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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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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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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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Outcome of haematopoietic stem cell transplantation in dyskeratosis congenita
Fioredda, F., Iacobelli, S., Korthof, E. T., Knol, C., van Biezen, A., Bresters, D., Veys, P., Yoshimi, A., Fagioli, F., Mats, B., et al
British journal of haematology. 2018
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Editor's Choice
Abstract
Dyskeratosis congenita (DC) is a genetic multisystem disorder with frequent involvement of the bone marrow. Haematopoietic stem cell transplantation (HSCT) is the only definitive cure to restore haematopoiesis, even though it cannot correct other organ dysfunctions. We collected data on the outcome of HSCT in the largest cohort of DC (n = 94) patients ever studied. Overall survival (OS) and event-free survival (EFS) at 3 years after HSCT were 66% and 62%, respectively. Multivariate analysis showed better outcomes in patients aged less than 20 years and in patients transplanted from a matched, rather than a mismatched, donor. OS and EFS curves tended to decline over time. Early lethal events were infections, whereas organ damage and secondary malignancies appeared afterwards, even a decade after HSCT. A non-myeloablative conditioning regimen appeared to be most advisable. Organ impairment present before HSCT seemed to favour the development of chronic graft-versus-host disease and T-B immune deficiency appeared to enhance pulmonary fibrosis. According to the present data, HSCT in DC is indicated in cases of progressive marrow failure, whereas in patients with pre-existing organ damage, this should be carefully evaluated. Further efforts to investigate treatment alternatives to HSCT should be encouraged.