survival was 40.6% (SE 3.1) in children allocated chemotherapy and 56.7% (5.7) in those assigned transplantation (hazard ratio 0.67 [95% CI 0.46-0.99]; p=0.02); 5-year survival was 50.1% (3.1) and 56.4% (5.9), respectively (0.73 [0.49-1.09]; p=0.12). INTERPRETATION: Children with very-high-risk acute lymphoblastic leukaemia benefit from related-donor haemopoietic-cell transplantation compared with chemotherapy. The gap between the two strategies increases as the risk profile of the patient worsens.

Reconstitution of lymphocyte subpopulations in children with inherited metabolic storage diseases after haematopoietic cell transplantation.

We prospectively evaluated the reconstitution of lymphocyte subpopulations in nine children with lysosomal diseases who underwent 11 allogeneic haematopoietic cell transplants (HCTs) following CD34(+) immunomagnetic enrichment, limited T-cell addback and in vivo B-cell depletion. Absolute lymphocyte count recovery was slow to cross the 5th percentile, occurring at a median of 10 months after HCT in patients with full chimaerism. Natural killer cells represented up to 90% of the total lymphoid population during the first 3 months. CD4(+) lymphocyte recovery occurred 9-18 months after HCT. In most patients, CD8(+) lymphocyte recovery was slow and comparable with that of CD4(+) lymphocytes. The CD4(+)/CD8(+) ratio normalised by 3-7 months after HCT in 50% of the patients. CD8(+) lymphocyte recovery was enhanced in patients with viral reactivation. Reconstitution of B-lymphocytes was particularly delayed in patients treated with rituximab. Declining chimaerism, rejection and viral reactivation were the most common problems in our series. Because of the unique graft manipulation, the pace of lymphocyte reconstitution was particularly slow, suggesting that these patients are at a significantly increased risk of infections for up to 2 years after HCT.

Hematopoietic stem cell transplantation (HSCT) in children with juvenile myelomonocytic leukemia (JMML): results of the EWOG-MDS/EBMT trial.

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only proven curative therapy for juvenile myelomonocytic leukemia (JMML). We, the European Working Group on Childhood MDS (EWOG-MDS) and the European Blood and Marrow Transplantation (EBMT) Group, report the outcome of 100 children (67 boys and 33 girls) with JMML given unmanipulated HSCT after a preparative regimen including busulfan, cyclophosphamide, and melphalan. Forty-eight and 52 children received transplants from an HLA-identical relative or an unrelated donor (UD), respectively. The source of hematopoietic stem cells was bone marrow, peripheral blood, and cord blood in 79, 14, and 7 children, respectively. Splenectomy had been performed before HSCT in 24 children. The 5-year cumulative incidence of transplantation-related mortality and leukemia recurrence was 13% and 35%, respectively. Age older than 4 years predicted an increased risk of disease recurrence. The 5-year probability of event-free survival for children given HSCT from either a relative or a UD was 55% and 49%, respectively (P = NS), with median observation time of patients alive being 40 months (range, 6 to 144). In multivariate analysis, age older than 4 years and female sex predicted poorer outcome. Results of this study compare favorably with previously published reports. Disease recurrence remains the major cause of treatment failure. Outcome of UD-HSCT recipients is comparable to that of children receiving transplants from an HLA-identical sibling.

CD34+ stem cell recovery after positive selection of "overloaded" immunomagnetic columns.

Techniques for CD34+ cell enrichment of hematopoietic progenitor cells in grafts destined for transplantation of certain patients with the aim of lowering the amount of infused T lymphocytes and subsequently decreasing the risk of graft versus host disease (GVHD) have been well developed. Adaptations of these techniques should be useful for isolation of other phenotypically defined stem cells. However, a major limitation of techniques now available consists of the number of total nucleated cells or phenotypically defined stem cells that can be processed in a single procedure. Here, we show that recommended levels are much lower than the levels of cells that can be effectively processed by immunomagnetic sorting. Twenty-nine procedures were performed using the Clini- MACS (Miltenyi Biotec) device, which is recommended for processing <6x10(10 )total nucleated cells or <6x10(8) CD34+ cells. Procedures were divided in groups according to their total cellular or CD34+ cell content. We achieved a median CD34+ cell recovery of 68.60% with a median purity of 98.56%, regardless of the loading dose when samples possessing 2-10x10(10) total nucleated cells and 0.8-12.5x10(8) CD34+ cells were applied to a single column. The median levels of CD3+ cells and CD19+ cells in the final product were depleted by 5 logs and 3.8 logs, respectively; no differences were noted when the initial loading dose was increased. Moreover, we found no correlation between the total number nucleated or CD34+ cells loaded and the resultant CD34+ cell recovery. In conclusion, levels of both total nucleated cells and CD34+ can be processed in a single procedure with satisfactory and similar CD34+ cell recovery when these columns are loaded with up to two times as many cells as recommended.