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1.
Impact of MRD on clinical outcomes of unrelated hematopoietic stem cell transplantation in patients with Ph(+) ALL: A retrospective nationwide study
Hirabayashi, S., Kondo, T., Nishiwaki, S., Mizuta, S., Doki, N., Fukuda, T., Uchida, N., Ozawa, Y., Kanda, Y., Imanaka, R., et al
American journal of hematology. 2023
Abstract
Measurable residual disease (MRD) status before transplantation has been shown to be a strong prognostic factor in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+) ALL). However, the outcomes of unrelated hematopoietic stem cell transplantation based on the MRD status have not been fully investigated. In this retrospective study, we compared the outcomes of 715 consecutive adults with Ph(+) ALL in complete remission who underwent unrelated cord blood transplantation (UCBT) (single-unit UCBT, n = 232 [4/6, 5/6, and 6/6 HLA match]), HLA-matched unrelated bone marrow transplantation (UBMT; n = 292 [8/8 HLA match]), or HLA-mismatched UBMT (n = 191 [7/8 HLA match]). In the MRD(+) cohort, adjusted 3-year leukemia-free survival rates were 59.8%, 38.3%, and 55.5% after UCBT, HLA-matched UBMT, and HLA-mismatched UBMT, respectively. In the MRD(-) cohort, the corresponding rates were 65.3%, 70.4%, and 69.7%, respectively. The MRD(+) HLA-matched UBMT group had a significantly higher risk of relapse than the MRD(+) HLA-mismatched UBMT group (hazard ratio [HR] in the MRD(+) HLA-mismatched UBMT group, 0.33; 95% confidence interval [CI] 0.15-0.74) and the MRD(+) UCBT group (HR in the MRD(+) UCBT group, 0.38; 95% CI 0.18-0.83). Furthermore, HLA-matched UBMT had a significant effect of MRD on death (HR 1.87; 95% CI 1.19-2.94), relapse or death (HR 2.24; 95% CI 1.50-3.34), and relapse (HR 3.12; 95% CI 1.75-5.57), while UCBT and HLA-mismatched UBMT did not. In conclusion, our data indicate Ph(+) ALL patients with positive MRD may benefit from undergoing UCBT or HLA-mismatched UBMT instead of HLA-matched UBMT to reduce leukemic relapse.
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2.
Durable outcomes of double cord blood transplantation in adults with acute lymphoblastic leukemia: high-risk features for early and long-term mortality
Yoon, J. H., Min, G. J., Park, S. S., Park, S., Lee, S. E., Cho, B. S., Eom, K. S., Kim, Y. J., Kim, H. J., Min, C. K., et al
Therapeutic advances in hematology. 2022;13:20406207221076762
Abstract
BACKGROUND Cord blood transplantation (CBT) has been reported as an acceptable option with comparable outcomes to conventional donors in adults with acute lymphoblastic leukemia (ALL). We aimed to analyze the long-term CBT outcomes and risk factors for early and long-term mortalities. METHODS Between 2006 and 2020, 112 patients (median age: 35 years; 62 Ph-negative ALL and 50 Ph-positive ALL) were treated with double CBT. Conditioning regimen consisted of total body irradiation (12 Gy) plus cytarabine (9.0 g/m(2)) plus fludarabine (150 mg/ m(2)), and graft-versus-host disease (GVHD) prophylaxis was attempted by administering tacrolimus plus mycophenolate mofetil. RESULTS The median time for neutrophil and platelet recovery was 25 days (range: 5-59 days) and 34 days (range: 7-185 days), respectively. The cumulative incidence of acute GVHD at 1 year was 43.8%, and the incidence of acute GVHD with grades III-IV was 8.9%. The overall cumulative incidence of chronic GVHD was 22.0%, and the incidence of moderate to severe chronic GVHD was 8.5%. After a median follow-up of 60.1 months (range: 5.7-181.3 months), the 5-year cumulative incidence of relapse (CIR) and nonrelapse mortality (NRM) were 15.9% and 28.5% (9.7% and 27.2% for CR1), respectively, and the 5-year overall survival (OS) was 57.9% (66.5% for CR1). In multivariate analysis of 88 patients receiving double CBT in CR1, delayed CR1 was related to high CIR, and age older than 40 years was associated with high NRM and early mortality. Unexpectedly, Ph-positive ALL with MRD had a higher NRM and early mortality than Ph-negative ALL and Ph-positive ALL without MRD subgroups, possibly due to delayed neutrophil and platelet recovery. CONCLUSION Our data suggest that double CBT for adult ALL in CR1 has a greater benefit in younger patients and in patients with Ph-positive ALL without MRD or Ph-negative ALL.
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Impact of Consolidative Unrelated Cord Blood Transplantation on Clinical Outcomes of Patients With Relapsed/Refractory Acute B Lymphoblastic Leukemia Entering Remission Following CD19 Chimeric Antigen Receptor T Cells
Xu, Q., Xue, L., An, F., Xu, H., Wang, L., Geng, L., Zhang, X., Song, K., Yao, W., Wan, X., et al
Frontiers in immunology. 2022;13:879030
Abstract
BACKGROUND While chimeric antigen receptor (CAR)-T cell therapy is becoming widely used in hematological malignancies with remarkable remission rate, their high recurrence remains an obstacle to overcome. The role of consolidative transplantation following CAR-T cell-mediated remission remains controversial. We conducted a retrospective study to explore whether bridging to unrelated cord blood transplantation (UCBT) could improve the prognosis of patients entering remission after CAR-T therapy with different characteristics through subgroup analyses. METHODS We reviewed 53 patients with relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) successfully infused with CD19 CAR-T cells and achieved complete remission (CR). In this study, 25 patients received consolidative UCBT (UCBT group) and 28 patients did not accept any intervention until relapse (non-UCBT group). Subgroup analysis on prognosis was then performed according to gender, age, number of previous relapses, tumor burden, presence of poor prognostic markers, and structure of CAR. RESULTS Compared with the non-UCBT group, patients who underwent consolidative UCBT had better median event-free survival (EFS; 12.3 months vs. 6.2 months; P = 0.035) and relapse-free survival (RFS; 22.3 months vs. 7.2 months; P = 0.046), while no significant difference was found in overall survival (OS; 30.8 months vs. 15.3 months; P = 0.118). Subsequent multivariate analysis revealed that bridging to UCBT was a protective factor for RFS (P = 0.048) but had no significant effect on EFS (P = 0.205) or OS (P = 0.541). In the subgroup analysis, UCBT has an added benefit in patients with specific characteristics. Patients who experienced ≥2 relapses or with sustained non-remission (NR) showed better RFS (P = 0.025) after UCBT. Better EFS was seen in patients with poor prognostic markers (P = 0.027). In the subgroup with pre-infusion minimal residual disease (MRD) ≥5% or with extramedullary disease (EMD), UCBT significantly prolonged EFS (P = 0.009), RFS (P = 0.017), and OS (P = 0.026). Patients with occurrence of acute graft-versus-host disease (aGVHD) appeared to have a longer duration of remission (P = 0.007). CONCLUSION Consolidative UCBT can, to some extent, improve clinical outcomes of patients with R/R B-ALL entering remission following CD19 CAR-T therapy, especially in patients with more recurrences before treatment, patients with poor prognostic markers, and patients with a higher tumor burden. The occurrence of aGVHD after UCBT was associated with better RFS.
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4.
A decision analysis for unrelated bone marrow transplantation or immediate cord blood transplantation for patients with Philadelphia chromosome-negative acute lymphoblastic leukemia in first complete remission: Unrelated BMT or immediate CBT for Ph-negative ALL
Kako, S., Hayakawa, F., Miyamura, K., Tanaka, J., Imai, K., Kanda, J., Morishima, S., Uchida, N., Doki, N., Ikegame, K., et al
Transplantation and cellular therapy. 2021
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Editor's Choice
Abstract
BACKGROUND A human leucocyte antigen (HLA)-matched relative is the first-choice donor for patients with Philadelphia chromosome (Ph)-negative acute lymphoblastic leukemia (ALL) in first complete remission (CR1). The most promising alternative donor is thought to be an HLA-matched unrelated donor (MUD) in patients who do not have an HLA-matched related donor. Cord blood transplantation (CBT) is one of alternative options. Higher rates of engraftment failure and non-relapse mortality are big problems, but the ready availability of cord blood can be an advantage because patients can immediately undergo transplantation before progression. OBJECTIVE To determine an appropriate alternative donor in patients with Ph-negative ALL in CR1, who do not have HLA-matched relatives. STUDY DESIGN Decision analyses using a Markov model were performed to compare immediate CBT, in which CBT was performed at 1 month after the achievement of CR1, with elective unrelated bone marrow transplantation (uBMT) from 8/8 MUD (8/8 uBMT) or uBMT from 7/8 MUD (7/8 uBMT), in which uBMT was performed at 4 months, in patients aged 16-55 years with Ph-negative ALL in CR1 who did not have HLA-matched relatives. We constructed a decision tree as described in Figure 1. The cycle length was set at 3 months, and analyses were performed for 19 cycles for uBMT and 20 cycles for CBT, which resulted in evaluation of the 5-year life expectancy after both decisions. Transition probabilities and utilities were estimated from prospective and retrospective Japanese studies and the registry database of Japan as summarized in Table 1. Subgroup analyses were performed according to risk stratification on the basis of the white blood cell count and cytogenetics at the diagnosis, and according to age stratification with a cutoff of 25 years. One-way sensitivity analyses for TPs and utilities were also performed. RESULTS The baseline analyses showed that the decision to perform 8/8 uBMT or 7/8 uBMT gave superior results, with quality-adjusted life years (QALYs) of 2.86, 2.84, and 2.75 in 8/8 uBMT, 7/8 uBMT, and CBT, respectively. One-way sensitivity analyses showed that the results of the baseline analyses were reversed if the probabilities of non-relapse mortality (NRM) in CBT improved. Subgroup analyses showed the similar results in lower-aged, higher-aged, and high-risk patients. However, QALY in 8/8 uBMT was worse than that in CBT in standard-risk patients. In one-way sensitivity analyses, the probabilities of NRM in uBMT and CBT affected the baseline results in all analyses except for comparisons between 8/8 uBMT and CBT in lower-aged and high-risk patients. In these 2 populations, the superiority of 8/8 uBMT was consistently demonstrated throughout the entire one-way sensitivity analyses. CONCLUSION For patients with Ph-negative ALL in CR1 who decide to undergo transplantation from an alternative donor, elective uBMT from either 8/8 MUD or 7/8 MUD is expected to give a better outcome than immediate CBT. However, CBT is a viable option, and improvements to reduce the probabilities of NRM in CBT may change these results.
PICO Summary
Population
Outcomes of patients identified from the Japan Transplant Registry Unified Management Program (TRUMP) database with Philadelphia chromosome-negative acute lymphoblastic leukaemia (Ph-negative ALL) age 16 to 55 years who underwent a first unrelated bone marrow transplantation (uBMT) in Japan (n= 327)
Intervention
Decision tree analysis using a Markov model comparing unrelated bone marrow transplantation (uBMT) to upfront cord blood transplantation, as follows:
Comparison
Comparison of 8/8 matched unrelated donor (MUD) transplant (n=163), 7/8 MUD (n=98) or Cord blood transplantation (CBT) with a single unit (n=66)
Outcome
The baseline analyses showed that the decision to perform 8/8 uBMT or 7/8 uBMT gave superior results, with quality-adjusted life years (QALYs) of 2.86, 2.84, and 2.75 in 8/8 uBMT, 7/8 uBMT, and CBT, respectively. One-way sensitivity analyses showed that the results of the baseline analyses were reversed if the probabilities of non-relapse mortality (NRM) in CBT improved. Subgroup analyses showed the similar results in lower-aged, higher-aged, and high-risk patients. However, QALY in 8/8 uBMT was worse than that in CBT in standard-risk patients. In one-way sensitivity analyses, the probabilities of NRM in uBMT and CBT affected the baseline results in all analyses except for comparisons between 8/8 uBMT and CBT in lower-aged and high-risk patients. In these 2 populations, the superiority of 8/8 uBMT was consistently demonstrated throughout the entire one-way sensitivity analyses.
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Unrelated cord blood transplantation with myeloablative conditioning for pediatric acute lymphoblastic leukemia in remission: prognostic factors
Kawahara, Y., Morimoto, A., Inagaki, J., Koh, K., Noguchi, M., Goto, H., Yoshida, N., Cho, Y., Hori, T., Hiwatari, M., et al
Bone Marrow Transplantation. 2021;56(2):357-367
Abstract
The number of individuals undergoing unrelated cord blood transplantation (UCBT) has increased in recent years; however, information on prognostic factors is limited. We retrospectively analyzed data from 475 children and adolescents receiving UCBT with myeloablative conditioning for acute lymphoblastic leukemia (ALL) in complete remission (CR), based on a nationwide registry. In the total patient cohort, 5-year leukemia-free survival (LFS) and overall survival (OS) rates after UCBT were 61.1% and 67.7%, respectively. UCBT at first CR and UCBT after 2007 were associated with good survival, while grade II-IV acute graft-versus-host disease (GVHD) was associated with low relapse rate but did not affect survival. Analysis according to human leukocyte antigen (HLA) disparity revealed that tacrolimus-based GVHD prophylaxis resulted in higher OS and lower relapse rate and nonrelapse mortality (NRM) than cyclosporine-based GVHD prophylaxis in patients transplanted with 6/6 and ≤4/6 HLA-matched umbilical cord blood. Furthermore, grade II-IV acute GVHD was associated with good LFS and low relapse rate, without high NRM, in patients receiving 5/6 HLA-matched UCBT. These data indicate that prognostic factors for ALL differ depending on HLA disparity in UCBT.
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CAR-T cell therapy followed by unrelated cord blood transplantation for the treatment of relapsed/refractory B-cell ALL in children and young adults: superior survival but relatively high posttransplant relapse
Sun, G., Tang, B., Wan, X., Yao, W., Song, K., Tu, M., Geng, L., Qiang, P., Wu, Y., Zhu, L., et al
Transplantation and cellular therapy. 2021
Abstract
BACKGROUND Several studies have indicated that chimeric antigen receptor T-cell (CAR-T) therapy followed by allogeneic hematopoietic stem cell transplantation is beneficial for relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). Whether consolidative unrelated cord blood transplantation (UCBT) is suitable in R/R B-ALL after CAR-T therapy remain uncertain. OBJECTIVE We aimed to assess the efficacy and safety of CAR-T therapy before UCBT for children and young adults R/R B-ALL patients. STUDY DESIGN We retrospectively analyzed 43 R/R B-ALL and under 18 years patients who underwent single-unit UCBT at the First Affiliated Hospital of University of Science and Technology of China (USTC) between February 2012 and November 2020. Among them, 21 patients achieved complete remission (CR) following CAR-T therapy before UCBT (the CAR-T group), and the remaining 22 patients remained non-remission (NR) without prior CAR-T therapy before UCBT (the NR group). The clinical outcomes between two groups were analyzed. RESULTS The median time from CAR-T therapy to UCBT was 62 (range,42 to 185) days. There were no significant differences in the incidences of grade II-IV, III-IV acute graft-versus-host disease (GVHD) and 2-year extensive chronic GVHD between the two groups. Compared with the NR group, a lower 2-year cumulative incidence of transplant-related mortality and higher probabilities of 2-year overall survival, leukemia-free survival, and GVHD-free relapse-free survival were found in the CAR-T group (P?=?0.037, 0.005, 0.028 and 0.017, respectively). However, the 2-year cumulative incidence of relapse (CIR) was comparably high between two groups (26.7% in the CAR-T group and 38.3% in the NR group, P?=?0.41). In the CAR-T group, patients with minimal residual disease (MRD) positive before UCBT had a high CIR comparing with those with MRD negative before UCBT (66.7% vs.19.2%, P?=?0.006). CONCLUSION CAR-T therapy followed by UCBT produces superior survival in R/R B-ALL, but treated patients still exhibit a high posttransplant relapse rate.
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Comparison of reduced-intensity/toxicity conditioning regimens for umbilical cord blood transplantation for lymphoid malignancies
Imahashi, N., Terakura, S., Kondo, E., Kako, S., Uchida, N., Kobayashi, H., Inamoto, Y., Sakai, H., Tanaka, M., Ishikawa, J., et al
Bone marrow transplantation. 2020
Abstract
To investigate which reduced-intensity conditioning (RIC)/reduced-toxicity conditioning (RTC) is superior for umbilical cord blood transplantation (UCBT) for lymphoid malignancies, we retrospectively compared three widely used RIC/RTC regimens: fludarabine/melphalan/total body irradiation (FM-TBI, n = 524), fludarabine/cyclophosphamide/total body irradiation (FC-TBI, n = 96), and fludarabine/busulfan/total body irradiation or melphalan (FB-based, n = 159). Among patients with acute lymphoblastic leukemia (ALL) (n = 314), there were no differences in overall survival (OS) by conditioning regimen. Among patients with malignant lymphoma (ML) (n = 465), FM-TBI and FC-TBI regimens had similar OS, whereas FB-based regimen had lower OS (hazard ratio [HR], 1.73; P < 0.01) than did FM-TBI regimen due to higher non-relapse mortality (HR, 1.72; P = 0.02). In addition, mycophenolate mofetil-containing GVHD prophylaxis was associated with better OS than methotrexate-containing GVHD prophylaxis among patients who received FM-TBI (HR, 0.65; P = 0.03) and FC-TBI (HR, 0.25; P < 0.01) regimens due to a decreased relapse risk. In summary, our results suggest that all three RIC/RTC regimens have comparable clinical outcomes in ALL, while the FM-TBI or FC-TBI regimens combined with mycophenolate mofetil-containing GVHD prophylaxis is preferable in RIC/RTC-UCBT for ML. Large prospective studies are warranted to confirm these results.
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8.
European Group for Blood and Marrow Transplantation Risk Score Predicts the Outcome of Patients with Acute Leukemia Receiving Single Umbilical Cord Blood Transplantation
Zhu, X., Huang, L., Zheng, C., Tang, B., Liu, H., Geng, L., Tong, J., Zhang, L., Zhang, X., Yao, W., et al
Biology of Blood & Marrow Transplantation. 2017;23(12):2118-2126
Abstract
The European Group for Blood and Marrow Transplantation (EBMT) risk score has been implemented as an important tool to predict patient outcomes after allogeneic hematopoietic stem cell transplantation. However, to our knowledge, this score has never been applied in cases of single umbilical cord blood transplantation (sUCBT). We retrospectively analyzed 207 consecutive patients with acute leukemia who received sUCBT at our center between February 2011 and December 2015. The probabilities of 3-year overall survival (OS) and leukemia-free survival (LFS) of the entire cohort were 65.0% and 59.8%, respectively, whereas the cumulative incidences of 3-year nonrelapse mortality (NRM) and relapse rate were 19.5% and 20.3%, respectively. In the univariate analysis, a higher EBMT risk score was associated with worse OS and LFS and higher NRM and relapse rate, ranging from 81.7%, 75.9%, 7.3%, and 15.3%, respectively, for patients with a score of 1 to 43.8%, 44.3%, 31.7%, and 23.9%, respectively, for patients with scores of 4 to 6. Hazard ratios of OS, LFS, and NRM all steadily increased for each additional score point. Importantly, the prognostic value of the EBMT risk score on OS, LFS, NRM, and relapse was maintained in the multivariate analysis. Moreover, considering the univariate analysis results of donor-recipient gender and mismatched allele-level HLA-A, -B, -C, and -DRB1 loci on patient outcomes and the fairly strong interaction between time from diagnosis to sUCBT and disease status, we developed a modified sUCBT-EBMT risk score by using degrees of 8-allele HLA match instead of donor type, donor-recipient gender combination, and time from diagnosis to sUCBT, and found that the modified score could also be used as a predictor for patient outcomes after sUCBT. The EBMT risk score is a good predictor of outcomes of patients with leukemia after sUCBT. The modified sUCBT-EBMT risk score can also be used as a pretransplant risk assessment, but this metric still requires further evaluation with a larger cohort.Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
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Factors Associated with Long-Term Risk of Relapse after Unrelated Cord Blood Transplantation in Children with Acute Lymphoblastic Leukemia in Remission
Page, K. M., Labopin, M., Ruggeri, A., Michel, G., Diaz de Heredia, C., O'Brien, T., Picardi, A., Ayas, M., Bittencourt, H., Vora, A. J., et al
Biology of Blood & Marrow Transplantation. 2017;23(8):1350-1358
Abstract
For pediatric patients with acute lymphoblastic leukemia (ALL), relapse is an important cause of treatment failure after unrelated cord blood transplant (UCBT). Compared with other donor sources, relapse is similar or even reduced after UCBT despite less graft-versus-host disease (GVHD). We performed a retrospective analysis to identify risk factors associated with the 5-year cumulative incidence of relapse after UCBT. In this retrospective, registry-based study, we examined the outcomes of 640 children (<18 years) with ALL in first complete remission (CR1; n=257, 40%) or second complete remission (CR2; n=383, 60%) who received myeloablative conditioning followed by a single-unit UCBT from 2000 to 2012. Most received antithymocyte globulin (88%) or total body irradiation (TBI; 69%), and cord blood grafts were primarily mismatched at 1 (50%) or 2+ (34%) HLA loci. Considering patients in CR1, the rates of 5-year overall survival (OS), leukemia-free survival (LFS), and relapse were 59%, 52%, and 23%, respectively. In multivariate analysis (MVA), acute GVHD (grades II to IV) and TBI protected against relapse. In patients in CR2, rates of 5-year OS, LFS, and the cumulative incidence of relapse were 46%, 44%, and 28%, respectively. In MVA, longer duration from diagnosis to UCBT (>=30 months) and TBI were associated with decreased relapse risk. Importantly, receiving a fully HLA matched graft was a strong risk factor for increased relapse in MVA. An exploratory analysis of all 640 patients supported the important association between the presence of acute GVHD and less relapse but also demonstrated an increased risk of nonrelapse mortality. In conclusion, the impact of GVHD as a graft-versus-leukemia marker is evident in pediatric ALL after UCBT. Strategies that promote graft-versus-leukemia while harnessing GVHD should be further investigated.
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10.
High-dose cytarabine added to CY/TBI improves the prognosis of cord blood transplantation for acute lymphoblastic leukemia in adults: a retrospective cohort study
Arai, Y., Kondo, T., Shigematsu, A., Tanaka, J., Takahashi, S., Kobayashi, T., Uchida, N., Onishi, Y., Ishikawa, J., Kanamori, H., et al
Bone Marrow Transplantation. 2016;51(12):1636-1639