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Unique reduced intensity conditioning haploidentical peripheral blood stem cell transplantation protocol for patients with hematological malignancy
Xu, J., Miao, W., Yuan, H., Liu, Y., Chen, G., Wang, H., Aizezi, G., Qu, J., Duan, X., Yang, R., et al
Transplantation and cellular therapy. 2023
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Editor's Choice
Abstract
Reduced-intensity conditioning haploid hematopoietic stem cell transplantation (RIC-haplo-HSCT) requires more hematopoietic progenitor and stem cells (HPSCs) to promote engraftment and immune reconstitution and needs stronger graft versus leukemia (GVL) effect. Peripheral blood stem cells (PBSCs) offer more advantages compared to bone marrow (BM). However, higher dose non-T cell depleted (non-TCD) in vitro PBSCs may increase the occurrence of severe graft versus host disease (GVHD). This prospective, single-arm clinical research was performed to investigate high-dose non-TCD in vitro PBSCs as graft, Flu/Ara-C/Bu (FAB) as conditioning regimen, adopting rATG to remove T cells in vivo, and enhancing GVHD prophylaxis with IL-2 receptor antagonist in RIC-haplo-HSCT in patients with hematological malignancies aged 50 to 70 years or < 50 years with comorbidities (HCT-CI scores ≥2) classified as intermediate to higher risk. The primary endpoint was day-100 acute GVHD (aGVHD). A total of 47 patients were enrolled; the median age was 52 years (range: 30-68 years), the median follow-up time was 34 months (range: 2-99), and the medium-infused doses of MNC, CD34+ cells, and CD3+ cells were 15.93 × 10(8)/kg, 8.68 × 10(6)/kg and 5.57 × 10(8)/kg, respectively. The cumulative incidence of grade II-IV aGVHD at day-100 was 30.3% (95% CI: 15.9-44.8), while that of grade III-IV aGVHD was 10.2% (95% CI: 0.6-19.8). The two-year cumulative incidence of chronic GVHD (cGVHD) was 34.9% (95% CI: 19.0-50.8). The two-year cumulative incidences of localized and extensive cGVHD were 26.1% (95% CI: 11.80-40.40) and 8.7% (95% CI: 3.26-20.65), respectively. The two-year cumulative incidence of relapse was 17.3% (95% CI: 5.1-29.5). The two-year overall survival and disease-free survival rates were 71.2% (95% CI: 57.9-84.5) and 66.2% (95% CI: 52.1-80.3), respectively. The outcomes showed that the incidence of aGVHD was not high, and the overall efficacy was good. This study demonstrated that this unique RIC-haplo-PBSCT protocol was effective in treating hematological malignancies. Nonetheless, larger prospective multi-center clinical trials and experimental studies should be performed to further confirm our findings.
PICO Summary
Population
Adults with haematological malignancies aged 50 to 70 years or less than 50 years but with intermediate or higher risk comorbidities (HCT-CI scores ≥2), from a single centre in China (n=47)
Intervention
Reduced intensity conditioning haploidentical HSCT: high-dose non-T-cell depleted in vitro peripheral blood stem cells as graft, Flu/Ara-C/Bu (FAB) as conditioning regimen, rabbit antithymocyte globulin (rATG) to remove T cells in vivo, and enhanced GVHD prophylaxis with IL-2 receptor antagonist.
Comparison
None
Outcome
The median age was 52 years (range: 30-68 years), the median follow-up time was 34 months (range: 2-99), and the medium-infused doses of MNC, CD34+ cells, and CD3+ cells were 15.93 × 10(8)/kg, 8.68 × 10(6)/kg and 5.57 × 10(8)/kg, respectively. The cumulative incidence of grade II-IV aGVHD at day-100 was 30.3% (95% CI: 15.9-44.8), while that of grade III-IV aGVHD was 10.2% (95% CI: 0.6-19.8). The two-year cumulative incidence of chronic GVHD (cGVHD) was 34.9% (95% CI: 19.0-50.8). The two-year cumulative incidences of localized and extensive cGVHD were 26.1% (95% CI: 11.80-40.40) and 8.7% (95% CI: 3.26-20.65), respectively. The two-year cumulative incidence of relapse was 17.3% (95% CI: 5.1-29.5). The two-year overall survival and disease-free survival rates were 71.2% (95% CI: 57.9-84.5) and 66.2% (95% CI: 52.1-80.3), respectively.
2.
Low-dose post-transplant cyclophosphamide with low-dose antithymocyte globulin for prevention of graft-versus-host disease in first complete remission undergoing 10/10 HLA-matched unrelated donor peripheral blood stem cell transplants: a multicentre, randomized controlled trial
Zu, Y., Li, Z., Gui, R., Liu, Y., Zhang, Y., Yu, F., Zhao, H., Fu, Y., Zhan, X., Wang, Z., et al
Bone marrow transplantation. 2022
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Editor's Choice
Abstract
The most widely used regimens of graft-versus-host disease (GVHD) prophylaxis in HLA-matched unrelated donor peripheral blood stem cell transplantation (MUD-PBSCT) are based on anti-thymocyte globulin (ATG) or post-transplant cyclophosphamide (PTCy). To improve the efficiency of GVHD prophylaxis, a novel regimen, composed of low-dose PTCy (20 mg/kg on day +3 and +4) and low-dose ATG (6 mg/kg), was evaluted in patients with hematological malignancies ungoing 10/10 HLA MUD-PBSCT in first remission (CR1). In our prospective, multicenter study, 104 patients were randomly assigned one-to-one to low-dose PTCy-ATG (n = 53) or standard-dose ATG (10 mg/kg, n = 51). Both the cumulative incidences (CIs) of grade II-IV acute GVHD (aGVHD) and chronic GVHD (cGVHD) at 2 years in low-dose PTCy-ATG cohort were significantly reduced (24.5% vs. 47.1%; P = 0.017; 14.1% vs. 33.3%; P = 0.013). The CI of non-relapse-mortality (NRM) was much lower (13.2% vs. 34.5%; P = 0.049) and GVHD-free, relapse-free survival (GRFS) was significantly improved at 2 years in low-dose PTCy-ATG arm (67.3% vs 42.3%; P = 0.032). The low-dose PTCy-ATG based GVHD prophylaxis is a promising strategy for patients in CR1 after 10/10 HLA MUD-PBSCT.
PICO Summary
Population
Participants aged 12-69 years with haematological malignancies receiving 10/10 matched unrelated donor (MUD) transplantation in three transplant centres in China (n=104)
Intervention
Post-transplant cyclophosphamide, 20 mg/kg on day +3 and +4 and low-dose (6mg/kg) antithymocyte globulin (low-dose PTCy-ATG, n=53)
Comparison
ATG 2.0 mg/kg/day on days −5 through -1 (standard-dose ATG, n=51)
Outcome
Both the cumulative incidences (CIs) of grade II-IV acute GVHD (aGVHD) and chronic GVHD (cGVHD) at 2 years in low-dose PTCy-ATG cohort were significantly reduced (24.5% vs. 47.1%; 14.1% vs. 33.3%). The CI of non-relapse-mortality (NRM) was much lower (13.2% vs. 34.5%) and GVHD-free, relapse-free survival (GRFS) was significantly improved at 2 years in low-dose PTCy-ATG arm (67.3% vs 42.3%).
3.
Myeloablative Conditioning for Allogeneic Transplantation Results in Superior Disease-Free Survival for Acute Myeloid Leukemia and Myelodysplastic Syndromes with Low/Intermediate, but not High Disease Risk Index: A CIBMTR Study: Superior DFS with MAC compared to RIC HCT in AML/MDS with low/intermediate risk DRI
Bejanyan, N., Zhang, M., Bo-Subait, K., Brunstein, C., Wang, H., Warlick, E. D., Giralt, S., Nishihori, T., Martino, R., Passweg, J., 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
Myeloablative (MAC) as compared to reduced-intensity conditioning (RIC) is generally associated with lower relapse risk after allogeneic hematopoietic cell transplantation (HCT) for acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). However, disease specific risk factors in AML/MDS can further inform when MAC vs. RIC may yield differential outcomes. We analyzed HCT outcomes stratified by the disease risk index (DRI) in 4387 adults (age 40-65 years) to identify the impact of conditioning intensity. In the low/intermediate risk DRI cohort, RIC was associated with lower non-relapse mortality (NRM) (HR=0.74, 95% CI 0.62-0.88; p<0.001), but significantly higher relapse risk (HR=1.54, 95% CI 1.35-1.76; p<0.001) and thus inferior disease-free survival (DFS) (HR=1.19, 95% CI 1.07-1.33; p=0.001). In the high/very high risk DRI cohort, RIC resulted in marginally lower NRM (HR=0.83, 95% CI 0.68-1.00; p=0.051), and significantly higher relapse risk (HR=1.23, 95% CI 1.08-1.41; p=0.002) leading to similar DFS using either RIC or MAC. These data support MAC over RIC as the preferred conditioning intensity for AML/MDS with low/intermediate risk DRI, but similar benefit to RIC in high/very high risk DRI. Novel MAC regimens with less toxicity could benefit all, but more potent anti-neoplastic approaches are needed for the high/very high risk DRI group.
PICO Summary
Population
Adult patients aged 40-65 years with acute myeloid leukaemia or myelodysplastic syndrome (AML/MDS) (n=4387)
Intervention
Reduced intensity conditioning (RIC) and low/intermediate risk (n=999), RIC and high/very high risk (n=728)
Comparison
Myeloablative conditioning (MAC) and low/intermediate risk (n=1539), MAC and high/very high risk (n=1121)
Outcome
In the low/intermediate risk disease risk index (DRI) cohort, RIC was associated with lower non-relapse mortality (NRM) , but significantly higher relapse risk and thus inferior disease-free survival (DFS). In the high/very high risk DRI cohort, RIC resulted in marginally lower NRM, and significantly higher relapse risk leading to similar DFS using either RIC or MAC.