Evaluation of genome sequencing as a diagnostic test in acute leukemia
| ISRCTN | ISRCTN66987142 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN66987142 |
- Submission date
- 19/08/2021
- Registration date
- 01/09/2021
- Last edited
- 06/12/2024
- Recruitment status
- Recruiting
- Overall study status
- Ongoing
- Condition category
- Cancer
Plain English summary of protocol
Background and study aims
Acute leukemia includes the blood cancers acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). About 350 adults and 100 children per year are diagnosed with acute leukemia in Sweden. Acute leukemias are characterized by recurrent genetic point mutations as well as large structural aberrations of the chromosomes. Increased knowledge of these genetic variants leads to a better understanding of why acute leukemias occur, and also has major importance for diagnosis, prognosis and choice of treatment, as well as evaluation of how the patient responds to treatment. Clinical diagnostics of acute leukemias currently include analysis of genetic variants using different molecular and microscopic methods. This study aims to perform comprehensive genetic analysis (whole-genome sequencing and whole-transcriptome sequencing) of acute leukemias in a clinical setting, to evaluate whether these methods can lead to improved clinical diagnostics and treatment.
Who can participate?
Patients with diagnosed or suspected acute leukemia, for whom a referral is written for genetic diagnostics, can participate. Both adults and children can participate, provided that the patient and/or guardian is able to provide informed consent.
What does the study involve?
Standard diagnostics of a suspected acute leukemia includes the collection of a bone marrow sample and one or several blood samples. In this study, leftover material from these samples will be used for a more comprehensive genetic analysis of the leukemia cells. To enable the comparison of the genetic variants observed in leukemia cells to those in healthy cells, a sample with normal cells is needed. This sample can be collected from a skin biopsy, buccal (mouth) swab, hair or nails. It can also be collected from normal blood cells that are isolated from the already collected blood or bone marrow sample or a blood sample collected when the patient is in remission.
The samples are sent to laboratories within healthcare that perform genetic diagnostics, where genetic material is extracted and analyzed. Information about identified genetic variants that are of relevance for the patient’s treatment or follow-up will be communicated to the treating physician.
What are the possible benefits and risks of participating?
Comprehensive genetic analysis can lead to the identification of genetic variants that enables improved risk stratification or additional treatment options. For most patients, participation in the study will not have any impact on treatment but may improve medical care in the future.
Participation in the study can involve the collection of an additional sample for the extraction of healthy cells. A skin biopsy can, despite the use of local anesthetic, sometimes lead to a small discomfort.
Genetic analysis can lead to the identification of inherited genetic variants of two major types:
1. Inherited genetic variants in genes of importance for the development of blood cancer. Such variants can have significance for treatment and follow-up of the patient and will be communicated to the treating physician. Close relatives to the patient may carry the same variant and have an increased risk of developing blood cancer. Patients with this type of variant will be offered genetic counselling and recommendations from a specialist.
2. Inherited variants in genes of importance for inherited diseases other than blood cancer (e.g., inherited cancer, neurologic disease). Such variants will not actively be searched for but may be found incidentally. When consenting to the study, patients can opt to receive information about this type of variant. Should such a variant be found, the patient will be offered genetic counselling and recommendations from a specialist.
Where is the study run from?
Karolinska University Hospital (Sweden)
When is the study starting and how long is it expected to run for?
January 2020 to June 2026
Who is funding the study?
1. Karolinska University Hospital (Sweden)
2. Skånes University Hospital (Sweden)
3. Sahlgrenska University Hospital (Sweden)
4. University Hospital of Umeå (Sweden)
5. Linköping University Hospital (Sweden)
6. Uppsala University Hospital (Sweden)
7. University Hospital Örebro (Sweden)
8. University of Gothenburg (Sweden)
9. Linköping University (Sweden)
10. Lund University (Sweden)
11. Karolinska Institute (Sweden)
12. Umeå University (Sweden)
13. Uppsala University (Sweden)
14. Örebro University (Sweden)
15. Illumina (USA)
16. Investigator initiated and funded
Who is the main contact?
Richard Rosenquist Brandell
richard.rosenquist@ki.se
Contact information
Scientific
Dept of Molecular Medicine and Surgery
Karolinska Institutet
Stockholm
171 76
Sweden
 ORCID ID |
0000-0002-0211-8788 |
|---|---|
| Phone | +46 (0)8 5177 3928 |
| richard.rosenquist@ki.se |
Public
Dept of Molecular Medicine and Surgery
Karolinska Institutet
Stockholm
171 76
Sweden
| Phone | +46 (0)8 5177 3928 |
|---|---|
| richard.rosenquist@ki.se |
Study information
| Study design | Multicentre observational longitudinal study |
|---|---|
| Primary study design | Observational |
| Secondary study design | Longitudinal study |
| Study setting(s) | Hospital |
| Study type | Diagnostic |
| Participant information sheet | https://genomicmedicine.se/wp-content/uploads/2021/05/Patientinformation-GMS-hematologi-Uppsala.pdf |
| Scientific title | Implementation and validation of whole-genome and transcriptome sequencing as a comprehensive diagnostic test in acute leukemia |
| Study acronym | GMS-AL-WGS |
| Study objectives | 1. Whole-genome sequencing (WGS) and whole-transcriptome sequencing (WTS) can detect all mandatory genetic aberrations in acute leukemia 2. WGS and WTS data can be generated and interpreted in a time frame that is acceptable for a diagnostic test 3. WGS and WTS data can be generated and interpreted at a cost that is acceptable for a diagnostic test 4. WGS and WTS can improve classification or risk stratification of acute leukemias compared to current standard of care diagnostics 5. WGS and WTS can improve patient management or choice of therapy for patients with acute leukemia |
| Ethics approval(s) | Approved 17/03/2021, Swedish Ethical Review Authority (Etikprövningsmyndigheten, Box 2110, 750 02 Uppsala, Sweden; +46 (0)10 475 08 00; registrator@etikprovning.se), ref: 2020/06673 Children: approval pending |
| Health condition(s) or problem(s) studied | Acute leukemia |
| Intervention | Tumor DNA and RNA are extracted from bone marrow and/or peripheral blood samples collected as part of standard diagnostics. An additional sample (skin biopsy, buccal swab or other tissue) may be collected for extraction of germline DNA. In addition to standard molecular diagnostics, comprehensive genetic analysis, i.e. whole-genome sequencing and whole-transcriptome sequencing, will be performed. Comprehensive genetic analysis can lead to findings of inherited genetic variants of two major types: 1. Inherited genetic variants that are of importance for the development of blood cancer. All participants will receive information about this type of variants if they are carriers, and offered genetic counselling and recommendations from a specialist. 2. Inherited genetic variants that are of importance for the development of other diseases than blood cancer. This type of variants will not be searched for actively but may be found incidentally. When consenting to the study, participants can opt to receive information about this type of variants. If such variants are found, participants will be offered genetic counselling and recommendations from a specialist. Follow-up of participants will be according to standard healthcare protocols. |
| Intervention type | Genetic |
| Primary outcome measure | 1. Percentage of acute leukemia patients for whom all mandatory genetic aberrations found by SoC are also detected by WGTS is measured by comparison of variants retrieved from WGTS and SoC, respectively, after completion of patient inclusion 2. Percentage of acute leukemia patients for whom genetic variants relevant for classification or risk stratification are identified by WGTS but not by SoC is measured by comparison of variants retrieved from WGTS and SoC, respectively, after completion of patient inclusion |
| Secondary outcome measures | 1. Percentage of patients for whom WGTS analysis and interpretation is successful in a given timeframe is measured by comparison of the number of days needed for WGTS analysis of each patient to the required turnaround-time, after completion of patient inclusion 2. Percentage of acute leukemia patients for whom patient management and/or therapy decision is changed based on variants only detected by WGTS is measured by analysis of patient journals/health records, after completion of patient inclusion 3. Micro-costing of WGTS compared to SoC is measured by comparison of costs associated with WGTS and SoC, respectively, after initiation of the study |
| Overall study start date | 01/01/2020 |
| Completion date | 30/06/2026 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | All |
| Sex | Both |
| Target number of participants | 450 |
| Key inclusion criteria | 1. Patients with diagnosed or suspected acute leukemia, for whom a referral is written for genetic diagnostics 2. Patients of any age can be included |
| Key exclusion criteria | Patients or guardians that are unable to provide written informed consent |
| Date of first enrolment | 01/06/2021 |
| Date of final enrolment | 31/12/2025 |
Locations
Countries of recruitment
- Sweden
Study participating centres
Stockholm
17 176
Sweden
Umeå
90737
Sweden
Uppsala
75185
Sweden
Gothenburg
41345
Sweden
Lund
22242
Sweden
Linköping
58185
Sweden
Örebro
70185
Sweden
Sponsor information
Hospital/treatment centre
Karolinska Vägen 22
Stockholm
17176
Sweden
| Phone | +46 (0)851770000 |
|---|---|
| info.karolinska@sll.se | |
| Website | https://www.karolinska.se/om-oss/ |
"ROR" |
https://ror.org/00m8d6786 |
Funders
Funder type
Hospital/treatment centre
No information available
Private sector organisation / Other non-profit organizations
- Alternative name(s)
- Skåne University Hospital, SUS
- Location
- Sweden
Private sector organisation / Universities (academic only)
- Alternative name(s)
- Sahlgrenska University Hospital, SU
- Location
- Sweden
No information available
No information available
No information available
Government organisation / Local government
- Alternative name(s)
- Örebro University Hospital, USÖ
- Location
- Sweden
Private sector organisation / Universities (academic only)
- Alternative name(s)
- University of Gothenburg
- Location
- Sweden
Government organisation / Local government
- Alternative name(s)
- Linköping University, Linköping University, LiU
- Location
- Sweden
Government organisation / Universities (academic only)
- Alternative name(s)
- Lund University, Universitas Lundensis, Universitas Gothorum Carolina, Royal Caroline Academy, Regia Academia Carolina, Lund University | Lund, Sweden | LU, Lunds universitet, LU
- Location
- Sweden
Government organisation / Local government
- Alternative name(s)
- Karolinska Institute, KI
- Location
- Sweden
Government organisation / Universities (academic only)
- Alternative name(s)
- Umeå University, Ubmeje universitiähta, Universitas Umensis
- Location
- Sweden
Government organisation / Universities (academic only)
- Alternative name(s)
- Uppsala University, UU_University, Uppsala Universitet, Sweden, UU
- Location
- Sweden
Private sector organisation / Universities (academic only)
- Alternative name(s)
- Örebro University
- Location
- Sweden
Government organisation / For-profit companies (industry)
- Alternative name(s)
- Illumina, Inc.
- Location
- United States of America
No information available
Results and Publications
| Intention to publish date | 31/12/2026 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Stored in non-publicly available repository |
| Publication and dissemination plan | Planned publications: 1. Study protocol 2. Microcosting analysis 3. Comparison of WGS/WTS and standard of care diagnostics 4. Health economics assessment |
| IPD sharing plan | The datasets generated during and/or analysed during the current study will be stored in a non-publically available repository. Data will be processed and stored according to the regulations within the General Data Protection Regulation (GDPR). Initially, data will be stored at each participating centre, with so-called restricted access. To enable population-based studies, data will be transferred to the National Genomic Platform within Genomic Medicine Sweden. If required upon publication, data will be stored in the European Genome-phenome Archive (EGA). Data will not be accessible to the public but will require permission from a Data Access Committee (DAC) which will be formed within the GMS working group for hematology. In addition to individuals with clinical hematologic and genetic expertise, the DAC will include individuals with juridical/ethical expertise. Consent from participants has been obtained to share genetic data for research and development purposes. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Protocol article | 24/03/2022 | 25/03/2022 | Yes | No |
Editorial Notes
06/12/2024: The following changes were made to the study record:
1. The recruitment end date was changed from 31/12/2024 to 31/12/2025.
2. The overall end date was changed from 30/06/2025 to 30/06/2026.
3. The intention to publish date was changed from 31/12/2025 to 31/12/2026.
05/06/2024: The following changes were made to the trial record:
1. The recruitment end date was changed from 30/06/2024 to 31/12/2024.
2. The overall end date was changed from 31/12/2024 to 30/06/2025.
3. The plain English summary was updated to reflect these changes.
04/12/2023: The recruitment end date was changed from 31/12/2023 to 30/06/2024.
05/06/2023: The recruitment end date was changed from 30/06/2023 to 31/12/2023.
08/12/2022: The following changes were made to the trial record:
1. The recruitment end date was changed from 01/12/2022 to 30/06/2023.
2. The intention to publish date was changed from 31/12/2023 to 31/12/2025.
25/03/2022: Publication reference added.
31/08/2021: Trial's existence confirmed by the Swedish Ethical Review Authority.
