Long-Term Survival and Late Deaths after Allogeneic Bone Marrow Transplantation

Socié, Gèrard; Stone, Judith V.; Wingard, John R.; Weisdorf, Daniel J.; Henslee‐Downey, P. Jean; Bredeson, Chris; Cahn, Jean Yves; Passweg, Jakob; Rowlings, Philip; Schouten, Harry C.; Kolb, Hans‐Jochem; Klein, John P.

doi:10.1056/nejm199907013410103

Cited by 622 publications

(176 citation statements)

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“…12 The site of relapse is not specified in previous reports of BuCy-treated patients 4,7,8 and only four patients in an EBMT review of AML transplants were noted to have an isolated EM relapse following a BuCy preparative regimen. 13 Late relapses of AML post-SCT are uncommon, 2,7,[25][26][27] and there are few reports on the specific incidence of late EM relapse. However, in the EBMT survey, there were 21 patients with isolated EM relapses of AML at a median of 20 months post-SCT and six patients relapsed beyond 36 months.…”

Section: Discussionmentioning

confidence: 99%

High incidence of extramedullary relapse of AML after busulfan/cyclophosphamide conditioning and allogeneic stem cell transplantation

et al. 1998

Bone Marrow Transplant

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Summary:While allogeneic stem cell transplantation (SCT) is curative for a significant number of patients with AML, relapse of disease within the bone marrow and/or extramedullary (EM) sites following high-dose therapy continues to limit the success of this treatment. Between October 1985 and December 1996, 81 adults underwent allogeneic SCT for de novo AML at our centre. Fortytwo patients remain alive and free of leukaemia with a median follow-up of 50 months. The 5-year actuarial event-free survivals (EFS) for all patients and for those undergoing SCT in CR1 or with advanced disease were 46% (95% confidence interval (CI) 34-58%), 63% (CI 46-76%), and 19% (CI 7-36%), respectively. Twentytwo patients relapsed at a median of 8 (range 1.6-54.5) months with the actuarial risk of relapse for all, CR1 and advanced disease patients being 38%, (CI 27-52%), 23% (CI 13-40%) and 68% (CI 46-88%), respectively. Ten patients relapsed at EM sites; six of these (27% of relapses) had an isolated EM relapse at a median of 31 (range 8.5-54) months. Three of the patients with isolated EM relapse survived у24 months following relapse and two patients remain disease-free at 29+ and 33+ months. BuCy conditioning followed by allogeneic SCT in AML results in satisfactory EFS although there is a significant risk of late isolated EM relapse. Keywords: acute myelogenous leukemia; extramedullary relapse; allogeneic BMT Allogeneic stem cell transplantation (SCT) is an effective therapy for patients with AML. 1-3 Long-term event-free survival (EFS) can be achieved in approximately 60% of patients undergoing SCT in first complete remission (CR1) 4-9 and 25-30% of those with more advanced disease. 1,2,4,10,11 However, there remains some controversy regarding the optimal transplant preparative regimen in AML. For patients transplanted in CR1, one randomized study demonstrated a regimen employing TBI to be superior to busulfan/cyclophosphamide (BuCy) conditioning, 7 while another showed the regimens to be equivalent. 8 One of the contributing factors to an unsuccessful result with SCT regardless of the preparative regimen utilized is relapse, occurring in 20-25% and 30-50% of AML patients transplanted during CR1 or with advanced disease, respectively. 1,2,4,7,9 The site of relapse after a TBI-based preparative regimen is usually the marrow with or without extramedullary (EM) disease. 12 Isolated EM relapse occurred in only 13% of patients developing recurrent disease after TBI conditioning in one study. 12 Little is known about the risk of isolated EM relapse of AML following BuCy with a small number of such patients reported recently in a survey by the European Group for Blood and Marrow Transplantation (EBMT) of more than 3000 AML transplants. 13 The present review was prompted by the observation that several patients receiving allogeneic SCT after BuCy at our institution experienced isolated EM relapse.

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Section: Discussionmentioning

confidence: 99%

High incidence of extramedullary relapse of AML after busulfan/cyclophosphamide conditioning and allogeneic stem cell transplantation

et al. 1998

Bone Marrow Transplant

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“…One study investigated long-term survival and late deaths among 1458 ALL patients who were disease free 2 years after allogeneic HSCT; the median follow-up was around 80 months. 162 Of the 167 deaths, new cancers accounted for around 10% of the primary causes of death, with graft versus host disease accounting for 23% of deaths.…”

Section: Haematopoietic Stem Cell Transplantationmentioning

confidence: 99%

The assessment and appraisal of regenerative medicines and cell therapy products: an exploration of methods for review, economic evaluation and appraisal

Hettle

Corbett

Hinde

et al. 2017

Health Technol Assess

103

143

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BackgroundThe National Institute for Health and Care Excellence (NICE) commissioned a ‘mock technology appraisal’ to assess whether changes to its methods and processes are needed. This report presents the findings of independent research commissioned to inform this appraisal and the deliberations of a panel convened by NICE to evaluate the mock appraisal.MethodsOur research included reviews to identify issues, analysis methods and conceptual differences and the relevance of alternative decision frameworks, alongside the development of an exemplar case study of chimeric antigen receptor (CAR) T-cell therapy for treating acute lymphoblastic leukaemia.ResultsAn assessment of previous evaluations of regenerative medicines found that, although there were a number of evidential challenges, none was unique to regenerative medicines or was beyond the scope of existing methods used to conceptualise decision uncertainty. Regarding the clinical evidence for regenerative medicines, the issues were those associated with a limited evidence base but were not unique to regenerative medicines: small non-randomised studies, high variation in response and the intervention subject to continuing development. The relative treatment effects generated from single-arm trials are likely to be optimistic unless it is certain that the historical data have accurately estimated the efficacy of the control agent. Pivotal trials may use surrogate end points, which, on average, overestimate treatment effects. To reduce overall uncertainty, multivariate meta-analysis of all available data should be considered. Incorporating indirectly relevant but more reliable (more mature) data into the analysis can also be considered; such data may become available as a result of the evolving regulatory pathways being developed by the European Medicines Agency. For the exemplar case of CAR T-cell therapy, target product profiles (TPPs) were developed, which considered the ‘curative’ and ‘bridging to stem-cell transplantation’ treatment approaches separately. Within each TPP, three ‘hypothetical’ evidence sets (minimum, intermediate and mature) were generated to simulate the impact of alternative levels of precision and maturity in the clinical evidence. Subsequent assessments of cost-effectiveness were undertaken, employing the existing NICE reference case alongside additional analyses suggested within alternative frameworks. The additional exploratory analyses were undertaken to demonstrate how assessments of cost-effectiveness and uncertainty could be impacted by alternative managed entry agreements (MEAs), including price discounts, performance-related schemes and technology leasing. The panel deliberated on the range of TPPs, evidence sets and MEAs, commenting on the likely recommendations for each scenario. The panel discussed the challenges associated with the exemplar and regenerative medicines more broadly, focusing on the need for a robust quantification of the level of uncertainty in the cost-effective estimates and the potential value of MEAs in limiting the exposure of the NHS to high upfront costs and loss associated with a wrong decision.ConclusionsIt is to be expected that there will be a significant level of uncertainty in determining the clinical effectiveness of regenerative medicines and their long-term costs and benefits, but the existing methods available to estimate the implications of this uncertainty are sufficient. The use of risk sharing and MEAs between the NHS and manufacturers of regenerative medicines should be investigated further.FundingThe National Institute for Health Research Health Technology Assessment programme.

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“…However, this issue cannot be disregarded especially when chemotherapeutic approaches and/or autologous HSCT, which 15 are associated with less morbidity continue to improve outcome in intermediate risk AML (15)(16)(17)(18). Several studies in recipients of alloHSCT have addressed the issue of late morbidity and late mortality occurring in patients, who were alive and well at 2 years after alloHSCT (102)(103)(104)(105)(106). A relative increase of 20% mortality, gradually occurring during the ensuing 2 decades, has been reported when comparing alloHSCT recipients with age matched controls.…”

Section: Adverse Effects Beyond 2 Years After Transplantation and Quamentioning

confidence: 99%

The European LeukemiaNet AML Working Party consensus statement on allogeneic HSCT for patients with AML in remission: an integrated-risk adapted approach

et al. 2012

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Allogeneic hematopoietic stem cell transplantation (alloHSCT) is frequently applied as part of treatment in acute myeloid leukemia (AML) in first or subsequent remission. It reduces relapse, but non-relapse mortality (NRM) and morbidity may counterbalance that beneficial effect. Here we review recent studies reporting new disease specific prognostic markers as well as alloHSCT related risk factors to be identified at specific time points during treatment. We propose risk assessment as a dynamic process during treatment, incorporating both disease and transplant related factors for the decision to proceed either to alloHSCT or with a non transplant strategy, whereby alloHSCT may be favored if projected disease free survival can be expected to be improved by at least 10%, based on individual risk assessment. Pivotal for such an approach are initial disease risk assessment, search for a sibling or unrelated donor early after diagnosis, and the incorporation of time dependent risk factors, all within the context of an integrated therapeutic management approach.4

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Long-Term Survival and Late Deaths after Allogeneic Bone Marrow Transplantation

Cited by 622 publications

References 25 publications

High incidence of extramedullary relapse of AML after busulfan/cyclophosphamide conditioning and allogeneic stem cell transplantation

High incidence of extramedullary relapse of AML after busulfan/cyclophosphamide conditioning and allogeneic stem cell transplantation

The assessment and appraisal of regenerative medicines and cell therapy products: an exploration of methods for review, economic evaluation and appraisal

The European LeukemiaNet AML Working Party consensus statement on allogeneic HSCT for patients with AML in remission: an integrated-risk adapted approach

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