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1.
Pediatric chemotherapy versus allo-HSCT for adolescent and adult Philadelphia chromosome-negative ALL in first complete remission: a meta-analysis
Pan, Z., Wang, L., Fu, W., Jiang, C., Zhang, Z., Chen, Q., Wang, L., Hu, X.
Annals of hematology. 2023
Abstract
Pediatric-inspired chemotherapy significantly improves survival for adolescent and adult patients with acute lymphoblastic leukemia (ALL). However, the benefits over allogeneic hematopoietic stem cell transplantation (allo-HSCT) remain unclear. To compare clinical outcomes between pediatric-inspired chemotherapy and allo-HSCT in consolidation therapy of adolescent and adult Philadelphia chromosome-negative (Ph-neg) ALL in first complete remission (CR1), related studies from MEDLINE, Embase, and Cochrane Controlled Register of Trials updated to July 2022 were searched. A total of 13 relevant trials including 3161 patients were included in the meta-analysis. Compared with allo-HSCT, pediatric-inspired chemotherapy achieved better OS (hazard risk (HR), 0.53; 95% confidence interval (CI), 0.41 to 0.68) and DFS (HR, 0.64; 95% CI, 0.48 to 0.86), with a significant reduction in NRM (risk ratio (RR), 0.30; 95% CI, 0.18 to 0.51), but no difference in the relapse rate (RR, 1.13; 95% CI, 0.93 to 1.39). When only studies based on intention-to-treat analysis were included, pediatric-inspired chemotherapy consistently conferred a survival advantage. In subgroup analyses, patients with baseline high-risk features demonstrated similar OS and DFS between pediatric-style chemotherapy and allo-HSCT, while pediatric-style chemotherapy had an OS and DFS advantage in standard-risk subgroup. Particularly, patients with positive minimal residual disease (MRD) achieved better OS and DFS if proceeded to allo-HSCT.
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2.
A comprehensive comparison between TBI vs non-TBI-based conditioning regimen in pediatric patients with acute lymphoblastic leukemia: A systematic review and meta-analysis
Ansari, F., Behfar, M., Jafari, L., Mohseni, R., Naji, P., Karamlou, Y., Amirzade-Iranaq, M. H., Hamidieh, A. A.
Leukemia research. 2023;135:107416
Abstract
INTRODUCTION We aimed to evaluate the efficacy, safety, and latent toxicity of total body irradiation (TBI)-based conditioning regimens compared to non-TBI regimens for pediatric patients (under 18 years old) with acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic stem cell transplantation (HSCT). METHODS A systematic search was performed on MEDLINE, Scopus, WOS, and PMC. Also, a search for grey literature was performed on Google Scholar and relevant articles' references were included. Relevant articles which met the inclusion criteria were retrieved up to October 31th, 2022. CMA version 2 was used for the quantitative synthesis of the data. RESULTS Eight studies on efficacy and safety of TBI and non-TBI as a conditioning regimen were analyzed and six comparative studies on late toxicity were investigated. The meta-analysis revealed a hazard ratio (HR) of 1.508 (95% CI 0.96-2.35) for overall survival (OS) in instances of non-TBI conditioning. Also, an HR of 1.503 (95% CI 1.006-2.25) for disease-free- survival (DFS) favoring TBI-based conditioning. Late complications were reported to be significantly higher in the TBI conditioning regimen group than in the non-TBI group. CONCLUSION It appears that non-TBI regimens are as effective as TBI regimens in pediatrics with ALL regarding OS. Occurrence of latent toxicity is higher with TBI conditioning regimen. Conversely, TBI-based regimens are superior to non-TBI conditioning regimens regarding DFS. Considering all aspects, non-TBI conditioning regimens can be an alternative treatment option for pediatric ALL undergoing HSCT.
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3.
Total Body Irradiation Versus Chemotherapy Conditioning in Pediatric Acute Lymphoblastic Leukemia Patients Undergoing Hematopoietic Stem Cell Transplant: A Systematic Review and Meta-Analysis
Rehman, M. E. U., Chattaraj, A., Mahboob, A., Ijaz, Z., Franco, D., Farhan, M., Dharma, K., Mumtaz, H., Saeed, S., Basit, J., et al
Clinical lymphoma, myeloma & leukemia. 2023
Abstract
Allogeneic hematopoietic stem cell transplant (HSCT) is indicated in pediatric patients with acute lymphoblastic leukemia (ALL) who have relapsed or are at a very high risk of relapse during first complete remission. Two types of myeloablative conditioning are employed before allogeneic HSCT total body irradiation (TBI)-based regimens and chemotherapy (CHT) alone. This study compares the efficacy and safety of TBI-based regimens and CHT-based conditioning in pediatric, adolescent, and young adult patients with ALL (0-24 years old). TBI-based and CHT-conditioning regimens were evaluated in 4262 and 1367 patients, respectively, from 15 studies. Compared to CHT alone, TBI-based regimens were associated with better overall survival (OS), relative risk (RR) 1.21, better event-free survival (RR 1.34), and a reduced risk of relapse (RR 0.69). Both approaches had comparable risk of acute graft-versus-host disease (GVHD), grades 3 to 4 acute GVHD, chronic GVHD, and nonrelapse mortality (NRM). In the subgroup analysis for patients in first complete remission, TBI-based regimens and CHT alone had comparable OS and NRM. Our results demonstrate the superiority of TBI-based regimens compared to CHT alone in pediatric patients with ALL.
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4.
Chemotherapy with the use of next-generation TKIs based on MRD has the potential to avoid hematopoietic stem cell transplantation in treatment for adults with Philadelphia chromosome-positive acute lymphoblastic leukemia
Xie, M., Shi, T., Jiang, Q., Jia, Y., Zhou, D., Tong, H., Jin, J., Zhu, H. H.
Cancer. 2023
Abstract
BACKGROUND Allogeneic hematopoietic stem cell transplantation (allo-HSCT) as postremission treatment is recommended for Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) in current guidelines. However, comparisons of later generation tyrosine kinase inhibitors (TKIs) plus chemotherapy with allo-HSCT have yielded similar outcomes. This meta-analysis was performed to evaluate allo-HSCT in first complete remission (CR1) versus chemotherapy for adult Ph+ ALL in the TKI era. METHODS Pooled assessment of the hematologic and molecular complete response rates was performed after 3-month TKI treatment. Hazard ratios (HRs) were determined for disease-free survival (DFS) and overall survival (OS) benefit with allo-HSCT. The effect of measurable residual disease status on survival benefit was also analyzed. RESULTS Thirty-nine retrospective and prospective single-arm cohort studies involving 5054 patients were included. Combined HRs indicated that in the general population, allo-HSCT favorably influenced DFS and OS. Achieving complete molecular remission (CMR) within 3 months after starting induction was a favorable survival prognostic factor regardless of whether the patient had undergone allo-HSCT. Among the patients with CMR, survival rates in the nontransplant subgroup were comparable with those in the transplant subgroup, with the estimated 5-year OS of 64% versus 58% and 5-year DFS of 58% versus 51%, respectively. The use of next-generation TKIs results in a higher proportion of patients achieving CMR (ponatinib 82% vs. imatinib 53%), while improving survival in nontransplant patients. CONCLUSION Our novel findings suggest that combination chemotherapy plus TKIs leads to a comparable survival benefit as with allo-HSCT for MRD-negative (CMR) patients. This study provides novel evidence for allo-HSCT indications for Ph+ ALL in CR1 in the TKI era.
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5.
Outcomes of Tyrosine Kinase Inhibitors Maintenance Therapy with or without Allogeneic Hematopoietic Stem Cell Transplantation in Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia in First Complete Remission: A Systematic Review and Meta-Analysis
Shahzad, M., Hussain, A., Tariq, E., Anwar, I., Faisal, M. S., Syed, L., Karam, A., Chaudhary, S. G., Ahmed, N., Bansal, R., et al
Clinical lymphoma, myeloma & leukemia. 2023
Abstract
We conducted a systematic review and meta-analysis to compare outcomes of tyrosine kinase inhibitor (TKI) maintenance therapy with or without allogeneic hematopoietic stem cell transplantation (HSCT) in Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) in first remission (CR1). A literature search was performed on PubMed, Cochrane, and Clinical trials.gov. After screening 1720 articles, 12 studies were included. Proportions and odds ratios (OR) with 95% confidence intervals (CI) were computed. I(2) provides an estimate of the percentage of variability in results across studies that is due to real differences and not due to chance. Of 1039 patients, 635 (61%) had TKI alone and 404 (39%) patients had HSCT followed by TKI. At 3 years, a trend towards poor overall survival (OS; OR 0.67, 95% CI 0.39-1.15, I(2) = 68%), (disease-free survival; OR 0.58, 95% CI 0.26-1.29, I(2) = 76%), and higher relapse rate (RR; OR = 2.52, 95% CI = 1.66-3.83, I(2) = 26%) was seen with TKI alone compared to HSCT-TKI. Although HSCT followed by TKI maintenance in Ph+ ALL has long been considered standard of care, the introduction of potent third-generation TKIs and bispecific T-cell engagers such as Blinatumomab has significantly improved outcomes while sparing the need for HSCT in newly diagnosed patients.
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6.
Comparison of blinatumomab and CAR T-cell therapy in relapsed/refractory acute lymphoblastic leukemia: a systematic review and meta-analysis
Zhai, Y., Hong, J., Wang, J., Jiang, Y., Wu, W., Lv, Y., Guo, J., Tian, L., Sun, H., Li, Y., et al
Expert review of hematology. 2023
Abstract
OBJECTIVES This study evaluated the benefits and risks of patients with refractory or relapsed acute lymphocytic leukemia (R/R ALL) treated with Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy and blinatumomab. METHODS PubMed, Web of Science, Embase, and the Cochrane Library were searched for relevant studies. RESULTS The pooled complete remission (CR) rate and minimal residual disease (MRD) negative rate were 48%, 31% for blinatumomab, and 86% and 80% for CAR T-cell therapy. CONCLUSIONS The CAR T-cell therapy group exhibited a higher likelihood of CR rate than the blinatumomab group in every analysis regardless of adjustment subgroups. CAR T-cell therapy was associated with a significantly prolonged overall survival (OS) and relapse-free survival (RFS) compared with blinatumomab (2-year OS 55% vs 25%; 2-year RFS 40% vs 22%). CAR T-cell therapy was more effective for achieving CR and bridging to allogeneic hematopoietic stem cell transplantation (allo-SCT) than blinatumomab (2-year OS 75% vs. 57%). An emerging role for blinatumomab is as a bridging agent pre-SCT and for patients who achieve an MRD-negative state pre-SCT, post-SCT outcomes are expected to be the same as CAR-T. For adverse effects (AEs), blinatumomab was associated with a lower rate of grade ≥ 3 hematological toxicity, CRS, and neurological events.
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7.
Systematic review and pooled analysis of survival outcomes in patients with relapsed or refractory B-cell acute lymphoblastic leukaemia who have undergone haematopoietic stem cell transplant
Russell-Smith, T. A., Chadda, S., LeReun, C., Bajko, P., Doogan, E.
European review for medical and pharmacological sciences. 2022;26(3):975-995
Abstract
OBJECTIVE Information about the long-term survival impact of hematopoietic stem cell transplant (HSCT) in adults with relapsed/refractory B-cell acute lymphoblastic leukaemia is limited. The objective was to conduct a systematic review identifying studies reporting survival in HSCT-receiving patients and apply parametric analyses to predict long-term survival. MATERIALS AND METHODS Twenty-five relevant studies were identified. Analyses were conducted in 10 studies (n=503; "global" analysis) reporting overall survival (OS) data as Kaplan-Meier curves or at patient level. Four studies (n=217; "subgroup" analysis) measured OS from the point of HSCT. Patient-level data were recreated from Kaplan-Meier curves and pooled, with six models tested for longer-term extrapolation. Additionally, a sensitivity analysis was undertaken involving removal of data from the oldest study cohort (recruited between 1981-1997) to determine if the year which patients received HSCT impacted survival compared to post-2009 data. RESULTS Median OS and five-year survival probability were 11.4 months and 24.4% (95% CI, 20.5-28.5%) in the global analysis, and 12.0 months and 28.4% (95% CI, 22.1-34.9%) in the subgroup analysis. The generalised gamma and Gompertz models fit longer-term extrapolation criteria. The generalised gamma model predicted survival at 10.4% vs. 14.8% (15 years), 8.3% vs. 12.8% (20 years), and 6.9% vs. 11.4% (25 years) for the global and subgroup analysis, respectively. The Gompertz model predicted survival to plateau at 23% vs. 25.6% just before 10 years. The sensitivity analysis excluding older data found median survival increased two-fold (25.3 vs. 12 months). CONCLUSIONS Results synthesize long-term evidence of outcomes for HSCT-receiving patients, providing a basis for treatment comparison. Risk of death is low beyond four years and newer data appears correlated with improved outcomes.
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8.
Is stem cell transplantation still needed for adult Philadelphia chromosome-positive acute lymphoblastic leukemia receiving tyrosine kinase inhibitors therapy?: A systematic review and meta-analysis
Ponvilawan, B., Kungwankiattichai, S., Charoenngam, N., Owattanapanich, W.
PloS one. 2021;16(6):e0253896
Abstract
BACKGROUND Hematopoietic stem cell transplantation (HSCT) is the current mainstay treatment for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). However, tyrosine kinase inhibitors (TKI) also play a significant role in the treatment of these patients. We conducted this systematic review and meta-analysis to compare the efficacy of allogeneic (allo-) HSCT, autologous (auto-) HSCT, and chemotherapy (CMT) alone-all in combination with TKIs in adult Ph+ ALL patients. MATERIALS AND METHODS This systematic review identified studies from the EMBASE and MEDLINE databases from inception to April 2021 using search terms related to "ALL" and "HSCT." Eligible studies could be randomized controlled trials or cohort studies that included adult Ph+ ALL patients who received a TKI and either allo-HSCT, auto-HSCT, or CMT alone, and that reported the number of patients in each group for each of our primary outcomes of interest: overall survival (OS) or disease-free survival (DFS). Point estimates and associated 95% confidence intervals (CI) from each study were combined using the Hantel-Maenszel method. RESULTS After two rounds of review, 26 cohort studies were determined to be eligible for the meta-analysis. Adult Ph+ ALL patients who received HSCT had better survival outcomes than those who did not receive any HSCT (pooled odds ratio [OR] for OS of 1.61, 95%CI: 1.08-2.40; I2 = 59%, and for DFS of 3.23, 95%CI: 2.00-5.23; I2 = 62% for allo-HSCT; and, pooled OR for OS of 7.04, 95%CI: 1.97-25.15; I2 = 0%, and for DFS of 5.78, 95%CI: 1.04-32.19; I2 = 42% for auto-HSCT). Allo-HSCT recipients had comparable OS and DFS, but lower relapse rate compared to auto-HSCT recipients. Funnel plot generally demonstrated no presence of publication bias. CONCLUSIONS This systematic review and meta-analysis demonstrated superior results of HSCT in Ph+ ALL patients compared to CMT alone. Moreover, auto-HSCT could be implemented with comparable survival outcomes to allo-HSCT in patients with no available donor or when haploidentical HSCT is not feasible.
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9.
Effects of different types of allogeneic hematopoietic stem cell transplantation donors on Philadelphia chromosome-positive acute lymphoblastic leukemia during the tyrosine kinase inhibitor era: A systematic review and meta-analysis
Ponvilawan, B., Owattanapanich, W., Charoenngam, N., Kungwankiattichai, S.
Hematology/oncology and stem cell therapy. 2021
Abstract
BACKGROUND Matched donor (MD) allogeneic hematopoietic stem cell transplantation (allo-HSCT) is currently the preferred choice of treatment for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+) ALL) patients who have achieved complete remission. This systematic review and meta-analysis was conducted to investigate the effects of allo-HSCTs from different donor types for Ph(+) ALL patients who received tyrosine kinase inhibitors (TKIs). METHODS Studies in EMBASE and MEDLINE between inception and December 2020 were identified using search terms related to "Ph(+) ALL" and "HSCT." Eligible studies were studies with Ph(+) ALL patients who received a TKI and allo-HSCT. The primary outcomes of interest-the overall survival (OS) or relapse-free survival (RFS)-needed to be reported. The Mantel-Haenszel method was used to combine the effect estimates and associated 95% confidence intervals (CIs) of each donor type. RESULTS Fourteen cohort studies were identified for the meta-analysis. Haploidentical (HID)-HSCT for Ph(+) ALL patients resulted in a superior RFS to MD-HSCT, with a pooled odds ratio (OR) of 1.57 (95% CI, 1.05-2.32; I(2) = 0%). However, HID-HSCT and MD-HSCT had comparable OS. Furthermore, HID-HSCT group had a significantly lower relapse rate than MD-HSCT group. On the other hand, the risks of graft-versus-host disease (GvHD) were higher for HID-HSCT and pooled OR of chronic GvHD rate. The OS and RFS of matched sibling-HSCT, matched unrelated-HSCT, and cord blood-HSCT were comparable with those of HID-HSCT. CONCLUSION This systematic review and meta-analysis showed that HID-HSCT is as effective as MD-HSCT in Ph(+) ALL patients.
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10.
Blinatumomab in Pediatric Acute Lymphoblastic Leukemia-From Salvage to First Line Therapy (A Systematic Review)
Queudeville, M., Ebinger, M.
Journal of clinical medicine. 2021;10(12)
Abstract
Acute lymphoblastic leukemia is by far the most common malignancy in children, and new immunotherapeutic approaches will clearly change the way we treat our patients in future years. Blinatumomab is a bispecific T-cell-engaging antibody indicated for the treatment of relapsed/refractory acute lymphoblastic leukemia (R/R-ALL). The use of blinatumomab in R/R ALL has shown promising effects, especially as a bridging tool to hematopoietic stem cell transplantation. For heavily pretreated patients, the response to one or two cycles of blinatumomab ranges from 34% to 66%. Two randomized controlled trials have very recently demonstrated an improved reduction in minimal residual disease as well as an increased survival for patients treated with blinatumomab compared to standard consolidation treatment in first relapse. Current trials using blinatumomab frontline for high-risk patients or as a consolidation treatment post-transplant will show whether efficacy is even higher in less heavily pretreated patients. Due to the distinct pattern of adverse events compared to high-dose conventional chemotherapy, blinatumomab could play an important role for patients with a risk for severe chemotherapy-associated toxicities. This systematic review discusses all published results for blinatumomab in children as well as all ongoing clinical trials.