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1.
Survival Benefit of Myeloablative Therapy with Autologous Stem Cell Transplantation in High-Risk Neuroblastoma: A Systematic Literature Review
Żebrowska, U., Balwierz, W., Wechowski, J., Wieczorek, A.
Targeted oncology. 2024
Abstract
BACKGROUND Multimodal treatment of newly diagnosed high-risk neuroblastoma (HRNB) includes induction chemotherapy, consolidation with myeloablative therapy (MAT) and autologous stem cell transplantation (ASCT), followed by anti-disialoganglioside 2 (GD2) immunotherapy, as recommended by the Children's Oncology Group (COG) and the Society of Paediatric Oncology European Neuroblastoma (SIOPEN). Some centres proposed an alternative approach with induction chemotherapy followed by anti-GD2 immunotherapy, without MAT+ASCT. OBJECTIVE The aim of this systematic literature review was to compare survival outcomes in patients with HRNB treated with or without MAT+ASCT and with or without subsequent anti-GD2 immunotherapy. PATIENTS AND METHODS The review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. MEDLINE via PubMed and EMBASE databases were systematically searched for randomised controlled trials (RCT) and observational comparative studies in patients with HRNB using search terms for 'neuroblastoma' and ('myeloablative therapy' OR 'stem cell transplantation'). Reporting of at least one survival outcome [event-free survival (EFS), progression-free survival, relapse-free survival and/or overall survival (OS)] was required for inclusion. Outcomes from RCTs were synthesized in meta-analysis, while meta-analysis of non-RCTs was not planned owing to expected heterogeneity. RESULTS Literature searches produced 2587 results with 41 publications reporting 34 comparative studies included in the review. Of these, 7 publications reported 4 RCTs, and 34 publications reported 30 non-RCT studies. Studies differed with respect to included populations, induction regimen, response to induction, additional treatments and transplantation procedures. Subsequent treatments of relapse were rarely reported and could not be compared. In the meta-analysis, EFS was in favour of MAT+ASCT over conventional chemotherapy or no further treatment [hazard ratio (HR) = 0.78, 95% confidence interval (CI) 0.67-0.91, p = 0.001] with a trend favouring MAT+ASCT for OS (HR = 0.86, 95% CI 0.73-1.00, p = 0.05). Tandem MAT+ASCT was found to improve EFS compared with the single procedure, with improvement in both EFS and OS in patients treated with anti-GD2 therapy. Non-RCT comparative studies were broadly consistent with evidence from the RCTs; however, not all reported survival benefits of MAT+ASCT (single or tandem). Limited comparative evidence on treatment without MAT+ASCT in patients treated with anti-GD2 immunotherapy suggests an increased risk of relapse. In relapsed patients, MAT+ASCT appears to improve OS, but evidence remains scarce. CONCLUSIONS Survival benefits in patients treated with MAT+ASCT confirm that the procedure should remain an integral part of multimodal therapy. In patients treated with anti-GD2 immunotherapy, limited evidence suggests that omitting MAT+ASCT is associated with an increased risk of relapse, and therefore, a change in clinical practice can currently not be recommended. Evidence suggests the use of tandem MAT+ASCT compared with the single procedure, with greater benefits observed in patients treated with anti-GD2 immunotherapy. Limited evidence also suggests improved survival following MAT+ASCT in relapsed patients, which needs to be viewed in light of emerging chemoimmunotherapy in this setting.
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2.
Population Pharmacokinetic Model of Intravenous Busulfan in Hematopoietic Cell Transplantation: Systematic Review and Comparative Simulations
Takahashi, T., Jaber, M. M., Brown, S. J., Al-Kofahi, M.
Clinical pharmacokinetics. 2023
Abstract
BACKGROUND Busulfan is commonly used in the chemotherapy prior to hematopoietic cell transplantation (HCT). Busulfan has a narrow therapeutic window and a well-established exposure-response relationship with important clinical outcomes. Model-informed precision dosing (MIPD) based on population pharmacokinetic (popPK) models has been implemented in the clinical settings. We aimed to systematically review existing literature on popPK models of intravenous busulfan. METHODS We systematically searched Ovid MEDLINE, EMBASE, Cochrane Library, Scopus, and Web of Science databases from inception to December 2022 to identify original popPK models (nonlinear mixed-effect modeling) of intravenous busulfan in HCT population. Model-predicted busulfan clearance (CL) was compared using US population data. RESULTS Of the 44 eligible popPK studies published since 2002, 68% were developed predominantly in children, 20% in adults, and 11% in both children and adults. The majority of the models were described using first-order elimination or time-varying CL (69% and 26%, respectively). All but three included a body-size descriptor (e.g., body weight, body surface area). Other commonly included covariates were age (30%) and GSTA1 variant (15%). Median between-subject and between-occasion variabilities of CL were 20% and 11%, respectively. Between-model variabilities in predicted median CL were < 20% in all of the weight tiers (10-110 kg) in the simulation based on US population data. CONCLUSION Busulfan PK is commonly described using a first-order elimination or time-varying CL. A simple model with limited covariates were generally sufficient to attain relatively small unexplained variabilities. However, therapeutic drug monitoring may still be necessary to attain a narrow target exposure.
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3.
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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4.
Meta-analysis of decitabine pretreatment-based allogeneic hematopoietic stem cell transplantation affecting transplantation-related complications and prognosis in patients with malignant hematological disease
Li, L., Zhao, Z., Li, X.
Cellular and molecular biology (Noisy-le-Grand, France). 2023;69(14):69-75
Abstract
Malignant hematological diseases (MHD) are a kind of bone marrow hematopoietic system disease caused by malignant clonal proliferation, including leukemia, lymphoma, myelodysplastic syndrome, etc. At present, there are too few meta-analyses on the effect of decitabine pretreatment-based allogeneic hematopoietic stem cell transplantation (allo-HSCT) on transplantation-related complications and prognosis of MHD patients. A systematic search of PubMed, MEDLINE, Science Direct, The Cochrane Library, CNKI, and CBM was performed. The relevant literature on decitabine pretreated allo-HSCT for the treatment of MHD was screened, and the screening time was up to May 1, 2023. After extensive investigation, only 5 articles met the criteria. Result: The results of this article showed that the odds ratio of mortality after decitabine conditioning treatment was 2.35, the incidence of complications after transplantation was 1.07, and the survival rate following transplantation was 0.82. Decitabine-based conditioning regimen can reduce the incidence of transplantation-related complications and improve the prognosis of MHD patients receiving allo-HSCT. Although it has limitations, it still has very important clinical implications.
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5.
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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6.
Treosulfan Versus Busulfan-based Conditioning in Pediatric Patients Undergoing Hematopoietic Stem Cell Transplantation: A Systematic Review and Meta-analysis
Wu, W., Xue, N., Yang, H., Gao, P., Guo, J., Han, D.
Journal of pediatric hematology/oncology. 2023
Abstract
It is unclear whether there is a difference in outcomes with treosulfan or busulfan-based conditioning in pediatric patients undergoing hematopoietic stem cell transplantation (HSCT). We reviewed the evidence on this topic through a systematic review and meta-analysis, the comparison between treosulfan and busulfan-based conditioning in pediatric patients undergoing HSCT for instance. Six studies were included. Meta-analysis showed that there was no difference in the incidence of acute graft versus host disease (odds ratio [OR]: 0.96; 95% CI: 0.57, 1.61), grade II to IV acute graft versus host disease (OR: 1.19; 95% CI: 0.83, 1.72), chronic GVHD (OR: 1.18; 95% CI: 0.70, 2.00), and veno-occlusive disease (OR: 0.92; 95% CI: 0.22, 3.85) between treosulfan and busulfan groups. Pooled analysis indicated marginally better survival with treosulfan-based conditioning (OR: 1.57; 95% CI: 1.00, 2.44), however, these results were unstable on sensitivity analysis. A meta-analysis found no difference in transplant-related mortality (OR: 0.70; 95% CI: 0.34, 1.42) between the two groups. Retrospective data from a heterogenous population indicates that there is no difference in the rate of GVHD after treosulfan versus busulfan-based conditioning for pediatric HSCT. A marginal improvement in survival was noted with treosulfan but the results remained unstable. Future randomized controlled trials are needed to provide better evidence.
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7.
Optimal regimen of levetiracetam for prevention of busulfan-induced seizure in patients undergoing hematopoietic stem cell transplantation: A review of available evidence
Tavajohi, R., Shahrami, B., Rostami, T., Kiumarsi, A., Honarmand, H., Hadjibabaie, M.
Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners. 2023;:10781552231159056
Abstract
OBJECTIVE This review aimed to summarize the available data and offer a practical recommendation regarding the optimal regimen of levetiracetam (LEV) for the prevention of busulfan-induced seizure (BIS) in patients undergoing hematopoietic stem cell transplantation (HSCT). DATA SOURCES Published articles by searching databases (PubMed, Google Scholar, Cochrane Library, ScienceDirect) were reviewed. All types of original studies performed in pediatric and adult populations have been investigated and required data was extracted. DATA SUMMARY Eleven articles were eligible to be included in this review. A loading dose was not used in any of the studies. LEV had been started from 6 to 48 h before busulfan (Bu) initiation and continued up to 24 to 48 h after its termination. The dose range of LEV was 10 to 20 mg/kg/day divided every 12 h in pediatrics and 500 to 1000 mg twice daily in adults. Both oral and intravenous (IV) routes of administration were used. Except for three studies, no seizure had occurred in patients who had received LEV. CONCLUSIONS Considering the available evidence, LEV with the dose range from 500 to 1000 mg twice daily in adults and 10 mg/kg twice daily (20 mg/kg/day in 2 divided doses) in children orally or IV started from 6 to 24 h before Bu initiation up to 24 to 48 h after the last dose of Bu seems to prevent BIS appropriately. More prospective clinical trials with a larger population are needed to validate the optimal dosing of LEV for BIS prophylaxis in patients undergoing HSCT.
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8.
Myeloablative conditioning regimens in adult patients with acute myeloid leukemia undergoing allogeneic hematopoietic stem cell transplantation in complete remission: a systematic review and network meta-analysis
Luo, C., Wu, G., Huang, X., Ding, Y., Huang, Y., Song, Q., Hou, Y., Chen, J., Li, X., Xu, S.
Bone Marrow Transplantation. 2023;58(2):175-185
Abstract
The optimal myeloablative conditioning (MAC) regimens in adult patients with acute myeloid leukemia (AML) undergoing allogeneic hemopoietic stem cell transplantation (allo-HSCT) in complete remission (CR) remain unclear. We performed a systematic review and network meta-analysis to compare the effects of different MAC regimens. Bayesian network meta-analysis was performed using WinBUGS version 1.4.3. The commonly used MAC regimen Bu/Cy (4-day busulfan for toal 16 mg/kg orally or 12.8 mg/kg intravenously, plus 2-day cyclophosphamide for toal 120 mg/kg intravenously) is chosen as the common comparator. Pooled hazard ratios (HRs) with the associated 95% credibility interval (95% CrI) are obtained for all comparisons. We included 19 eligible studies, involving 8104 AML patients and 9 MAC regimens. Compared with Bu/Cy, 3-day busulfan plus fludarabine and thiotepa (Bu3/Flu/TT) is associated with significantly better overall survival (HR, 0.70; 95% CrI, 0.51 to 0.96) and lower risk of relapse (HR, 0.59; 95% CrI, 0.35 to 0.98). Bu3/Flu/TT is also associated with superior overall survival than Cy/TBI (cyclophosphamide plus total body irradiation), and lower risk of relapse than Bu4/Flu (4-day busulfan plus fludarabine). These results suggest that thiotepa-based new MAC regimen Bu3/Flu/TT is associated with improved outcomes in AML patients undergoing allo-HSCT in CR and worth further investigation.
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9.
Busulfan and subsequent malignancy: An evidence-based risk assessment
Long-Boyle, J. R., Kohn, D. B., Shah, A. J., Spencer, S. M., Sevilla, J., Booth, C., López Lorenzo, J. L., Nicoletti, E., Shah, A., Reatz, M., et al
Pediatric blood & cancer. 2023;:e30738
Abstract
BACKGROUND The incidence of secondary malignancies associated with busulfan exposure is considered low, but has been poorly characterized. Because this alkylating agent is increasingly utilized as conditioning prior to gene therapy in nonmalignant hematologic and related disorders, more precise characterization of busulfan's potential contribution to subsequent malignant risk is warranted. PROCEDURE We conducted a literature-based assessment of busulfan and subsequent late effects, with emphasis on secondary malignancies, identifying publications via PubMed searches, and selecting those reporting at least 3 years of follow-up. RESULTS We identified eight pediatric and 13 adult publications describing long-term follow-up in 570 pediatric and 2076 adult hematopoietic cell transplant (HCT) recipients. Secondary malignancies were reported in 0.5% of pediatric HCT recipients, with no cases of myelodysplastic syndrome (MDS) or acute myelocytic leukemia (AML). Fatal secondary malignancies were reported in 0.8% of 1887 evaluable adult HCT recipients, and an overall incidence of secondary malignancies of 4.8% was reported in a subset of 389 evaluable adult patients. We also reviewed long-term results from eight publications evaluating lentiviral- and human promotor-based HSC-targeted gene therapy in 215 patients with nonmalignant conditions, in which busulfan/treosulfan monotherapy or busulfan/fludarabine was the only conditioning. Two malignancies were reported in patients with sickle cell disease (SCD), one of which was potentially busulfan-related. No additional malignancies were reported in 173 patients with follow-up of 5-12 years. CONCLUSION The incidence of busulfan-related secondary malignancies is low, and likely to be substantially less than 1% in pediatric transplant recipients, especially those receiving busulfan monotherapy for nonmalignant conditions other than SCD.
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10.
Triplet RVd Induction for Transplant-Eligible Newly Diagnosed Multiple Myeloma: A Systematic Review and Meta-Analysis
Yang, G., Geng, C., Jian, Y., Zhou, H., Chen, W.
Advances in therapy. 2022
Abstract
INTRODUCTION The combination of lenalidomide, bortezomib, and dexamethasone (RVd) has become standard of care for transplant-eligible patients with newly diagnosed MM (NDMM). This study aimed to determine the efficacy of RVd as induction therapy in terms of response rates and survival outcomes of transplant-eligible patients with NDMM. METHODS The databases of Medline, Embase, and Cochrane Library were searched until February 1, 2021. Both randomized controlled trials (RCT) and non-RCTs from the available literature were extracted as one-arm data to assess the efficacy of each triplet regimen for the target patients in terms of response rates and survival rates for transplant-eligible patients with NDMM. Data was summarized as estimated pooled value regarding each evaluated index. Risk of bias of studies was assessed with standard methods. RESULTS The findings of 71 studies published from 2008 to 2020 were analyzed. For RVd induction, the overall response rate (ORR), very good partial response or better (≥ VGPR) rate, and complete response or better (≥ CR) rate after induction were 0.91 (95% CI 0.86-0.95), 0.23 (95% CI 0.17-0.29), and 0.56 (95% CI 0.51-0.61), respectively. Indirect comparisons in efficacy were made between RVd and other traditional triplet regimens. RVd induction led to a better ≥ CR rate than bortezomib, cyclophosphamide, and dexamethasone (VCd) regimen in both postinduction and post-ASCT phase, ≥ CR rate 0.11 (95% CI 0.08-0.15) and 0.21 (95% CI 0.12-0.32), respectively. The 1-year overall survival (OS) rate and 3-year OS rate of RVd regimen were longer than that of bortezomib, thalidomide, and dexamethasone (VTd), 0.97 (95% CI 0.94-0.98) vs 0.71 (95% CI 0.61-0.80), and 0.90 (95% CI 0.79-0.98) vs 0.70 (95% CI 0.64-0.75), respectively. CONCLUSIONS The RVd induction demonstrated confident response rates and survival benefits for transplant-eligible patients with NDMM.