A Study Protocol for Validation and Implementation of Whole-Genome and -Transcriptome Sequencing as a Comprehensive Precision Diagnostic Test in Acute Leukemias

Eva Berglund; Gisela Barbany; Christina Orsmark-Pietras; Linda Fogelstrand; Jonas Abrahamsson; Irina Golovleva; Helene Hallböök; Martin Höglund; Vladimir Lazarevic; Lars-Åke Levin; Jessica Nordlund; Ulrika Norèn-Nyström; Josefine Palle; Tharshini Thangavelu; Lars Palmqvist; Valtteri Wirta; Lucia Cavelier; Thoas Fioretos; Richard Rosenquist

doi:10.3389/fmed.2022.842507

A Study Protocol for Validation and Implementation of Whole-Genome and -Transcriptome Sequencing as a Comprehensive Precision Diagnostic Test in Acute Leukemias

Front Med (Lausanne). 2022 Mar 24:9:842507. doi: 10.3389/fmed.2022.842507. eCollection 2022.

Authors

Eva Berglund¹, Gisela Barbany^{2

3}, Christina Orsmark-Pietras^{4

5

6}, Linda Fogelstrand^{7

8}, Jonas Abrahamsson⁹, Irina Golovleva¹⁰, Helene Hallböök¹¹, Martin Höglund¹¹, Vladimir Lazarevic¹², Lars-Åke Levin¹³, Jessica Nordlund¹⁴, Ulrika Norèn-Nyström¹⁵, Josefine Palle¹⁶, Tharshini Thangavelu¹³, Lars Palmqvist^{7

8}, Valtteri Wirta¹⁷, Lucia Cavelier¹, Thoas Fioretos^{4

5

6}, Richard Rosenquist^{2

3}

Affiliations

¹ Department of Immunology, Genetics and Pathology, Clinical Genomics Uppsala, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
² Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
³ Clinical Genetics, Karolinska University Hospital, Solna, Sweden.
⁴ Department of Clinical Genetics and Pathology, Office for Medical Services, Division of Laboratory Medicine, Lund, Sweden.
⁵ Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden.
⁶ Clinical Genomics Lund, Science for Life Laboratory, Lund University, Lund, Sweden.
⁷ Department of Clinical Chemistry, Sahlgrenska University Hospital, Gothenburg, Sweden.
⁸ Department of Laboratory Medicine, Institute of Biomedicine, Clinical Genomics Gothenburg, Science for Life Laboratory, University of Gothenburg, Gothenburg, Sweden.
⁹ Clinical Sciences, Queen Silvias Childrens Hospital, Gothenburg, Sweden.
¹⁰ Department of Medical Biosciences, University of Umeå, Umeå, Sweden.
¹¹ Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
¹² Department of Hematology, Oncology and Radiation Physics, Skåne University Hospital, Lund, Sweden.
¹³ Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden.
¹⁴ Department of Medical Sciences and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
¹⁵ Department of Clinical Sciences, Pediatrics, Umeå University, Umeå, Sweden.
¹⁶ Women's and Children's Health, Uppsala University, Uppsala, Sweden.
¹⁷ Department of Microbiology, Tumor and Cell Biology, Clinical Genomics Stockholm, Science for Life Laboratory, Karolinska Institutet, Solna, Sweden.

Abstract

Background: Whole-genome sequencing (WGS) and whole-transcriptome sequencing (WTS), with the ability to provide comprehensive genomic information, have become the focal point of research interest as novel techniques that can support precision diagnostics in routine clinical care of patients with various cancer types, including hematological malignancies. This national multi-center study, led by Genomic Medicine Sweden, aims to evaluate whether combined application of WGS and WTS (WGTS) is technically feasible and can be implemented as an efficient diagnostic tool in patients with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). In addition to clinical impact assessment, a health-economic evaluation of such strategy will be performed.

Methods and analysis: The study comprises four phases (i.e., retrospective, prospective, real-time validation, and follow-up) including approximately 700 adult and pediatric Swedish AML and ALL patients. Results of WGS for tumor (90×) and normal/germline (30×) samples as well as WTS for tumors only will be compared to current standard of care diagnostics. Primary study endpoints are diagnostic efficiency and improved diagnostic yield. Secondary endpoints are technical and clinical feasibility for routine implementation, clinical utility, and health-economic impact.

Discussion: Data from this national multi-center study will be used to evaluate clinical performance of the integrated WGTS diagnostic workflow compared with standard of care. The study will also elucidate clinical and health-economic impacts of a combined WGTS strategy when implemented in routine clinical care.

Clinical trial registration: [https://doi.org/10.1186/ISRCTN66987142], identifier [ISRCTN66987142].

Keywords: acute lymphoblastic leukemia; acute myeloid leukemia; clinical utility; diagnostic efficiency; health-economic evaluation; technical feasibility; whole-genome sequencing; whole-transcriptome sequencing.

Copyright © 2022 Berglund, Barbany, Orsmark-Pietras, Fogelstrand, Abrahamsson, Golovleva, Hallböök, Höglund, Lazarevic, Levin, Nordlund, Norèn-Nyström, Palle, Thangavelu, Palmqvist, Wirta, Cavelier, Fioretos and Rosenquist.