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1.
Intrabone transplant of a single unwashed umbilical cord blood unit with ATG-free and sirolimus-based GvHD prophylaxis: fast immune-reconstitution and long-term disease control in 30 patients with high-risk diseases
Giglio, F., Xue, E., Barone, A., Lorentino, F., Greco, R., Ruggeri, A., Zambelli, M., Parisi, C., Milani, R., Clerici, D., et al
Transplantation and cellular therapy. 2023
Abstract
INTRO Several strategies have been explored with the attempt of improving safety and feasibility of umbilical cord blood transplant (UCBT) in adults. AIM: The aim of this retrospective analysis was to examine the safety and efficacy of intrabone transplant of a single unwashed cord blood unit in an ATG-free, sirolimus-based graft-versus-host prophylaxis platform. METHODS We collected data of all consecutive UCBT infused intrabone and unwashed at San Raffaele Hospital in Milan between 2012 and 2021. RESULTS Thirty-one consecutive UCBT were identified. All but 3 units had a high-resolution HLA typing on 8 loci at time of selection. At cryopreservation, the median number of CD34(+) cells and total nucleated cells (TNCs) were 1 × 10(5)/kg (0.6-12.0) and 2.8 × 10(7)/kg (1.48-5.6), respectively. Eighty seven percent of patients received myeloablative conditioning; seventy seven percent of patients were transplanted for acute myeloid leukemia. Median follow-up among survivors was 38.2 months (range 10.4-123.6). No adverse events were related to the intrabone infusion at bedside under short-conscious peri-procedural sedation and to the no wash technique. After thawing, CD34(+) and TNCs were 0.8 × 10(5)/kg (0.1-2.3) and 1.42 × 10(7)/kg (0.69-3.2) respectively. Median time to engraftment was 27 and 53 days for neutrophils and platelets, respectively; one patient rejected the transplant and was subsequently rescued with a salvage transplant. Median time to CD3(+) above 100/μL was 30 days. 100-day CI of III-IV aGvHD was 12.9% (95%CI 4-27.3%), 2-year CI of moderate-to-severe chronic GvHD was 11.8% (95% CI 2.7-28.3%); at 2-year, OS was 52.7% (95%CI 33-69%), relapse incidence was 30.7% (95% CI 13.7-49.6%) and TRM of 29% (95%CI 14.3-45.6%). In univariate analysis CD34(+) infused counts did not impact on transplant outcomes. In patients transplanted in first complete remission, relapse rate was 13% with an OS above 90% at 2 years. CONCLUSIONS Intrabone infusion of single CB unit was feasible, with no adverse reactions related to the no wash/intrabone infusion. We documented a low incidence of chronic GVHD and disease relapse with a fast immune-reconstitution.
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2.
Haplo-Cord transplantation with 8mg/kg anti-thymocyte globulin as graft-versus-host disease prophylaxis compared to haploidentical transplantation with 10mg/kg anti-thymocyte globulin in the treatment of acute leukemia
Yuan, F., Li, G., Li, M., Wei, X., Fu, Y.
Transplantation and cellular therapy. 2023
Abstract
BACKGROUND Clinical outcomes of the transplantation strategy combined with a haploidentical stem cell graft and an unrelated umbilical cord blood unit (haplo-cord HSCT) with low-dose anti-thymocyte globulin as graft-versus-host disease prophylaxis for the treatment of acute leukemia (AL) remains unclear. OBJECTIVE This study aimed to explore the clinical outcomes of haplo-cord HSCT in acute leukemia patients with the GVHD prevention strategy of 8 mg/kg ATG compared with haplo- transplantation with 10 mg/kg ATG. METHODS A total of 130 patients with acute leukemia who underwent allogeneic HSCT from January 2016 to December 2020 were included in this study, including 70 patients who received haploidentical stem cell graft and an unrelated umbilical cord blood unit (haplo-cord HSCT) with 8 mg/kg anti-thymocyte globulin (ATG) (Haplo-cord-ATG 8 group) and haploidentical HSCT with 10 mg/kg ATG (Haplo-ATG 10 group) in 60 patients. Clinical data were collected and analyzed retrospectively. RESULTS Patients in the haplo-cord-ATG 8 group were significantly older (P=0.000). Haplo-cord transplant with reduced ATG to 8mg/kg results in more rapid neutrophil recovery(P=0.036). No differences were observed in platelet recovery or the incidences of EBV viremia, bloodstream infection, or hemorrhagic cystitis between the two groups. Grade II-IV acute GVHD rate by day 100 was higher in the haplo-ATG 10 group (27.16% vs 11.48%, P = 0.033) as well as chronic GVHD rate at 1 year (14.60% vs 3.36%, P = 0.048). CMV reaction rate was higher in the haplo- ATG 10 group (48.31% vs 26.30%, P = 0.022). With a median follow-up of 27.4 months for the haplo-cord- ATG 8 group and 27.5 months for the haplo-ATG 10 group, overall survival at 2 years was 79.4% and 62.8% (P=0.005), event-free survival was 76.3% vs 55.9% (P=0.001), the cumulative incidence of relapse (CIR) was 10.11% vs 25.97% (p= 0.164), and non-relapse mortality was 14.33% vs 24.43% (P=0.040), respectively. Multivariate analysis showed CIBMTR DRI was the only significant predictor for relapse, NRM, OS, and EFS. CONCLUSION Haplo-cord transplantation supported by cord blood with 8mg/kg ATG as graft-versus-host disease prophylaxis results in better outcomes compared with haplo-transplantation with 10mg/kg ATG.
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3.
Improved survival after single-unit cord blood transplantation using fludarabine and melphalan-based reduced-intensity conditioning for malignant lymphoma: impact of melphalan dose and graft-versus-host disease prophylaxis with mycophenolate mofetil
Sakatoku, K., Kim, S. W., Okamura, H., Kanaya, M., Kato, K., Yamasaki, S., Uchida, N., Kobayashi, H., Fukuda, T., Takayama, N., et al
Annals of hematology. 2022
Abstract
We evaluated 413 adult patients with lymphoma who underwent unrelated cord blood transplantation (UCBT) with fludarabine and melphalan (FM)-based reduced-intensity conditioning between 2002 and 2017 to investigate longitudinal changes in outcomes and the optimal melphalan dose and graft-versus-host disease (GVHD) prophylaxis regimen. Outcomes were compared between FM80/100 (melphalan dose: 80 or 100 mg/m(2)) and FM140 (melphalan dose: 140 mg/m(2)), as well as between calcineurin inhibitor (CNI) plus methotrexate (MTX), CNI plus mycophenolate mofetil (MMF), and CNI alone. The 3-year overall survival (OS) and non-relapse mortality (NRM) rates improved over time (OS: 27% in 2000s vs. 42% in 2010s, p < 0.001; NRM: 43% in 2000s vs. 26% in 2010s, p < 0.001). Multivariable analysis showed that in the 2000s, melphalan dose and GVHD prophylaxis regimen did not affect any outcomes. In the 2010s, FM80/100 (vs. FM140) related to better OS (hazard ratio [HR] 0.62, p = 0.01) and NRM (HR 0.52, p = 0.016). MTX + CNI and CNI alone (vs. CNI + MMF) related to worse OS (CNI + MTX, HR 2.01, p < 0.001; CNI alone, HR 2.65, p < 0.001) and relapse/progression (CNI + MTX, HR 2.40, p < 0.001; CNI alone, HR 2.13, p = 0.023). In recent years, the use of FM80/100 and CNI + MMF significantly reduced the risk of NRM and relapse/progression, respectively, and resulted in better OS after UCBT for lymphoma.
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4.
Prognostic impact of switching from cyclosporine to corticosteroids early after single cord blood transplantation
Takano, K., Konuma, T., Monna-Oiwa, M., Isobe, M., Kato, S., Takahashi, S., Nannya, Y.
Annals of hematology. 2022
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5.
Impact of posttransplant cyclophosphamide on the outcome of patients undergoing unrelated single-unit umbilical cord blood transplantation for pediatric acute leukemia
Li, X. Y., Zhan, L. P., Liu, D. D., Han, X. W., Chen, H., Wu, Z. Z., Wang, Y., Que, L. P., Wu, X. J., Liu, S., et al
BMC cancer. 2022;22(1):1190
Abstract
BACKGROUND Umbilical cord blood transplantation (UCBT) from unrelated donors is one of the successful treatments for acute leukemia in childhood. The most frequent side effect of UCBT is peri-engraftment syndrome (PES), which is directly associated with the greater prevalence of acute and chronic graft-versus-host-disease (aGvHD and cGvHD). In haploidentical stem cell transplantation, posttransplant cyclophosphamide (PTCY) has been demonstrated to be an effective method against GvHD. However, the effects of PTCY as a GvHD prophylactic in UCBT had not been investigated. This study aimed to evaluate the effects of PTCY on the outcomes of UCBT for pediatric acute leukemia. METHODS This retrospective study included 52 children with acute leukemia who underwent unrelated single-unit UCBT after myeloablative conditioning regimens. The results from the PTCY and non-PTCY groups were compared. RESULTS The incidence of transplantation-related mortality in non-PTCY and PTCY were 5% and 10% (p = 0.525), respectively. The incidence of relapse in non-PTCY and PTCY were 5% and 23% (p = 0.095), respectively. Second complete remission status (CR2) was an independent risk factor for relapse-free survival (hazard ratio = 9.782, p = 0.001). The odds ratio for sepsis or bacteremia incidence was significantly greater in the PTCY group (9.524, p = 0.017). PTCY group had increased rates of cytomegalovirus activity and fungal infection. The incidence of PES, aGvHD, cGvHD, and hemorrhagic cystitis in the PTCY group was lower than that in the non-PTCY group, although it was not significantly different. Additionally, higher doses of PTCY (29 mg/kg and 40 mg/kg) were associated with lower incidences of aGvHD and severe GvHD (65% and 29%, respectively) than lower doses (93% and 57%, respectively). Engraftment time and graft failure incidence were similar across groups. CONCLUSION The results support the safety and efficiency of PTCY as part of PES controlling and GvHD prophylaxis in single-unit UCBT for children with acute leukemia. A PTCY dosage of 29 mg/kg to 40 mg/kg appears to be more effective in GvHD prophylaxis for UCBT patients.
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6.
Guidelines for the Prevention and Management of Graft-versus-Host Disease after Cord Blood Transplantation
Ponce, D. M., Politikos, I., Alousi, A., Carpenter, P. A., Milano, F., MacMillan, M. L., Barker, J. N., Horwitz, M. E.
Transplantation and cellular therapy. 2021;27(7):540-544
Abstract
The incidence of graft-versus-host disease (GVHD) after cord blood (CB) transplantation (CBT) is lower than expected given the marked degree of human leukocyte antigen (HLA)-mismatch of CB grafts. While the exact mechanism that underlies this biology remains unclear, it is hypothesized to be due to the low number of mostly immature T-cells infused as part of the graft1,2, and increased tolerance of CB-derived lymphocytes induced by the state of pregnancy. Nevertheless, acute GVHD (aGVHD) is a significant complication of CBT. In contrast, the incidence of chronic GVHD (cGVHD) following CBT is lower than what is observed following matched related or unrelated donor HSC transplantation (HSCT)3-6. This review outlines the guidelines for the prevention and management of acute and chronic GVHD following CBT.
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7.
Clinical Characteristics of Posttransplant Lymphoproliferative Disorder After Cord Blood Transplantation Without Antithymocyte Globulin
Sumi, M., Satomi, H., Kitahara, M., Kazumoto, H., Shishido, T., Kaiume, H., Sato, K., Ueki, T., Hiroshima, Y., Ito, I., et al
Clinical lymphoma, myeloma & leukemia. 2021
Abstract
BACKGROUND CBT with ATG use is a well-known PTLD risk factor. However, little is known regarding the clinical features of PTLD after ATG-free CBT. PATIENTS AND METHODS We analyzed the incidence, risk factors and prognosis of PTLD in 183 adults undergoing ATG-free CBT. RESULTS Fifteen patients (diffuse large B-cell lymphoma, n = 9, mucosa-associated lymphoid tissue lymphoma, n = 2 nondestructive PTLD, n = 1, T-cell lymphoma, n = 3) developed PTLD. The 2-year CuI of PTLD was 8.0% (95% CI: 4.6-12.7). Pathologically, all 12 B-cell PTLD patients had Epstein-Barr virus (EBV), compared with 1 of 3 T-cell PTLD patients. All patients, excluding one with nondestructive PTLD, showed extranodal involvement. In the univariate analysis, the 2-year CuI of PTLD was significantly higher in patients who received mycophenolate mofetil to prevent graft-versus-host disease than in nonrecipients (11.2%/2.9%, P = .0457). However, multivariate analysis revealed no independent PTLD risk factors. All 11 PTLD patients who received specific therapy achieved complete remission. The 1-year overall survival of PTLD patients was 70.9%. CONCLUSION Although we found a higher CuI of PTLD than previously reported, the prognosis was generally good. In CBT recipients, many factors, including MMF use, may be associated with the clinical features of PTLD.
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8.
Effect of methotrexate dose in graft-versus-host disease prophylaxis after single-unit cord blood transplantation in adult acute myeloid leukemia
Terakura, S., Kuwatsuka, Y., Sugita, J., Takahashi, S., Ozawa, Y., Ozeki, K., Yoshioka, S., Nakamae, H., Kawakita, T., Sawa, M., et al
International journal of hematology. 2021
Abstract
To investigate the association between methotrexate (MTX) dosage and engraftment, graft-versus-host disease (GVHD) incidence, and survival in umbilical cord blood transplantation (UCBT), we compared transplant outcomes after UCBT with various GVHD prophylaxis regimens, using registry data with additional data collection. Patients transplanted for acute myeloid leukemia with a calcineurin inhibitor (CNI) and either MTX or mycophenolate mofetil (MMF) combination were selected. In total, 888 single-unit UCBTs (MTX(15-10-10), 415; MTX(10-7-7), 294; MTX(5-5-5), 71; MMF, 108) were included. In multivariate analyses with MTX(15-10-10) as the reference, the likelihood of neutrophil and platelet engraftment was significantly worse in the MTX(10-7-7) group, and similarly better in MMF group compared with MTX(15-10-10). All variables including CyA vs Tac and 4-group GVHD prophylaxis became significant for the risk of grade II-IV acute GVHD in the final multivariate model. We observed significant additional effects of combined MTX dose in the Tac group, which were larger with lower MTX dose and MMF. No significant difference was observed in survival risk among GVHD prophylaxis groups. Despite the potential background differences in the combined CNI and conditioning regimen, we conclude that the recommended GVHD prophylaxis is a combination of CyA plus MTX(15-10-10) or Tac plus MMF.
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9.
Prognostic impact of the dosage of methotrexate combined with tacrolimus for graft-versus-host disease prophylaxis after cord blood transplantation
Adachi, M., Yokota, D., Hirata, H., Koyauchi, K., Dohtan, S., Oka, S., Sakamoto, N., Takaba, M., Takemura, T., Nagata, Y., et al
International journal of hematology. 2021
Abstract
The optimal dosage of methotrexate (MTX) for graft-versus-host disease (GVHD) prophylaxis after cord blood transplantation (CBT) has not been well elucidated. Therefore, we conducted a retrospective study comparing a mini-MTX group (5 mg/m(2) on day 1, 3 and 6) to a short-MTX group (10 mg/m(2) on day 1 and 7 mg/m(2) on day 3 and 6) after CBT. Sixty-three patients were classified as the mini-MTX group and 20 as the short-MTX group. The median time and cumulative incidence of neutrophil engraftment did not vary between the two groups. The cumulative incidence of grade 2-4 and grade 3-4 acute GVHD was similar in both groups. Overall survival in the mini-MTX group was significantly lower than in the short-MTX group (46.9% vs. 88.7% at 1 year, p?0.01), contributing to higher non-relapse mortality (NRM) in the mini-MTX group (32.0% vs. 5.0% at 1 year, p?=?0.02). In multivariate analysis, the mini-MTX regimen was the most powerful prognostic factor for OS (hazard ratio 4.11; p?=?0.03). Although the reduced dosage of MTX had no effect on neutrophil engraftment, increased NRM due to higher incidence of infection, graft failure, and severe acute GVHD resulted in a lower survival rate in the mini-MTX group after CBT.
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10.
Altered effect of killer immunoglobulin-like receptor-ligand mismatch by graft versus host disease prophylaxis in cord blood transplantation
Yokoyama, H., Hirayama, M., Takahashi, Y., Uchida, N., Tanaka, M., Onizuka, M., Ozawa, Y., Onai, D., Katsuoka, Y., Wake, A., et al
Bone marrow transplantation. 2021
Abstract
The role of killer immunoglobulin-like receptor-ligand mismatch (KIR-ligand mismatch) between donors and recipients undergoing cord blood transplantation (CBT) is controversial. If each immunosuppressant differently affects natural killer (NK) cell function, the effect of KIR-ligand mismatch may be altered depending on the type of graft versus host disease (GVHD) prophylaxis. To verify this hypothesis, the difference in the effect of KIR-ligand mismatch was retrospectively assessed between patients who received CBT for acute leukemia, myelodysplastic syndrome, or chronic myeloid leukemia, as well as GVHD prophylaxis comprising tacrolimus plus methotrexate (MTX) or mycophenolate mofetil (MMF). In the MMF group (n?=?1363), KIR-ligand mismatch augmented the incidence of non-relapse mortality (NRM; hazard ratio [HR], 1.40; P?=?0.008), which worsened overall survival (OS; HR, 1.30, P?=?0.0077). In the analysis of each KIR-ligand mismatch type, HLA-C2 mismatch had a favorable effect on relapse incidence (HR, 0.56; P?=?0.0043) and OS (HR, 0.72; P?=?0.037) only in the MTX group. In the MMF group, HLA-A3/A11 mismatch worsened NRM (HR, 1.93; P?0.001) and OS (HR, 1.48; P?=?0.014). These results imply that the effects of KIR-ligand mismatch differ with the type of GVHD prophylaxis and that assessing the KIR-ligand mismatch status is important for CBT.