Outcome of adults with acute lymphocytic leukemia after second salvage therapy

O’Brien, Susan; Thomas, Debbie; Ravandi, Farhad; Faderl, Stefan; Cortes, Jorge; Borthakur, Gautum; Pierce, Sherry; Garcia‐Manero, Guillermo; Kantarjian, Hagop M.

doi:10.1002/cncr.23919

Cited by 133 publications

(126 citation statements)

References 135 publications

(169 reference statements)

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“…173 The study reporting the best historical comparison data still had some key differences with regard to the Marqibo trial population, most notably in terms of line of treatment, eligibility for transplant and site of adjudication. 175 Comparisons were made with the closest matched subgroup of patients in the historical study: patients who received third-line single-agent treatment. 173 Clofarabine was assessed in 2006 and thus the aforementioned O'Brien study 175 Summary of issues to consider to inform the creation of the target product profiles and hypothetical data sets…”

Section: Exemplar Technology Appraisal Of a Regenerative Medicinementioning

confidence: 99%

“…175 Comparisons were made with the closest matched subgroup of patients in the historical study: patients who received third-line single-agent treatment. 173 Clofarabine was assessed in 2006 and thus the aforementioned O'Brien study 175 Summary of issues to consider to inform the creation of the target product profiles and hypothetical data sets…”

Section: Exemplar Technology Appraisal Of a Regenerative Medicinementioning

confidence: 99%

“…However, five of these did not report sufficient detail on the results to be considered further. 159,160,[175][176][177] A summary of the patient characteristics in the remaining seven studies is provided in Appendix 6. None of the prognostic models specifically focused on the population of interest.…”

Section: Defining a Historical Controlmentioning

confidence: 99%

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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

104

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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Section: Exemplar Technology Appraisal Of a Regenerative Medicinementioning

confidence: 99%

Section: Exemplar Technology Appraisal Of a Regenerative Medicinementioning

confidence: 99%

See 1 more Smart Citation

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

104

143

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“…Reported rates of complete remission (CR) after salvage treatment range from 18%-45%, and median survival times range from 2-8 months, with less than 10% survival after 5 years in most studies. [2][3][4][5][6][7] Achievement of CR and subsequent HSCT is the only curative option in relapsed adult ALL; 2,3,6 however, this can only be achieved in a subgroup…”

Section: Introductionmentioning

confidence: 99%

International reference analysis of outcomes in adults with B-precursor Ph-negative relapsed/refractory acute lymphoblastic leukemia

et al. 2016

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A dults with relapsed/refractory acute lymphoblastic leukemia have an unfavourable prognosis, which is influenced by disease and patient characteristics. To further evaluate these characteristics, a retrospective analysis of 1,706 adult patients with Ph-negative relapsed/refractory B-precursor acute lymphoblastic leukemia diagnosed between 1990-2013 was conducted using data reflecting the standard of care from 11 study groups and large centers in Europe and the United States. Outcomes included complete remission, overall survival, and realization of stem cell transplantation after salvage treatment. The overall complete remission rate after first salvage was 40%, ranging from 35%-41% across disease status categories (primary refractory, relapsed with or without prior transplant), and was lower after second (21%) and third or greater (11%) salvage. The overall complete remission rate was higher for patients diagnosed from 2005 onward (45%, 95% CI: 39%-50%). One-and three-year survival rates after first, second, and third or greater salvage were 26% and 11%, 18% and 6%, and 15% and 4%, respectively, and rates were 2%-5% higher among patients diagnosed from 2005. Prognostic factors included younger age, longer duration of first remission, and lower white blood cell counts at primary diagnosis. This large dataset can provide detailed reference outcomes for patients with relapsed/refractory Ph-negative B-precursor acute lymphoblastic leukemia. clinicaltrials.gov identifier: 02003612 IntroductionOverall prognosis among adult acute lymphoblastic leukemia (ALL) patients has improved by optimisation of front-line therapy, 1 but outcomes remain poor for patients who relapse or are refractory to initial treatment. Reported rates of complete remission (CR) after salvage treatment range from 18%-45%, and median survival times range from 2-8 months, with less than 10% survival after 5 years in most studies.2-7 Achievement of CR and subsequent HSCT is the only curative option in relapsed adult ALL; 2,3,6 however, this can only be achieved in a subgroup For these reasons, new treatment options are needed for adult patients with relapsed/refractory (r/r) ALL, and a number of promising compounds are currently under clinical evaluation. 8,9 The rarity of adult r/r ALL, 10 combined with the very poor outcomes and non-standardised approaches of salvage therapies, make it difficult to conduct randomised trials of new compounds. Approvals of new treatments are therefore often based on evidence from phase 2 single-arm trials. 11-14To attain a more precise estimate of clinical practice outcomes in adult r/r ALL, and to evaluate important patient subgroups, we pooled data from major national study groups and large individual sites treating adult ALL from Europe and the United States to create the most extensive clinical dataset available in this population.The analysis aimed to describe patient characteristics and outcome parameters (achievement of CR, overall survival [OS] and realization of allogeneic HSCT) among adult patients with P...

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“…120 These outcomes appeared favorable compared with published historical data in patients with Ph-negative ALL treated with other agents at second relapse (n = 56; CR rate, 4%; median OS, 7.5 weeks; early induction death, 30%). 120,121 The most common grade 3 or greater treatment-related toxicities with VSLI included neuropathy (23%), neutropenia (15%), thrombocytopenia (6%), anemia (5%; no grade 4), and tumor lysis syndrome (5%). Febrile neutropenia occurred in 3% of patients (no grade 4).…”

Section: Treatment Of Relapsed Ph-negative Allmentioning

confidence: 99%

Acute Lymphoblastic Leukemia, Version 2.2015

Alvarnas

Brown

Aoun

et al. 2015

J Natl Compr Canc Netw

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138

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Treatment of acute lymphoblastic leukemia (ALL) continues to advance, as evidenced by the improved risk stratification of patients and development of newer treatment options. Identification of ALL subtypes based on immunophenotyping and cytogenetic and molecular markers has resulted in the inclusion of Philadelphia-like ALL and early T-cell precursor ALL as subtypes that affect prognosis. Identification of Ikaros mutations has also emerged as a prognostic factor. In addition to improved prognostication, treatment options for patients with ALL have expanded, particularly with regard to relapsed/refractory ALL. Continued development of second-generation tyrosine kinase inhibitors and the emergence of immunotherapy, including blinatumomab and chimeric antigen receptor T-cell therapy, have improved survival. Furthermore, incorporation of minimal residual disease (MRD) monitoring has shown insight into patient outcomes and may lead to treatment modification or alternative treatment strategies in select populations. This excerpt focuses on the sections of the ALL guidelines specific to clinical presentation and diagnosis, treatment of relapsed/refractory ALL, and incorporation of MRD monitoring. To view the most recent complete version of these guidelines, visit NCCN.org. (J Natl Compr Canc Netw 2015;13:1240-1279 NCCN Categories of Evidence and ConsensusCategory 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate. Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate. Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate. Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate. These guidelines are also available on the Internet. For the latest update, visit NCCN.org.

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Outcome of adults with acute lymphocytic leukemia after second salvage therapy

Cited by 133 publications

References 135 publications

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

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

International reference analysis of outcomes in adults with B-precursor Ph-negative relapsed/refractory acute lymphoblastic leukemia

Acute Lymphoblastic Leukemia, Version 2.2015

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