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1.
Occurrence of long-term effects after hematopoietic stem cell transplantation in children affected by acute leukemia receiving either busulfan or total body irradiation: results of an AIEOP (Associazione Italiana Ematologia Oncologia Pediatrica) retrospective study
Saglio, F., Zecca, M., Pagliara, D., Giorgiani, G., Balduzzi, A., Calore, E., Favre, C., Faraci, M., Prete, A., Tambaro, F. P., et al
Bone marrow transplantation. 2020
Abstract
Patients given allogeneic hematopoietic stem cell transplantation (alloHSCT) present an increased incidence of long-term toxicities that can be attributed to the preparative regimen. We retrospectively analyzed in a population of 670 children receiving allo-HSCT for acute leukemia the occurrence of different late effects in function of the choice made between total body irradiation (TBI) and busulfan, as part of the preparative regimen. In univariable analysis, we found that patients treated with TBI developed cataract in 24% of the cases compared with 4% in patients treated with BU (p = 0.0001) and that the incidence of secondary malignant neoplasia (SMN) was higher in patients treated with TBI (18%) as compared with those prepared to the allograft with a Bu-based regimen (0%) (p = 0.019). Conditioning regimen did not show a statistically significant correlation with the occurrence of all the other investigated late effects. In multivariable analysis, TBI remained associated with the occurrence of cataracts (Relative Risk: 0.33 p = 0.012) and secondary malignancies (Relative Risk 3.96 x 10e-6 p < 0.001); however, other variables, as GvHD and disease type, were also correlated with these long-term sequels, indicating that in our study population the preparative regimen is not the only factor influencing the incidence of these complications.
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2.
Myeloablative conditioning for allo-HSCT in pediatric ALL: FTBI or chemotherapy?-A multicenter EBMT-PDWP study
Willasch, A. M., Peters, C., Sedlacek, P., Dalle, J. H., Kitra-Roussou, V., Yesilipek, A., Wachowiak, J., Lankester, A., Prete, A., Hamidieh, A. A., et al
Bone marrow transplantation. 2020
Abstract
Although most children with acute lymphoblastic leukemia (ALL) receive fractionated total body irradiation (FTBI) as myeloablative conditioning (MAC) for allogeneic hematopoietic stem cell transplantation (allo-HSCT), it is an important matter of debate if chemotherapy can effectively replace FTBI. To compare outcomes after FTBI versus chemotherapy-based conditioning (CC), we performed a retrospective EBMT registry study. Children aged 2-18 years after MAC for first allo-HSCT of bone marrow (BM) or peripheral blood stem cells (PBSC) from matched-related (MRD) or unrelated donors (UD) in first (CR1) or second remission (CR2) between 2000 and 2012 were included. Propensity score weighting was used to control pretreatment imbalances of the observed variables. 3.054 patients were analyzed. CR1 (1.498): median follow-up (FU) after FTBI (1.285) and CC (213) was 6.8 and 6.1 years. Survivals were not significantly different. CR2 (1.556): median FU after FTBI (1.345) and CC (211) was 6.2 years. Outcomes after FTBI were superior as compared with CC with regard to overall survival (OS), leukemia-free survival (LFS), relapse incidence (RI), and nonrelapse mortality (NRM). However, we must emphasize the preliminary character of the results of this retrospective "real-world-practice" study. These findings will be prospectively assessed in the ALL SCTped 2012 FORUM trial.
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3.
Treosulfan-fludarabine-thiotepa-based conditioning treatment before allogeneic hematopoietic stem cell transplantation for pediatric patients with hematological malignancies
Kalwak, K., Mielcarek, M., Patrick, K., Styczynski, J., Bader, P., Corbacioglu, S., Burkhardt, B., Sykora, K. W., Drabko, K., Gozdzik, J., et al
Bone marrow transplantation. 2020
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Editor's Choice
Abstract
Treosulfan-based conditioning prior to allogeneic transplantation has been shown to have myeloablative, immunosuppressive, and antineoplastic effects associated with reduced non-relapse mortality (NRM) in adults. Therefore, we prospectively evaluated the safety and efficacy of treosulfan-based conditioning in children with hematological malignancies in this phase II trial. Overall, 65 children with acute lymphoblastic leukemia (35.4%), acute myeloid leukemia (44.6%), myelodysplastic syndrome (15.4%), or juvenile myelomonocytic leukemia (4.6%) received treosulfan intravenously at a dose of 10 mg/m(2)/day (7.7%), 12 g/m(2)/day (35.4%), or 14 g/m(2)/day (56.9%) according to their individual body surface area in combination with fludarabine and thiotepa. The incidence of complete donor chimerism at day +28 was 98.4% with no primary and only one secondary graft failure. At 36 months, NRM was only 3.1%, while relapse incidence was 21.7%, and overall survival was 83.0%. The cumulative incidence of acute graft-vs.-host disease was 45.3% for grades I-IV and 26.6% for grades II-IV. At 36 months, 25.8% overall and 19.4% moderate/severe chronic graft-vs.-host disease were reported. These data confirm the safe and effective use of treosulfan-based conditioning in pediatric patients with hematological malignancies. Therefore, treosulfan/fludarabine/thiotepa can be recommended for myeloablative conditioning in children with hematological malignancies.

PICO Summary
Population
Children with haematological malignancies (n=65)
Intervention
Conditioning with treosulfan, dosed according to body surface area, in combination with fludarabine and thiotepa
Comparison
None
Outcome
The incidence of complete donor chimerism at day +28 was 98.4% with no primary and only one secondary graft failure. At 36 months, NRM was only 3.1%, while relapse incidence was 21.7%, and overall survival was 83.0%. The cumulative incidence of acute graft-vs.-host disease was 45.3% for grades I-IV and 26.6% for grades II-IV. At 36 months, 25.8% overall and 19.4% moderate/severe chronic graft-vs.-host disease were reported.
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4.
Use of letermovir in off-label indications: Infectious Diseases Working Party of European Society of Blood and Marrow Transplantation retrospective study
Styczynski, J., Tridello, G., Xhaard, A., Medinger, M., Mielke, S., Taskinen, M., Blijlevens, N., Rodriguez, M. A. B., Solano, C., Nikolousis, E., et al
Bone marrow transplantation. 2020
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Editor's Choice
Abstract
Letermovir (LMV) is licensed for prophylaxis of CMV infection in allogeneic hematopoietic cell transplant adult CMV-seropositive patients. Due to its favorable safety profile, LMV brings potential for use in other clinical situations, outside the approved indication. The objective of the study was to analyze the efficacy and safety of the use of LMV in off-label indications in EBMT centers. A total of 49 patients were reported including 44 adults and 5 children. LMV was administered for: secondary prophylaxis (37 adults, 3 children), primary prophylaxis (2 children), pre-emptive treatment (5 adults), and therapy of CMV disease (2 adults; pneumonia, colitis). Cyclosporine was concomitantly used in 26 patients. Overall, LMV was used for a median 112 days (range: 10-473). Cumulative incidence of breakthrough infections during secondary prophylaxis was 10.1% (95% CI?=?3.1-21.9). Prophylactic treatment with LMV resulted in 94.9% (95% CI?=?81.0-98.7), and 81.9% (95% CI?=?65.7-90.9) probability of, respectively, 60 and 120-day survival without CMV infection in patients receiving secondary prophylaxis. During therapy of CMV infection/disease, probability of 60 and 120-day overall survival was 100% and 71.4% (95% CI?=?25.8-92.0), respectively. No breakthrough infection occurred in children on LMV prophylaxis. Adverse events were reported in 15/49 (30.4%) patients: the most common being nausea/vomiting (22.4%). In conclusion, the efficacy of the use of LMV as secondary prophylaxis was high, and the preliminary experience with the use of LMV for the treatment of patients with refractory CMV infection/disease was positive. Our data showed that higher dose or prolonged therapy did not result in increased rate of adverse events.

PICO Summary
Population
Patients in EBMT centres
Intervention
Survey on the use of LMV in off-label indications in EBMT centers
Comparison
None
Outcome
A total of 49 patients were reported including 44 adults and 5 children. LMV was administered for: secondary prophylaxis (37 adults, 3 children), primary prophylaxis (2 children), pre-emptive treatment (5 adults), and therapy of CMV disease (2 adults; pneumonia, colitis). Cyclosporine was concomitantly used in 26 patients. Overall, LMV was used for a median 112 days (range: 10-473). Cumulative incidence of breakthrough infections during secondary prophylaxis was 10.1%. Prophylactic treatment with LMV resulted in 94.9%, and 81.9% probability of, respectively, 60 and 120-day survival without CMV infection in patients receiving secondary prophylaxis. During therapy of CMV infection/disease, probability of 60 and 120-day overall survival was 100% and 71.4%, respectively. No breakthrough infection occurred in children on LMV prophylaxis. Adverse events were reported in 15/49 (30.4%) patients: the most common being nausea/vomiting (22.4%).
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Haploidentical HSCT with post transplantation cyclophosphamide versus unrelated donor HSCT in pediatric patients affected by acute leukemia
Saglio, F., Berger, M., Spadea, M., Pessolano, R., Carraro, F., Barone, M., Quarello, P., Vassallo, E., Fagioli, F.
Bone marrow transplantation. 2020
Abstract
T-cell replete hematopoietic stem cell transplantation (HSCT) from a haploidentical donor followed by high doses of cyclophosphamide has been demonstrated to provide the best chances of a cure for many children in need of an allograft but who lack both a sibling and an unrelated donor. In this study we retrospectively compared the outcome of pediatric patients undergoing T-replete haploidentical HSCT (Haplo) for acute leukemia with those undergoing transplantation from unrelated HLA-matched donor (MUD) and HLA mismatched unrelated donor (MMUD) from 2012 to 2017 at our Center. Both univariable and multivariable analyses showed similar 5-year overall survival rates for MUD, MMUD, and Haplo patients: 71% (95% CI 56-86), 72% (95% CI 55-90), and 75% (95% CI 54-94), respectively (p?=?0.97). Haplo patients showed reduced event-free survival rates compared to MUD and MMUD patients: 30% (95% CI 12-49) versus 70% (95% CI 55-84) versus 53% (95% CI 35-73), respectively (p?=?0.007), but these data were not confirmed by a multivariable analysis. Non-relapse mortality (NRM) and relapse incidence (RI) were similar for the three groups. Therefore, our data confirm that Haplo is a suitable clinical option for pediatric patients needing HSCT when lacking both an MUD and an MMUD donor.
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Successfully treated severe COVID-19 and invasive aspergillosis in early hematopoietic cell transplantation setting
Spadea, M., Carraro, F., Saglio, F., Vassallo, E., Pessolano, R., Berger, M., Scolfaro, C., Grassitelli, S., Fagioli, F.
Transpl Infect Dis. 2020;:e13470
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Abstract
So far, we do not have any published database regarding HCT patients during the present pandemic. We herein describe the first case of COVID-19 presenting in the early hematopoietic cell transplantation (HCT) setting.
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The impact of donor type on outcomes and cost of allogeneic hematopoietic cell transplant for pediatric leukemia: a merged CIBMTR and PHIS analysis: Pediatric acute leukemia transplant risks and utilization
Arnold, S. D., Brazauskas, R., He, N., Li, Y., Hall, M., Atsuta, Y., Dalal, J., Hahn, T., Khera, N., Bonfim, C., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
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Editor's Choice
Abstract
IMPORTANCE AlloHCT may be associated with significant morbidity and mortality that result in increased healthcare utilization. To date, no multi-center comparative cost analyses have been performed specifically evaluating alloHCT in children with acute leukemia. OBJECTIVES To describe the relationship between survival and healthcare utilization while investigating the hypothesis that matched sibling donor (MSD) alloHCT has significantly lower inpatient healthcare utilization compared to unrelated donor (URD) and that among URD, umbilical cord blood transplants (UCB) will have higher initial but lower long-term utilization. DESIGN Retrospective cohort study Setting: Clinical and transplant outcomes data from the Center for International Blood and Marrow Transplant Research (CIBMTR) were merged with inpatient cost data from the Pediatric Health Information System (PHIS) database using a probabilistic merge methodology. PARTICIPANTS The merged dataset contained U.S. patients age 1-21 years who received alloHCT for acute leukemia from 2004-2011 with comprehensive CIBMTR data at a PHIS hospital. EXPOSURE AlloHCT analyzed by donor type with specific analysis of utilization and costs using PHIS claims data. MAIN OUTCOME The primary outcomes of overall survival (OS), leukemia free survival (LFS), and inpatient costs were evaluated using Kaplan-Meier curves, Cox, and Poisson models. RESULTS 632 patients were identified in both CIBMTR and PHIS. 5-year LFS was 60% for MSD, 47% for well-matched matched unrelated donor bone marrow (MUD), 48% for mismatched unrelated donor, and 45% for UCB (p=0.09). Total adjusted costs were significantly lower for MSD versus MUD by day 100 (adjusted cost ratio (ACR) 0.73, CI 0.62-0.86, p<0.001), and higher for UCB versus MUD (ACR 1.27, CI 1.11-1.45, p<0.001). By 2yrs, total adjusted costs remained significantly lower for MSD when compared to MUD (ACR 0.67, CI 0.56-0.81, p<0.001) and higher for UCB compared to MUD (ACR 1.25, 95% CI 1.02-1.52, p=0.0280). CONCLUSIONS UCB and MUD alloHCT provide similar survival outcomes; however, MUD alloHCT has a significant advantage in cost by day 100 and 2 years. Ongoing research is needed to determine if the cost difference among URD alloHCT remains significant with a larger sample size and/or beyond the 2 years following alloHCT.

PICO Summary
Population
U.S. patients age 1-21 years who received alloHCT for acute leukemia from 2004-2011 (n=632)
Intervention
Matched sibling donor transplantation (MSD, n=102)
Comparison
Matched unrelated donor transplantation (MUD, n=186) Mismatched unrelated donor transplantation (MMUD, n=87), Umbilical cord blood transplantation (UCB, n=257)
Outcome
5-year LFS was 60% for MSD, 47% for well-matched matched unrelated donor bone marrow (MUD), 48% for mismatched unrelated donor, and 45% for UCB. Total adjusted costs were significantly lower for MSD versus MUD by day 100 (adjusted cost ratio (ACR) 0.73), and higher for UCB versus MUD (ACR 1.27). By 2yrs, total adjusted costs remained significantly lower for MSD when compared to MUD (ACR 0.67) and higher for UCB compared to MUD (ACR 1.25).
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Steroid-refractory acute graft-versus-host disease graded III-IV in pediatric patients. A mono-institutional experience with a long-term follow-up
Berger, M., Pessolano, R., Carraro, F., Saglio, F., Vassallo, E., Fagioli, F.
Pediatric transplantation. 2020;:e13806
Abstract
aGvHD remains a major obstacle to successful HSCT. We report our experience on steroid-refractory aGvHD III and IV from 1989 to 2017. Ninety patients with aGvHD III or IV were stratified according to the HSCT year: 1989-1998, 1999-2007, and 2008-2017 and to aGvHD extension (GvHD III vs IV) and finally the probability of OS, RI, and TRM was calculated accordingly. aGvHD III patients had a substantial improvement over time: day 100 OS raised from 64% (95% CI 39-89) in the first cohort to 100% in the latest (P = .022), and it was mainly due to a reduction of TRM (it was 28% [95% CI 12-65] in the first cohort to 0% in the latest (P = .01). The aGvHD IV patients did not present a significant improvement. Day 100 OS was 42% (95% CI 16-68) in the first group and 54% (95% CI 25-83) in the year 2008-2017 (P = NS), and the day-100 TRM was very similar (it was 57% [95% CI 36-90] in the first cohort and 45% [95% CI 23-89] in the latest (P = NS). We report significant improvements in OS and TRM in patients diagnosed with grade III aGvHD. Patients with the most severe aGvHD appear to have no or fewer benefits on long-term outcomes.
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Advanced glycation end products and chronic inflammation in adult survivors of childhood leukemia treated with hematopoietic stem cell transplantation
Felicetti, F., Cento, A. S., Fornengo, P., Cassader, M., Mastrocola, R., D'Ascenzo, F., Settanni, F., Benso, A., Arvat, E., Collino, M., et al
Pediatric blood & cancer. 2019;:e28106
Abstract
BACKGROUND Among survivors of pediatric acute lymphoblastic leukemia (ALL), those who received hematopoietic stem cell transplantation (HSCT) conditioned with total-body irradiation (TBI) show the highest risk of late complications, including cardiovascular (CV) disease. Advanced glycation end products (AGEs) have been associated with CV disease in diabetes mellitus and other clinical conditions. This study explores AGEs plasma levels, inflammatory status, and lipid profile in survivors of pediatric ALL who received HSCT conditioned with TBI. PROCEDURE Inclusion criteria were (a) previous diagnosis of ALL at age < 18 years, treated with HSCT conditioned with TBI; (b) age > 18 at the time of the study enrollment; (c) off-therapy for at least five years. Radiotherapy other than TBI, preexisting heart disease, glucose metabolism impairment, body mass index > 25, active graft versus host disease (GvHD), smoking, or treatment with cholesterol lowering medications were exclusion criteria. Eighteen survivors and 30 age-matched healthy controls were enrolled. RESULTS AGEs plasma levels were markedly higher in ALL survivors than in healthy subjects (2.15 +/- 2.21 vs 0.29 +/- 0.15 pg/mL, P < 0.01). Survivors also showed higher levels of high-sensitivity C-reactive protein (2.32 +/- 1.70 vs 0.88 +/- 1.09 mg/dL, P < 0.05), IL-1beta (7.04 +/- 1.52 vs 4.64 +/- 2.02 pg/mL, P < 0.001), IL17 (37.44 +/- 3.51 vs 25.19 +/- 6.34 pg/mL, P < 0.001), an increased glutathione/reduced glutathione ratio (0.085 +/- 0.07 vs 0.041 +/- 0.036, P < 0.05) and slight alterations in their lipid profile. CONCLUSIONS Our data show AGEs accumulation and chronic inflammation in ALL survivors who received HSCT conditioned with TBI. These alterations may contribute to the increased risk of CV disease reported in these subjects.
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Autoimmune cytopenias (AIC) following allogeneic haematopoietic stem cell transplant for acquired aplastic anaemia: a joint study of the Autoimmune Diseases and Severe Aplastic Anaemia Working Parties (ADWP/SAAWP) of the European Society for Blood and Marrow Transplantation (EBMT)
Miller, P. D. E., Snowden, J. A., De Latour, R. P., Iacobelli, S., Eikema, D. J., Knol, C., Marsh, J. C. W., Rice, C., Koh, M., Fagioli, F., et al
Bone marrow transplantation. 2019
Abstract
This retrospective study explored the incidence of autoimmune cytopenia (AIC) in 530 paediatric and adult patients with acquired aplastic anaemia (aAA) who underwent first allogeneic HSCT between 2002 and 2012. AIC was a rare complication with a cumulative incidence of AIC at 1, 3, 5 and 10 years post HSCT of 2.5% (1.2-3.9 95% CI), 4.4% (2.6-6.2 95% CI), 4.6% (2.8-6.5 95% CI) and 5.1% (3.1-7.2 95% CI). Overall survival at 5 years after diagnosis of AIC was 85.9% (71-100 95% CI). Twenty-five patients were diagnosed with AIC at a median of 10.6 (2.6-91.5) months post HSCT. Eight (32%) patients were diagnosed with immune thrombocytopenia (ITP), seven (28%) with autoimmune haemolytic anaemia (AIHA), seven (24%) with Evans syndrome and four (16%) with autoimmune neutropenia (AIN). Treatment strategies were heterogeneous. Complete responses were seen in 12 of 25 patients, with death in three patients. In multivariable Cox analysis of a subgroup of 475 patients, peripheral blood stem cell (PBSC) transplant was associated with higher risk of AIC compared with bone marrow (BM) when conditioning regimens contained fludarabine and/or alemtuzumab (2.81 [1.06-7.49 95% CI]; p = 0.038), or anti-thymocyte globulin (ATG) (2.86 [1.11-7.37 95% CI]; p = 0.029). Myeloablative conditioning was associated with a lower risk of AIC compared with reduced intensity conditioning (RIC) in fludarabine and/or alemtuzumab (0.34 [0.12-0.98 95% CI]; p = 0.046) and ATG containing regimens (0.34 [0.12-0.95 95% CI]; p = 0.04). These findings provide clinically useful information regarding the incidence of a rare and potentially life-threatening complication of allogeneic HSCT for aAA, and further support for BM as the preferred stem cell source for transplant of patients with aAA.