PTJA16 - Venetoclax for acute myeloid leukaemia EUnetHTA Joint Action 3 WP4 Relative effectiveness assessment of pharmaceutical technologies VENETOCLAX WITH A HYPOMETHYLATING AGENT FOR THE TREATMENT OF ADULT PATIENTS WITH NEWLY DIAGNOSED ACUTE MYELOID LEUKAEMIA (AML) WHO ARE INELIGIBLE FOR INTENSIVE CHEMOTHERAPY Project ID: PTJA16 Assessment Report Version 2.0, 03 September 2021 Template version 2.2, April 2020 This Assessment was started as part of the project / joint action ‘724130 / EUnetHTA JA3’ w hich has received funding from the European Union’s Health Programme (2014- 2020). Even though EUnetHTA JA3 has formaly ended in May 2021, the authors of this assessment continued their commitment to finalize this assessment under the agreed methodology of EUnetHTA Joint Action 3. September 21 EUnetHTA Joint Action 3 WP4 1 PTJA16 - Venetoclax for acute myeloid leukaemia DOCUMENT HISTORY AND CONTRIBUTORS Version Date Description V0.1 10/05/2021 First draft V0.2 04/06/2021 Input from dedicated reviewers has been processed V0.3 21/06/2021 Input from medical editor and manufacturer(s) has been processed V1.0 08/07/2021 Final assessment report V2.0 03/09/2021 The following corrections were made: Table 4.16 “Summary of findings for venetoclax + azacitidine versus azacitidine alone in AML”. For the outcome “Treatment discontinuations due to AEs” (mean follow-up 1 month) the reported Relative effect [95% CI] RR 1.28 [1.12–1.46] is corrected to RR 1.21 [0.82-1.78 ]. Table A3 “GRADE - Venetoclax + azacitidine compared to azacitidine + placebo for adult patients with newly-diagnosed acute myeloid leukaemia (AML) who are ineligible for intensive chemotherapy (VIALE-A)”. For the outcome “Treatment discontinuations due to AEs” (mean follow-up 1 month): The reported Relative effect [95% CI] RR 1.28 [1.12–1.46] is corrected to RR 1.21 [0.82-1.78] and the reported Absolute effect [95% CI] of 56 more per 1000 (from 24 more to 93 more) is corrected to 42 more per 1000 (from 40 fewer to 124 more). Disclaimer The content of this Assessment Report represents a consolidated view based on the consensus within the Authoring Team; it cannot be considered to reflect the views of the European Network for Health Technology Assessment (EUnetHTA), the EUnetHTA participating institutions, the European Commission and/or the Consumers, Health, Agriculture and Food Executive Agency or any other body of the European Union. The European Commission and the Agency do not accept any responsibility for use that may be made of the information it contains. Assessment team Author(s) The Norwegian Medicines Agency (NOMA), Norway Co-Author(s) Agency for Medicinal Products and Medical Devices of the Republic of Slovenia (JAZMP), Slovenia Information Norwegian Institute of Public Health (NIPHNO), Norway Specialist Dedicated Agencia Española de Medicamentos y Productos Sanitarios (AEMPS), Spain Reviewer(s) HTA Department of State Expert Centre of Ministry of Health, Ukraine State Medicines Control Agency of Lithuania (SMCA), Lithuania September 21 EUnetHTA Joint Action 3 WP4 2 PTJA16 - Venetoclax for acute myeloid leukaemia Further contributors External experts Lina Benajiba, MD, PhD Answered specific questions from the Authoring Team during this assessment Manufacturer(s) [v0.2] AbbVie Preparation of the submission dossier Factual accuracy check Medical editor [v0.2] Compuscript Medical editing of the 2nd draft assessment Patient(s) / patient organisation(s) / citizens -Association of Cancer Patients in Input in response to an open call for patient input published on 21st Finland, Finland September 2020 -MOHA, Hungary -Blodkreftforeningen, Norway -Hrvatska Udruga Leukemija i Limfomi , Croatia -Patientforeningen for Lymfekræft, Leukæmi og MDS, Denmark -Diagnoza Leukemie, z.s., Czech Republic -Leukaemia Care, United Kingdom -Deutsche Leukämie- & Lymphom- Hilfe, Germany Project Management Zorginstituut Nederland (ZIN), Coordination between involved parties throughout the assessment Netherlands Conflict of interest All authors, co-authors, dedicated reviewers, observers, external experts (health care professionals, patients or patient representatives) involved in the production of this assessment have declared they have no conflicts of interest in relation to the technology and comparator(s) assessed according to the EUnetHTA declaration of interest form. Conflict of Interest was evaluated following the EUnetHTA Procedure Guidance for handling DOI form (https://eunethta.eu/doi). Copyright: EUnetHTA assessments are published under a “CC/BY/NC” Creative Commons Licence. How to cite this assessment Please cite this assessment as follows: EUnetHTA PTJA16. Authoring Team. Venetoclax with a hypomethylating agent for the treatment of adult patients with newly diagnosed acute myeloid leukaemia (AML) who are ineligible for intensive chemotherapy. Joint Assessment. Diemen (The Netherlands): EUnetHTA; 2021. [date of citation]. 108 pages. Report No.: PTJA16. Available from: https //www.eunethta.eu Contact the EUnetHTA Secretariat [email protected] with inquiries about this assessment. September 21 EUnetHTA Joint Action 3 WP4 3 PTJA16 - Venetoclax for acute myeloid leukaemia TABLE OF CONTENTS EXECUTIVE SUMMARY OF THE ASSESSMENT OF VENETOCLAX ..................................... 10 INTRODUCTION .................................................................................................................. 10 OBJECTIVE AND SCOPE ....................................................................................................... 10 METHODS ......................................................................................................................... 11 LITERATURE SEARCH AND ASSESSMENT APPROACH ................................................................. 11 RESULTS .......................................................................................................................... 12 DISCUSSION ...................................................................................................................... 14 CONCLUSION ..................................................................................................................... 15 1 BACKGROUND............................................................................................................... 16 1.1 OVERVIEW OF THE DISEASE OR HEALTH CONDITION ............................................................ 16 1.2 CURRENT CLINICAL PRACTICE ......................................................................................... 18 1.3 FEATURES OF THE INTERVENTION .................................................................................... 20 2 OBJECTIVE AND SCOPE ............................................................................................... 26 3 METHODS ...................................................................................................................... 28 3.1 INFORMATION RETRIEVAL ............................................................................................... 28 3.2 DATA EXTRACTION ........................................................................................................ 30 3.3 RISK-OF-BIAS ASSESSMENT ............................................................................................ 30 3.4 RESULTS AND ANALYSES FOR THE STUDIES INCLUDED......................................................... 31 3.5 PATIENT INVOLVEMENT .................................................................................................. 31 4 RESULTS........................................................................................................................ 32 4.1 INFORMATION RETRIEVAL ............................................................................................... 32 4.2 STUDIES INCLUDED IN THE ASSESSMENT ........................................................................... 32 4.3 STUDIES EXCLUDED ...................................................................................................... 33 4.4 CHARACTERISTICS OF STUDIES OF VENETOCLAX IN COMBINATION WITH A HMA ....................... 33 4.5 STATISTICS .................................................................................................................. 41 4.6 OUTCOMES INCLUDED ................................................................................................... 43 4.7 PARTICIPANT FLOW ....................................................................................................... 45 4.8 RISK OF BIAS................................................................................................................ 46 4.9 EXTERNAL VALIDITY ...................................................................................................... 46 4.10 RESULTS FOR THE CLINICAL EFFECTIVENESS AND SAFETY OF VENETOCLAX + HMAS......... 47 4.11 INDIRECT EVIDENCE ............................................................................................... 57 5 PATIENT INVOLVEMENT ................................................................................................ 63 6 DISCUSSION .................................................................................................................. 64 6.1 QUESTION AND SCOPE................................................................................................... 64 6.2 INFORMATION RETRIEVAL ............................................................................................... 64 6.3 DESIGN AND CONDUCT OF CLINICAL STUDIES: EFFICACY AND SAFETY DATA............................