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Mutation of the TP53 gene in acute lymphoblastic leukemia does not affect survival outcomes after haploidentical hematopoietic stem cell transplantation
Zhou, C., Zheng, F., Lanping, X., Xiaohui, Z., Chang, Y., Xiaodong, M., Yuqian, S., Xiaojun, H., Wang, Y.
International journal of cancer. 2022
Abstract
Previous studies have demonstrated that TP53 mutation is correlated with insufficient therapy response and unfavorable prognosis in acute lymphoblastic leukemia (ALL). Few studies have investigated the impact of TP53 mutation in ALL patients after haploidentical hematopoietic stem cell transplantation (haplo-HSCT). We completed a retrospective study of 65 ALL patients with available TP53 status who underwent haplo-HSCT. They were divided into a TP53 mutation group (TP53(mut) ) and a TP53 wild-type (TP53(wt) ) group. TP53(mut) showed comparable 2-year cumulative incidence of relapse (CIR) rates (13.1% vs. 12.5%, P=0.96) and 2-year leukemia-free survival (LFS) (74.2% versus 77.4%, P=0.80) with TP53(wt) . No significant differences in 2-year overall survival (OS) rates (82.9% versus 87.3%, P=0.61) or 2-year NRM rates (12.7% versus 10.2%, P=0.69) were observed in TP53(mut) and TP53(wt) patients. Multivariate analysis suggested that white blood cell (WBC) count at initial diagnosis (>50x10(9) /L: hazard ratio (HR)=3.860, P=0.016) and age (>40 years old: HR=4.120, P=0.012) are independent risk factors for 2-year LFS. Our study showed that TP53 mutations may not be related to the unfavorable impact on survival in ALL patients after treatment with haplo-HSCT. The present results suggested that haplo-HSCT may eliminate the poor prognosis effect of TP53 mutation in ALL. This article is protected by copyright. All rights reserved.
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Total body irradiation plus fludarabine versus thiotepa, busulfan plus fludarabine as a myeloablative conditioning for adults with acute lymphoblastic leukemia treated with haploidentical hematopoietic cell transplantation. A study by the Acute Leukemia Working Party of the EBMT
Swoboda, R., Labopin, M., Giebel, S., Angelucci, E., Arat, M., Aljurf, M., Sica, S., Pavlu, J., Socié, G., Bernasconi, P., et al
Bone marrow transplantation. 2022
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Editor's Choice
Abstract
Optimal conditioning for adults with acute lymphoblastic leukemia (ALL) treated with haploidentical hematopoietic cell transplantation (haplo-HCT) and post-transplant cyclophosphamide has not been established so far. We retrospectively compared outcomes for two myeloablative regimens: fludarabine + total body irradiation (Flu-TBI, n = 117) and thiotepa + iv. busulfan + fludarabine (TBF, n = 119). Patients transplanted either in complete remission (CR) or with active disease were included in the analysis. The characteristics of both groups were comparable except for patients treated with TBF were older. In univariate analysis the incidence of non-relapse mortality (NRM) at 2 years was increased for TBF compared to Flu-TBI (31% vs. 19.5%, p = 0.03). There was a tendency towards reduced incidence of relapse after TBF (p = 0.11). Results of multivariate analysis confirmed a reduced risk of NRM using Flu-TBI (HR = 0.49, p = 0.03). In the analysis restricted to patients treated in CR1 or CR2, the use of Flu-TBI was associated with a decreased risk of NRM (HR = 0.34, p = 0.009) but an increased risk of relapse (HR = 2.59, p = 0.01) without significant effect on survival and graft-versus-host disease. We conclude that for haplo-HCT recipients with ALL, Flu-TBI may be preferable for individuals at high risk of NRM while TBF should be considered in cases at high risk of relapse.
PICO Summary
Population
Adults with acute lymphoblastic leukemia (ALL) treated with haploidentical (n=haematopoietic cell transplantation (haplo-HCT) and post-transplant cyclophosphamide (n=236)
Intervention
Fludarabine + total body irradiation conditioning (Flu-TBI, n=117)
Comparison
Thiotepa + iv. busulfan + fludarabine conditioning (TBF, n=119)
Outcome
In univariate analysis the incidence of non-relapse mortality (NRM) at 2 years was increased for TBF compared to Flu-TBI (31% vs. 19.5%). There was a tendency towards reduced incidence of relapse after TBF. Results of multivariate analysis confirmed a reduced risk of NRM using Flu-TBI (HR = 0.49). In the analysis restricted to patients treated in CR1 or CR2, the use of Flu-TBI was associated with a decreased risk of NRM (HR = 0.34) but an increased risk of relapse (HR = 2.59) without significant effect on survival and graft-versus-host disease.
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Comparable outcomes in patients with B-cell acute lymphoblastic leukemia receiving haploidentical hematopoietic stem cell transplantation: Pretransplant minimal residual disease-negative complete remission following chimeric antigen receptor T-cell therapy versus chemotherapy
Yang, T. T., Meng, Y., Kong, D. L., Wei, G. Q., Zhang, M. M., Wu, W. J., Shi, J. M., Luo, Y., Zhao, Y. M., Yu, J., et al
Frontiers in immunology. 2022;13:934442
Abstract
INTRODUCTION Chimeric antigen receptor (CAR) T-cell (CAR-T) therapy followed by haploidentical hematopoietic stem cell transplantation (haplo-HSCT) markedly improves the long-term survival of patients with refractory/relapsed (R/R) B-cell acute lymphoblastic leukemia (B-ALL). METHODS We performed a parallel comparison of transplant outcomes in 168 B-ALL patients undergoing haplo-HSCT after achieving minimal residual disease (MRD)-negative complete remission (CR) from CAR-T therapy (n = 28) or chemotherapy (n = 140) between January 2016 and August 2021. We further divided the chemotherapy group into the first CR group (chemo+CR1, n = 118) and a second or more CR group (chemo+≥CR2, n = 22). RESULTS With a median follow-up period of 31.0 months, the 2-year overall survival (OS), leukemia-free survival (LFS), non-relapse mortality (NRM), and relapse rates in the CAR-T and chemotherapy groups did not differ significantly (OS, 87.9% vs. 71.5 %; LFS, 72.0% vs. 66.8%; NRM, 3.9% vs. 13.7%; relapse, 24.1% vs. 19.4%). Multivariate analysis confirmed that ≥CR2 at transplantation following chemotherapy was an independent risk factor associated with poor OS (hazard ratio (HR) 4.22 [95% CI, 1.34-13.293], p = 0.014) and LFS (HR 2.57 [95% CI, 1.041-6.343], p = 0.041). The probabilities of OS and LFS at 2 years in the CAR-T group were comparable to those in the chemo+CR1 group but significantly higher than those in the chemo+≥CR2 group (OS, 87.9% vs. 37.8%, p = 0.007; LFS, 72.0% vs. 41.7%, p = 0.043). No significant differences in the incidences of NRM were noted among the three groups. CONCLUSIONS Our results demonstrated that patients with R/R B-ALL receiving haplo-HSCT after CAR-T therapy achieved comparable outcomes to patients transplanted post-chemotherapy-based MRD-negative CR1, without increased risk of transplant-related mortality and toxicity.
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Infusion of haploidentical HSCs combined with allogenic MSCs for the treatment of ALL patients
Ding, L., Han, D. M., Yan, H. M., Zhou, J. X., Zheng, X. L., Zhu, L., Xue, M., Liu, J., Mao, N., Guo, Z. K., et al
Bone marrow transplantation. 2022
Abstract
Although haploidentical stem cell transplantation (haplo-HSCT) offers almost all acute lymphoblastic leukaemia (ALL) patients an opportunity for immediate transplantation, it exhibits a higher incidence of graft failure and graft versus host disease (GVHD). Mesenchymal stem cells (MSCs) are characterised by their haematopoiesis-promoting and immunomodulatory capacity. Thus, we designed a combination of haplo-HSCT and MSCs for ALL patients. ALL patients (n = 110) were given haploidentical HSCs combined with allogenic MSCs, and ALL patients without MSC infusion (n = 56) were included as controls. The 100-day cumulative incidences of grade ≥2 acute GVHD (aGVHD) and grade ≥3 aGVHD were 40.00% and 9.09% compared to 42.32% (P = 0.79) and 22.79% (P = 0.03) in patients without MSC infusion, respectively. The 3-year cumulative incidences of chronic GVHD (cGVHD) and extensive cGVHD were 22.27% and 10.27% compared to 32.14% (P = 0.19) and 22.21% (P = 0.04) in patients without MSC infusion, respectively. No significant differences in the 3-year relapse incidence, nonrelapse mortality, leukaemia-free survival or overall survival in groups with and without MSC cotransplantation were observed. Multivariate analysis showed that MSC infusion contributed to a lower risk of developing extensive cGVHD. Our data suggested that haplo-HSCT combined with MSCs may provide an effective and safe treatment for ALL patients.
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Comparisons of Long-Term Survival and Safety of Haploidentical Hematopoietic Stem Cell Transplantation After CAR-T Cell Therapy or Chemotherapy in Pediatric Patients With First Relapse of B-Cell Acute Lymphoblastic Leukemia Based on MRD-Guided Treatment
Hu, G., Cheng, Y., Zuo, Y., Chang, Y., Suo, P., Jia, Y., Lu, A., Wang, Y., Jiao, S., Zhang, L., et al
Frontiers in immunology. 2022;13:915590
Abstract
Measurable residual disease (MRD) positivity before haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is an independent prognostic factor in determining outcomes in patients with B-cell acute lymphoblastic leukemia (ALL). In this study, we conducted a parallel comparison of the efficacy and safety in patients with suboptimal MRD response after reinduction who underwent haplo-HSCT after chimeric antigen receptor T-cell (CAR-T) therapy or chemotherapy. Forty B-cell ALL patients who relapsed after first-line chemotherapy and with an MRD ≥0.1% after reinduction were analyzed. The median pre-HSCT MRD in the CAR-T group (n = 26) was significantly lower than that in the chemotherapy group (n = 14) (0.009% vs. 0.3%, p = 0.006). The CAR-T group exhibited a trend toward improved 3-year leukemia-free survival and a significantly improved 3-year overall survival compared to the chemotherapy group [71.8% (95% confidence interval (CI): 53.9-89.6) vs. 44.4% (95% CI: 15.4-73.4), p = 0.19 and 84.6% (95% CI: 70.6-98.5) vs. 40.0% (95% CI: 12.7-67.2), p = 0.008; respectively]. Furthermore, no increased risk of graft-versus-host disease, treatment-related mortality, or infection was observed in the CAR-T group. Our study suggests that CAR-T therapy effectively eliminates pre-HSCT MRD, resulting in better survival in the context of haplo-HSCT.
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Treatments of Ph-like acute lymphoblastic leukemia: a real-world retrospective analysis from a single large center in China
Xu, G. F., Liu, L. M., Wang, M., Zhang, Z. B., Xie, J. D., Qiu, H. Y., Chen, S. N.
Leukemia & lymphoma. 2022;:1-11
Abstract
Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a high-risk subtype of ALL. We retrospectively studied 70 cases with Ph-like ALL and here present the largest study of CAR-T cell treatment and haplo-HSCT for this leukemia. Median age was 26 years and median leukocyte count was 31.44 × 10(9)/L. The proportion of patients receiving chemotherapy, KIs, CAR-T cells, and allo-HSCT was 19%, 30%, 46%, and 61%, respectively. The overall response rate was 62%, 73%, and 100% after one month of KI treatment combined with chemotherapy, CAR-T cell therapy, and allo-HSCT, respectively. Five-year DFS and OS were 35% and 51%, respectively. The five-year cumulative incidence of relapse and non-relapse mortality was 63% and 11%, respectively. Allo-HSCT was associated with a better DFS (p = 0.010) and OS (p = 0.000) by univariate analysis. In conclusion, allo-HSCT after KIs together with chemotherapy or CAR-T cell therapy is a safe and feasible treatment modality for Ph-like ALL.
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Haploidentical hematopoietic stem cell transplantation may improve long-term survival for children with high-risk T-cell acute lymphoblastic leukemia in first complete remission
Zhang, Y., Bai, L., Cheng, Y., Lu, A., Wang, Y., Wu, J., Zhang, X., Zuo, Y., Xu, L., Jia, Y., et al
Chinese medical journal. 2022;135(8):940-949
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Abstract
BACKGROUND The role of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in children with high-risk (HR) T-cell acute lymphoblastic leukemia (T-ALL) in first complete remission (CR1) is still under evaluation. Moreover, relapse is the main factor affecting survival. This study aimed to explore the effect of allo-HSCT (especially haploidentical HSCT [haplo-HSCT]) on improving survival and reducing relapse for HR childhood T-ALL in CR1 and the prognostic factors of childhood T-ALL in order to identify who could benefit from HSCT. METHODS A total of 74 newly diagnosed pediatric T-ALL patients between January 1, 2012 and June 30, 2018 were enrolled in this retrospective study. Patients were stratified into the low-risk chemotherapy cohort (n = 16), HR chemotherapy cohort (n = 31), and HR transplant cohort (n = 27). Characteristics, survival outcomes, and prognostic factors of all patients were then analyzed. RESULTS Patient prognosis in the HR chemotherapy cohort was significantly worse than that in the low-risk chemotherapy cohort (5year overall survival [OS]: 58.5% vs. 100%, P = 0.003; 5-year event-free survival [EFS]: 54.1% vs. 83.4%, P = 0.010; 5-year cumulative incidence of relapse [CIR]: 45.2% vs. 6.3%, P = 0.011). In HR patients, allo-HSCT improved the 5-year EFS and CIR compared to that of chemotherapy (5-year EFS: 80.1% vs. 54.1%, P = 0.041; 5-year CIR: 11.6% vs. 45.2%, P = 0.006). The 5-year OS was higher in the HR transplant cohort than that in the HR chemotherapy cohort (81.0% vs. 58.5%, P = 0.084). Minimal residual disease re-emergence was an independent risk factor for 5-year OS, EFS, and CIR; age ≥10 years was an independent risk factor for OS and EFS; and high white blood cell count was an independent risk factor for EFS and CIR. CONCLUSION Allo-HSCT, especially haplo-HSCT, could effectively reduce relapse of children with HR T-ALL in CR1.
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Outcomes of Unmanipulated Haploidentical Transplantation Using Post-Transplant Cyclophosphamide (PT-Cy) in Pediatric Patients With Acute Lymphoblastic Leukemia
Ruggeri, A., Galimard, J. E., Paina, O., Fagioli, F., Tbakhi, A., Yesilipek, A., Navarro, J. M. F., Faraci, M., Hamladji, R. M., Skorobogatova, E., et al
Transplantation and cellular therapy. 2021;27(5):424.e1-424.e9
Abstract
HLA-haploidentical transplantation (haplo-HCT) using post-transplantation-cyclophosphamide (PT-Cy) is a feasible procedure in children with malignancies. However, large studies on Haplo-HCT with PT-Cy for childhood acute lymphoblastic leukemia (ALL) are lacking. We analyzed haplo-HCT outcomes in 180 children with ALL. Median age was 9 years, and median follow-up was 2.7 years. Disease status was CR1 for 24%, CR2 for 45%, CR+3 for 12%, and active disease for 19%. All patients received PT-Cy day +3 and +4. Bone marrow (BM) was the stem cell source in 115 patients (64%). Cumulative incidence of 42-day engraftment was 88.9%. Cumulative incidence of day-100 acute graft-versus-host disease (GVHD) grade II-IV was 28%, and 2-year chronic GVHD was 21.9%. At 2 years, cumulative incidence of nonrelapse mortality (NRM) was 19.6%. Cumulative incidence was 41.9% for relapse and 25% for patients in CR1. Estimated 2-year leukemia free survival was 65%, 44%, and 18.8% for patients transplanted in CR1, CR2, CR3+ and 3% at 1 year for active disease. In multivariable analysis for patients in CR1 and CR2, disease status (CR2 [hazard ratio {HR} = 2.19; P = .04]), age at HCT older than 13 (HR = 2.07; P = .03) and use of peripheral blood stem cell (PBSC) (HR = 1.98; P = .04) were independent factors associated with decreased overall survival. Use of PBSC was also associated with higher NRM (HR = 3.13; P = .04). Haplo-HCT with PT-Cy is an option for children with ALL, namely those transplanted in CR1 and CR2. Age and disease status remain the most important factors for outcomes. BM cells as a graft source is associated with improved survival.
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[Comparison of the clinical outcomes of haploidentical and matched-sibling donor stem cell transplantation for T cell acute lymphoblastic leukemia in complete remission]
Cao, X. Y., Wei, Z. J., Liu, D. Y., Zhou, J. R., Xiong, M., Zhao, Y. L., Lu, Y., Sun, R. J., Zhang, J. P., Ma, W., et al
Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi. 2021;42(3):210-216
Abstract
Objective: To compare the efficacy of haplotype hematopoietic stem cell transplantation (HIDT) and sibling matched hematopoietic stem cell transplantation (MSDT) in the treatment of complete remission (CR) acute T-lymphoblastic leukemia (T-ALL) . Methods: We retrospectively analyzed the clinical characteristics and outcomes of 98 patients who underwent HSCT in Hebei Yanda Ludaopei hospital with HID (n=81) or ISD (n=17) between May 2012 and May 2016. Results: The incidence of grades 2-4 and 3-4 acute-versus-host disease 100 days after HSCT were 51.9% (95% Confidence interval [CI] 42.0%-64.0%) vs 29.4% (95% CI 14.1%-61.4%) (P=0.072) and 9.8% (95% CI 5.1%-19.1%) vs 11.8% (95% CI 3.2%-43.3%) (P=1.000) for HIDT and MSDT. The 100-day cumulative incidences of CMV and EBV viremia were 53.1% (95% CI 43.3%-65.2%) vs 29.4% (95% CI 14.1%-61.4%) (P=0.115) and 35.8% (95% CI 26.8%-47.9%) vs11.8% (95% CI 3.2%-43.3%) (P=0.048) . The 5-year overall survival, leukemia-free survival, cumulative incidences of relapse, and no-relapse mortality were 60.5% (95% CI 5.4%-49.0%) vs 68.8% (95% CI 11.8%-40.0%) (P=0.315) , 58.0% (95% CI 5.5%-46.5%) vs 68.8% (95% CI 11.8%-40.0%) (P=0.258) , 16.1% (95% CI 9.8%-26.4%) vs 11.8% (95% CI 3.2%-43.3%) (P=0.643) , 25.9% (95% CI 17.9%-37.5%) vs 19.4% (95% CI 6.9%-54.4%) (P=0.386) for HIDT and MSDT, respectively. Conclusion: HID could be a valid alternative donor for patients with T-ALL in CR lacking an identical donor.
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Outcome of T-cell-replete haploidentical stem cell transplantation improves with time in adults with acute lymphoblastic leukemia: A study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation
Nagler, A., Labopin, M., Koc, Y., Angelucci, E., Tischer, J., Arat, M., Pioltelli, P., Bernasconi, P., Chiusolo, P., Diez-Martin, J. L., et al
Cancer. 2021
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Editor's Choice
Abstract
BACKGROUND The use of haploidentical hematopoietic cell transplantation (haplo-HCT) with posttransplantation cyclophosphamide prophylaxis is gaining traction in patients with acute lymphoblastic leukemia (ALL). METHODS The Acute Leukemia Working Party/European Society for Blood and Marrow Transplantation registry was used to evaluate the outcomes of adult patients with ALL who underwent haplo-HCT during 2011 through 2015 and compared them with the outcomes of those who underwent transplantation during 2016 through 2018. RESULTS The analysis consisted of 195 patients, including 79 who underwent transplantation during 2011 through 2015 and 116 who underwent transplantation during 2016 through 2018. Overall, the 2-year leukemia-free survival and relapse incidence rates were 56.5% and 21%, respectively. The 100-day incidence of grade 2 through 4 acute graft-vs-host disease (GVHD) was 34.5%. The rates of nonrelapse mortality (NRM) and overall survival (OS) were 22.5% and 64.7%, respectively. Patients who underwent transplantation during 2016 through 2018 experienced improved rates of leukemia-free survival (64.9% vs 47.3%; P = .019) and OS (75.5% vs 53.5%; P = .006). Patients who underwent transplantation during 2016 through 2018 developed more grade 2 through 4 acute GVHD (42% vs 26.4%; P = .047). The incidence of relapse, GVHD-free/relapse-free survival, grade 3 and 4 acute GVHD, chronic GVHD, and extensive chronic GVHD did not differ significantly between groups. In multivariate analysis, more recently transplanted patients had a significantly reduced risk of NRM (hazard ratio, 0.44; 95% CI, 0.22-0.89; P = .022) and improved OS (hazard ratio, 0.47; 95% CI, 0.26-0.86; P = .014). A comparable analysis of patients who had acute myeloid leukemia during the same timeframes did not reveal any statistically significant differences in any outcomes. CONCLUSIONS The outcome of adult patients with ALL who receive posttransplant cyclophosphamide has improved over time, with an impressive 2-year OS of 75% and, most recently, an NRM rate of only 17%.
PICO Summary
Population
Adult patients undergoing haploidentical transplantation for acute lymphoblastic leukemia reported to the EBMT registry (n=195)
Intervention
Haploidentical transplantation between 2016-2018 (n=116)
Comparison
Haploidentical transplantation between 2011-2015 (n=79)
Outcome
For the entire cohort, the 2-year leukemia-free survival and relapse incidence rates were 56.5% and 21%, respectively. The 100-day incidence of grade 2 through 4 acute graft-vs-host disease (GVHD) was 34.5%. The rates of non-relapse mortality (NRM) and overall survival (OS) were 22.5% and 64.7%, respectively. Patients who underwent transplantation during 2016 through 2018 experienced improved rates of leukemia-free survival (64.9% vs 47.3%) and OS (75.5% vs 53.5%). Patients who underwent transplantation during 2016 through 2018 developed more grade 2 through 4 acute GVHD (42% vs 26.4%). The incidence of relapse, GVHD-free/relapse-free survival, grade 3 and 4 acute GVHD, chronic GVHD, and extensive chronic GVHD did not differ significantly between groups. In multivariate analysis, more recently transplanted patients had a significantly reduced risk of NRM (hazard ratio, 0.44) and improved OS (hazard ratio, 0.47). A comparable analysis of patients who had acute myeloid leukemia during the same timeframes did not reveal any statistically significant differences in any outcomes.