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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.
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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3.
Impact of Total Body Irradiation-Based Myeloablative Conditioning Regimens in Patients with Acute Lymphoblastic Leukemia Undergoing Allogeneic Hematopoietic Stem Cell Transplantation: Systematic Review and Meta-Analysis
Khimani, F., Dutta, M., Faramand, R., Nishihori, T., Perez, A. P., Dean, E., Nieder, M., Perez, L., Mishra, A., Elmariah, H., et al
Transplantation and Cellular Therapy. 2021;27(7):620.e1-620.e9
Abstract
Allogeneic hematopoietic cell transplantation (allo-HCT) is a curative treatment option for patients with acute lymphoblastic leukemia (ALL). Both total body irradiation (TBI)-based and chemotherapy only-based myeloablative transplantation conditioning regimens have been applied, but the optimal regimen remains unclear. We performed a systematic review to assess the efficacy of TBI-based versus chemotherapy only-based myeloablative conditioning regimens. We searched PubMed, Embase, and Cochrane databases and meeting abstracts for all studies comparing TBI-based and chemotherapy only-based conditioning regimens in patients who underwent allo-HCT for ALL. Two authors independently reviewed all studies for inclusion and extracted data related to overall survival (OS), progression-free survival (PFS), nonrelapse mortality (NRM), relapse, and acute and chronic graft-versus-host disease (GVHD). Eight studies were included in the final analysis. The overall methodological quality of the included studies was optimal. TBI-based regimens showed evidence of benefit compared with chemotherapy only-based conditioning regimens in terms of relapse (relative risk [RR], 0.82; 95% confidence interval [CI], 0.72 to 0.94; 6 studies, 5091 patients), OS (hazard ratio [HR], 0.76; 95% CI, 0.64 to 0.89; 7 studies, 4727 patients), and PFS (HR, 0.74; 95% CI, 0.63 to 0.85; 7 studies, 4727 patients). The TBI-based regimen did not increase the likelihood of grade II-IV acute GVHD (RR, 1.12; 95% CI, 0.92 to 1.36; 5 studies, 4996 patients) or chronic GVHD (RR, 1.10; 95% CI, 1.00 to 1.21; 5 studies, 4490 patients), or NRM (RR, 0.94; 95% CI, 0.69 to 1.28; 6 studies, 4522 patients). However, TBI-based regimens were associated with an increased risk of grade III-IV acute GVHD (RR, 1.29; 95% CI, 1.01 to 1.63; 3 studies, 3675 patients). A subgroup comparison of patients age ≥16 years showed similar results. This systematic review represents evidence supporting the use of TBI-based conditioning regimen in patients undergoing allo-HCT for ALL who are candidates for myeloablative conditioning, as it offers better OS, PFS, and less relapse with acceptable NRM.
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4.
High-dose chemotherapy and autologous haematopoietic stem cell rescue for children with high-risk neuroblastoma
Yalçin, B., Kremer, L. C., van Dalen, E. C.
The Cochrane Database of Systematic Reviews. 2015;2015(10):Cd006301
Abstract
BACKGROUND Despite the development of new treatment options, the prognosis of high-risk neuroblastoma patients is still poor; more than half of patients experience disease recurrence. High-dose chemotherapy and haematopoietic stem cell rescue (i.e. myeloablative therapy) might improve survival. This review is the second update of a previously published Cochrane review. OBJECTIVES Primary objectiveTo compare the efficacy, that is event-free and overall survival, of high-dose chemotherapy and autologous bone marrow or stem cell rescue with conventional therapy in children with high-risk neuroblastoma. Secondary objectivesTo determine adverse effects (e.g. veno-occlusive disease of the liver) and late effects (e.g. endocrine disorders or secondary malignancies) related to the procedure and possible effects of these procedures on quality of life. SEARCH METHODS We searched the electronic databases The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2014, issue 11), MEDLINE/PubMed (1966 to December 2014) and EMBASE/Ovid (1980 to December 2014). In addition, we searched reference lists of relevant articles and the conference proceedings of the International Society for Paediatric Oncology (SIOP) (from 2002 to 2014), American Society for Pediatric Hematology and Oncology (ASPHO) (from 2002 to 2014), Advances in Neuroblastoma Research (ANR) (from 2002 to 2014) and American Society for Clinical Oncology (ASCO) (from 2008 to 2014). We searched for ongoing trials by scanning the ISRCTN register (www.isrct.com) and the National Institute of Health Register (www.clinicaltrials.gov). Both registers were screened in April 2015. SELECTION CRITERIA Randomised controlled trials (RCTs) comparing the efficacy of myeloablative therapy with conventional therapy in high-risk neuroblastoma patients. DATA COLLECTION AND ANALYSIS Two authors independently performed study selection, data extraction and risk of bias assessment. If appropriate, we pooled studies. The risk ratio (RR) and 95% confidence interval (CI) was calculated for dichotomous outcomes. For the assessment of survival data, we calculated the hazard ratio (HR) and 95% CI. We used Parmar's method if hazard ratios were not reported in the study. We used a random-effects model. MAIN RESULTS We identified three RCTs including 739 children. They all used an age of one year as the cut-off point for pre-treatment risk stratification. The first updated search identified a manuscript reporting additional follow-up data for one of these RCTs, while the second update identified an erratum of this study. There was a significant statistical difference in event-free survival in favour of myeloablative therapy over conventional chemotherapy or no further treatment (three studies, 739 patients; HR 0.78, 95% CI 0.67 to 0.90). There was a significant statistical difference in overall survival in favour of myeloablative therapy over conventional chemotherapy or no further treatment (two studies, 360 patients; HR 0.74, 95% CI 0.57 to 0.98). However, when additional follow-up data were included in the analyses the difference in event-free survival remained statistically significant (three studies, 739 patients; HR 0.79, 95% CI 0.70 to 0.90), but the difference in overall survival was no longer statistically significant (two studies, 360 patients; HR 0.86, 95% CI 0.73 to 1.01). The meta-analysis of secondary malignant disease and treatment-related death did not show any significant statistical differences between the treatment groups. Data from one study (379 patients) showed a significantly higher incidence of renal effects, interstitial pneumonitis and veno-occlusive disease in the myeloablative group compared to conventional chemotherapy, whereas for serious infections and sepsis no significant difference between the treatment groups was identified. No information on quality of life was reported. In the individual studies we evaluated different subgroups, but the results were not univocal in all studies. All studies had some methodological limitations. AUTHORS' CONCLUSIONS Based on the currently available evidence, myeloablative therapy seems to work in terms of event-free survival. For overall survival there is currently no evidence of effect when additional follow-up data are included. No definitive conclusions can be made regarding adverse effects and quality of life, although possible higher levels of adverse effects should be kept in mind. A definitive conclusion regarding the effect of myeloablative therapy in different subgroups is not possible. This systematic review only allows a conclusion on the concept of myeloablative therapy; no conclusions can be made regarding the best treatment strategy. Future trials on the use of myeloablative therapy for high-risk neuroblastoma should focus on identifying the most optimal induction and/or myeloablative regimen. The best study design to answer these questions is a RCT. These RCTs should be performed in homogeneous study populations (e.g. stage of disease and patient age) and have a long-term follow-up. Different risk groups, using the most recent definitions, should be taken into account.It should be kept in mind that recently the age cut-off for high risk disease was changed from one year to 18 months. As a result it is possible that patients with what is now classified as intermediate-risk disease have been included in the high-risk groups. Consequently the relevance of the results of these studies to the current practice can be questioned. Survival rates may be overestimated due to the inclusion of patients with intermediate-risk disease.
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5.
Bortezomib-cyclophosphamide-dexamethasone (VCD) versus bortezomib-thalidomide-dexamethasone (VTD) -based regimens as induction therapies in newly diagnosed transplant eligible patients with multiple myeloma: a meta-analysis
Leiba, M., Kedmi, M., Duek, A., Freidman, T., Weiss, M., Leiba, R., Nagler, A., Avigdor, A.
British Journal of Haematology. 2014;166(5):702-10
Abstract
Three-drug induction regimens have become the standard of care in newly diagnosed transplant-eligible multiple myeloma patients. Two frequently used protocols are bortezomib, cyclophosphamide and dexamethasone (VCD) and bortezomib, thalidomide and dexamethasone (VTD). Comparisons between the two are lacking. The present study aimed to identify the differences in response rate and toxicity between the two regimens. Databases were searched using the terms 'VTD' or 'VCD' and 'induction regimens for newly diagnosed multiple myeloma'. Prospective trials evaluating initial response in transplant eligible patients were included. The main outcome measures were response rates and adverse events. Eight clinical trials were eligible for analysis. Overall 672 patients were treated with either VCD (n = 157) or VTD (n = 515) as induction therapy. Patients treated with VTD presented with a significantly higher complete/near complete response (34% vs. 6%, P = 0·002) as well as a higher very good partial response rate or better, following induction therapy (62% vs. 27%, P < 0·0001). Although grade 3-4 neurotoxicity was more frequent during VTD therapy (11% vs. 6%, P = 0·057), a higher incidence of overall grade 3-4 adverse events was found in the VCD-treated patients (74% vs. 51%, P < 0·001). VTD induction therapy may be superior in achieving deeper response rate following induction therapy, and is better tolerated.
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6.
Continuous treatment with new agents for newly diagnosed multiple myeloma
Zou, Y., Sheng, Z., Lu, H., Yu, J.
Anti-Cancer Drugs. 2013;24(5):527-33
Abstract
To examine the role of novel agents such as bortezomib, lenalidomide, and thalidomide as continuous therapy (induction and consolidation/maintenance) in the treatment of newly diagnosed patients with multiple myeloma, we carried out a meta-analysis of randomized-controlled trials. A comprehensive literature search (Medline, Embase, the Cochrane controlled trials register, and the Science Citation Index) was performed. The initial search yielded 849 citations, of which 11 randomized-controlled trials enrolling 4775 patients fulfilled the inclusion criteria. Continuous addition of bortezomib to conventional therapy before and after autologous stem cell transplantation prolonged overall survival significantly: the summary hazard ratio was 0.80, 95% confidence interval [0.64, 0.99] (P=0.04). Continuous therapy with novel agents consistently improved progression-free survival (PFS) compared with therapy with conventional agents alone. For those patients ineligible for a transplant, the summary hazard ratios for PFS were 0.69 [0.56, 0.85] (P<0.001) for continuous thalidomide therapy and 0.47 [0.33, 0.68] (P<0.001) for continuous lenalidomide therapy; for those patients ineligible for a transplant, the summary hazard ratios for PFS were 0.68 [0.59, 0.79] (P<0.001) for continuous thalidomide therapy and 0.72 [0.61, 0.85] (P<0.001) for continuous lenalidomide therapy. In summary, continuous therapy with novel agents improved PFS consistently, and bortezomib may improve the overall survival of patients with newly diagnosed myeloma when it is added to standard transplantation therapy continuously.
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7.
Bortezomib-containing induction regimens in transplant-eligible myeloma patients: a meta-analysis of phase 3 randomized clinical trials
Nooka, A. K., Kaufman, J. L., Behera, M., Langston, A., Waller, E. K., Flowers, C. R., Gleason, C., Boise, L. H., Lonial, S.
Cancer. 2013;119(23):4119-28
Abstract
BACKGROUND The objective of this meta-analysis in patients with myeloma was to test the hypothesis that the addition of bortezomib to induction therapy not only improves the depth of response but also improves post-transplant progression-free survival (PFS) and overall survival (OS) outcomes. METHODS Phase 3 trials that randomized newly diagnosed, transplant-eligible patients with myeloma to receive either a bortezomib-containing induction regimen (BCIR) or a nonbortezomib-containing induction regimen (NBCIR) were identified. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were adapted for data synthesis, and comprehensive meta-analysis software was used to report pooled data as hazard ratios or odds ratios under a random-effects model. RESULTS Four published phase 3 trials that included 2169 patients were analyzed. The postinduction and post-transplant pooled odds ratio for achieving a complete response/near complete response or a very good partial response or better and the overall response rate were higher with BCIR. The pooled hazard ratios for 3-year PFS and OS were 0.71 (95% confidence interval, 0.60-0.83; P < .00,001) and 0.79 (95% confidence interval, 0.66-0.96; P = .014), respectively, favoring BCIR. The odds of developing selected grade ≥ 3 toxicities (peripheral neuropathy and varicella-zoster virus reactivation) also were higher with BCIR. CONCLUSIONS The current meta-analysis demonstrated that BCIR results in an improved depth of response, which translates into improved post-transplant PFS and OS outcomes despite a higher incidence of toxicity. This analysis supports the concept that the choice of induction regimen can influence post-transplant outcomes such as PFS and OS.
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8.
Intensified therapy followed by autologous stem-cell transplantation (ASCT) versus conventional therapy as first-line treatment of follicular lymphoma: a meta-analysis
Wang, B., Ren, C., Zhang, W., Ma, X., Xia, B., Sheng, Z.
Hematological Oncology. 2013;31(1):29-33
Abstract
There are two different international standards for the treatment of follicular lymphoma (FL): intensified therapy followed by autologous stem-cell transplantation (ASCT) and conventional therapy in the first-line setting. However, their role remains unclear. Our aim was to define the treatment effect of intensified therapy followed by ASCT compared with conventional therapy as first-line treatment of patients with FL in terms of overall survival (OS) and event-free survival (EFS). We searched for randomised controlled trials in Medline, Embase, the Cochrane controlled trials register and the Science Citation Index (1985 to June 2011). Effect measures used were hazard ratios (HR) for OS, EFS and secondary tumour rate. Two independent review authors extracted data and assessed quality of trials. Four trials were identified, covering a total of 941 subjects. The random-effects summary HR by comparing the treatment effect on OS between intensified and conventional therapy was 0.95 [0.70, 1.30] (p = 0.75), indicating that no additional survival benefit was derived from the intensified therapy followed by ASCT. A significant benefit of intensified therapy followed by ASCT as first-line treatment was detected in terms of EFS: the random-effects summary HR (intensified versus conventional therapy) was 0.59 [0.44, 0.79] (p < 0.001). This meta-analysis showed that despite its superior EFS, intensified therapy followed by ASCT does not improve the OS compared with conventional therapy.
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9.
High-dose chemotherapy followed by stem cell transplantation in the management of retinoblastoma: a systematic review
Jaradat, I., Mubiden, R., Salem, A., Abdel-Rahman, F., Al-Ahmad, I., Almousa, A.
Hematology/oncology & stem cell therapy. 2012;5(2):107-17
Abstract
BACKGROUND AND OBJECTIVES In recent years, there has been an increasing role for stem cell transplantation in the management of retinoblastoma. The aim of this study was to systematically review the role high-dose chemotherapy followed by stem cell transplantation in the treatment of patients with metastatic or relapsed, trilateral or bilateral advanced retinoblastoma, and in patients with tumor at the surgical margin of the optic nerve and/or extrascleral extension. DESIGN Systematic literature review. METHODS We performed an extensive PubMed database search on 25 February 2012 for studies describing the use of high-dose chemotherapy followed by stem cell transplantation in the management of patients with retinoblastoma. RESULTS We located 15 studies that met the inclusion criteria and that included 101 patients. Following treatment for metastatic and relapsed disease, 44 of 77 patients (57.1%) were alive with no evidence of disease at the time of follow-up. However, a higher rate of local relapse developed in patients with CNS metastases (73.1%), which dropped to 47.1% in patients who received thiotepa. In patients with trilateral or bilateral advanced retinoblastoma, 5 of 7 (71.4%) with reported outcome data were alive with no evidence of disease at the time of follow-up. In patients with tumor at the surgical margin of the optic nerve and/or extrascleral extension, 6 of 7 patients (85.7%) were alive with no evidence of disease at the time of follow-up. CONCLUSIONS Durable tumor control is possible in patients with non-CNS metastases, trilateral or bilateral advanced retinoblastoma, and in patients with tumor at the surgical margin of the optic nerve and/or extrascleral extension. Patients with CNS metastases require thiotepa to improve tumor control.