LeukemiaSIRIUSNCT05046444
Solving Riddles Through Sequencing
An observational study of Leukemia and Hematologic Malignancy, run by Munich Leukemia Laboratory at 1 site in Germany.
Trial summary
During the last decades hematologists have excelled at improving and refining the classification, diagnosis, and thus ultimately the therapeutic decision-making process for their patients. This continuous evolution proceeded in parallel to seminal discoveries in basic science such as FISH, PCR and NGS. Read more about this study
- Who is it for?
- Ages 18 to 99 years
- Conditions the study is for
- Leukemia, Hematologic Malignancy, Rare Diseases
- What is being tested?
- Next Generation Sequencing
- How many people
- 100 participants
- Where
- 1 siteGermany
- Study dates
- 19 Jan 2022to 1 Oct 2027
- Phase
- Observational
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 99 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Study population: SIRIUS is conducted as a monocentric prospective case-control study. The study population consists of carefully chosen patients with potential hematological malignancy, for which current diagnostic methods were not sufficient to provide clear-cut diagnosis and definitive clinical guidance. SIRIUS is entirely a non-interventional study without therapeutic consequences for direct patient care.
Who may be able to join
- Patients having been investigated with a suspected hematological disorder and:
- Having unclear diagnosis after internal routine diagnosis
- Unusual clinical course
- Unusual r/r status or non-responder
- Multiple parallel hematological conditions
- Difficult/rare therapy associated/secondary neoplasms
Show all 10Show fewer
- Current diagnostic workup is not satisfactory in terms of (1) accuracy (2) clinical behavior
- Only samples of patients min. 18 years of age will be used
- Material with a minimum of 20% tumor content in bone marrow or peripheral blood sample
- Patient´s informed consent
Who cannot join
- Sample is not fit for state-of-the-art diagnosis, fails initial quality control. For quality insurance we will exclude samples with wrong anticoagulant sent. Samples with damage due to meteorological reasons (freeze-thaw damage or elevated temperature) will be excluded.
- Samples with to scarce material jeopardizing routine gold-standard diagnosis will be excluded (tumor content < 20 %).
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
Germany1 site, 1 recruiting
- Recruiting
MLL Munich Leukemia Laboratory
Munich
Torsten Haferlach, MD
About this study
Official title: Testing the Diagnostic Supremacy of Sequencing-only Approaches in Hematologic Malignancies: an Observational Trial
During the last decades hematologists have excelled at improving and refining the classification, diagnosis, and thus ultimately the therapeutic decision-making process for their patients. This continuous evolution proceeded in parallel to seminal discoveries in basic science such as FISH, PCR and NGS. So far, the current WHO classification serves as reference to diagnostic decision making and is largely based on 5 diagnostic pillars: cytomorphology of peripheral blood and/or bone marrow smears, histology and immunohistochemistry of bone marrow trephine biopsies or lymph nodes, immunophenotyping, chromosome banding analysis supplemented by FISH analysis, molecular genetics including PCR and targeted panel sequencing via NGS. This leads to a swift diagnosis in 90 % of all cases. The leftover 10 % remain a challenge for hematopathologists and clinicians alike and are resolved through interdisciplinary teams in the context of specialized boards. With the advent of high throughput sequencing (mainly WGS and WTS) the possibility of a comprehensive and detailed portrait of the genetic alterations - specifically in challenging cases - has become a realistic alternative to classical methods. In SIRIUS the investigators will prospectively challenge this hypothesis to address the question of how often a better or final diagnosis can be delivered by WGS and/or WTS and if unclear cases can be efficiently resolved.
Read the detailed description
- Background and Rationale Treatment of hematological diseases relies on a single cardinal prerequisite: correct classification within the broad specter of malignant diseases arising from the hematopoietic system. With the ever-expanding availability of distinct yet complementary diagnostic tools, our understanding of the landscape of hematological diseases steadily increases. As such, the current consensus classification as summarized through the WHO classification (2017) represents a compass guiding diagnostic algorithms to the correct diagnosis. Today, the gold standard of routine diagnostic process relies on five methodological pillars: cytomorphology, histology, chromosomal cytogenetics, immunophenotyping, and molecular genetic testing. This leads to a treatment enabling diagnosis in the vast majority of cases. However, approximately 10 % of cases remain unresolved from a diagnostic point of view and hence do not lead to a satisfactory diagnosis according to current WHO standards (2017). The investigators intend to solve this issue to provide illuminating diagnostic guidance for the best possible patient´s care.
- Objectives To address this problem, the investigators hypothesize that novel high throughput sequencing methods, e.g., whole genome and/or whole transcriptome sequencing are able - by virtue of painting a more delicate genetic portrait of a tumor sample - to provide a more accurate diagnosis.
To this end the investigators generated a reference collection of 5,500 samples with the full spectrum of hematological malignancies, for which the investigators performed whole-genome sequencing as well as whole-transcriptome sequencing. Moreover, gold standard diagnoses according to WHO classification with all needed techniques, all performed in MLL, clinical data and therapy response data are fully available for these cases. The main advantage of this reference collection consists of the unambiguity of each diagnosis, providing a reference framework for any further classification and diagnosis especially in difficult cases.
Therefore, SIRIUS will compare the diagnostic superiority of WGS or WTS to the combined approach with gold standard results and by matching the obtained results to the nearest "digital sibling" within our reference cohort of more than 5,500 WGS and WTS (both in 93% of cases). To this end, the investigators will use an inhouse developed matching algorithm, which is able to match genomic or transcriptomic profiles to a group of similar cases and gold standard results from timepoint of this study. Current workflows intended to generate WTS/WGS data from patient samples - all while fulfilling state of the art accreditation (ISO 15189) - require up to 5 - 7 days. This is largely comparable to classical methods but holds the promise to replace error prone and arduous iterations in the methodological work up. The objective is to test whether WTS and/or WGS based approaches can surpass classical methods regarding diagnostic precision and routine reliability. Here the investigators will test this hypothesis in a prospective real-world setting under diagnostically difficult circumstances.
- Conditions
- Leukemia, Hematologic Malignancy, Rare Diseases, Refractory Leukemia, Refractory Lymphoma, Unknown Primary Tumors
- Being tested
- Next Generation Sequencing
- Medical subject headings
- Leukemia, Hematologic Neoplasms, Rare Diseases, Lymphoma, Neoplasms, Unknown Primary
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Next Generation SequencingDiagnostic test
Also called NGS, Whole genome Sequencing
NON-Interventional Observation only study comparing sequencing-only approaches to classical diagnostic methods
| Study group | Role | What they receive |
|---|---|---|
| Unclear diagnosis via conventional methods | The study population consists of carefully chosen patients with potential hematological malignancy, for which current diagnostic methods were not sufficient to provide clear-cut diagnosis and definitive clinical guidance. SIRIUS will be conducted for a total number of 110 patients with inconclusive diagnosis by gold standard techniques for a total of up to nine months after the first enrollment. Receives: Diagnostic Test: Next Generation Sequencing |
What is being measured
The primary outcome is the main question the study is designed to answer.
sequencing only versus gold standard diagnosis
The primary endpoint will be assessed as follows: unclear cases will be subjected to three diagnostic algorithms:
- Inhouse at referring site by histopathological diagnosis in the context of a hematological tumor board according to current standards
- Current gold-standard diagnostic workup as performed routinely by the MLL
- WGS and WTS sequencing plus matching to nearest digital sibling in 5,5k cohort
We will compare the accuracy for approach #3 for each patient/case by comparing the sequencing results with the therapy guiding approach in domo and Current gold-standard diagnostic workup as performed routinely by the MLL. Accuracy and overlap or discordance will be measured in percentage (%) of total cohort. Time Frame of Outcome: At diagnosis for each case/patient throughout the complete duration of study for approximately 1 year.
Measured: Time Frame of Outcome: At diagnosis for each case/patient throughout the complete duration of study for approximately 1 year.
Secondary outcomes (4)
turnaround time
Turnaround time until potential therapy guiding diagnosis will be measure and compared in days.
Measured: The time frame will be consisting of an assessment at diagnosis for next 14 days per case/patient.
actionable targets
The number of potential actionable targets will be determined for each case. We will assess this number in absolute numbers for each patient and for which a therapy has been approved but identification was missed in during classical gold standard diagnosis.
Measured: This outcome will be measured one year after diagnosis. (1 year after diagnosis)
disease stage
We will Identify the putative disease stage based on sequencing only approaches in comparison to normal gold standard diagnosis as well as clinical history. Results will be denoted as percentage (%) of correctly classified cases.
Measured: This outcome will be measured one year after diagnosis. (1 year after diagnosis)
Micro-cost analysis
We will measure all costs for respective assays and personnel to finally compare workflows 2 and 3 (see primary outcome 1.).
Measured: The estimated timeframe for this outcome will be the timepoint of diagnosis for each patient (approximately 5 days)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted16 Sep 2021
- Study start19 Jan 2022
- Primary completion31 Aug 2027 (estimated)
- Study completion1 Oct 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for LeukemiaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Case only
- Time perspective
- Prospective
- Enrolment
- 100 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Munich Leukemia Laboratory
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- Illumina, Inc.
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05046444
- Sponsor's protocol ID
- MLL_002
- Acronym
- SIRIUS
- Status last verified
- Oct 2026
- First submitted
- 22 Jul 2021
- Last updated
- 9 Oct 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 9 Oct 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Testing the Diagnostic Supremacy of Sequencing-only Approaches in Hematologic Malignancies: an Observational Trial
- ClinicalTrials.gov ID
- NCT05046444
- Acronym / sponsor ID
- SIRIUS / MLL_002
- Conditions
- Leukemia, Hematologic Malignancy, Rare Diseases, Refractory Leukemia, Refractory Lymphoma, Unknown Primary Tumors
- Study type
- Observational
- Recruitment status
- Recruiting
- Enrolment
- 100 participants (estimated)
- Lead sponsor
- Munich Leukemia LaboratoryIndustry (pharma, biotech, devices)
- Collaborators
- Illumina, Inc.
- Study start
- 19 Jan 2022 (actual)
- Primary completion
- 31 Aug 2027 (estimated)
- Study completion
- 1 Oct 2027 (estimated)
- First posted
- 16 Sep 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
During the last decades hematologists have excelled at improving and refining the classification, diagnosis, and thus ultimately the therapeutic decision-making process for their patients. This continuous evolution proceeded in parallel to seminal discoveries in basic science such as FISH, PCR and NGS. So far, the current WHO classification serves as reference to diagnostic decision making and is largely based on 5 diagnostic pillars: cytomorphology of peripheral blood and/or bone marrow smears, histology and immunohistochemistry of bone marrow trephine biopsies or lymph nodes, immunophenotyping, chromosome banding analysis supplemented by FISH analysis, molecular genetics including PCR and targeted panel sequencing via NGS. This leads to a swift diagnosis in 90 % of all cases. The leftover 10 % remain a challenge for hematopathologists and clinicians alike and are resolved through interdisciplinary teams in the context of specialized boards. With the advent of high throughput sequencing (mainly WGS and WTS) the possibility of a comprehensive and detailed portrait of the genetic alterations - specifically in challenging cases - has become a realistic alternative to classical methods. In SIRIUS the investigators will prospectively challenge this hypothesis to address the question of how often a better or final diagnosis can be delivered by WGS and/or WTS and if unclear cases can be efficiently resolved.
Detailed description
- Background and Rationale Treatment of hematological diseases relies on a single cardinal prerequisite: correct classification within the broad specter of malignant diseases arising from the hematopoietic system. With the ever-expanding availability of distinct yet complementary diagnostic tools, our understanding of the landscape of hematological diseases steadily increases. As such, the current consensus classification as summarized through the WHO classification (2017) represents a compass guiding diagnostic algorithms to the correct diagnosis. Today, the gold standard of routine diagnostic process relies on five methodological pillars: cytomorphology, histology, chromosomal cytogenetics, immunophenotyping, and molecular genetic testing. This leads to a treatment enabling diagnosis in the vast majority of cases. However, approximately 10 % of cases remain unresolved from a diagnostic point of view and hence do not lead to a satisfactory diagnosis according to current WHO standards (2017). The investigators intend to solve this issue to provide illuminating diagnostic guidance for the best possible patient´s care.
- Objectives To address this problem, the investigators hypothesize that novel high throughput sequencing methods, e.g., whole genome and/or whole transcriptome sequencing are able - by virtue of painting a more delicate genetic portrait of a tumor sample - to provide a more accurate diagnosis.
To this end the investigators generated a reference collection of 5,500 samples with the full spectrum of hematological malignancies, for which the investigators performed whole-genome sequencing as well as whole-transcriptome sequencing. Moreover, gold standard diagnoses according to WHO classification with all needed techniques, all performed in MLL, clinical data and therapy response data are fully available for these cases. The main advantage of this reference collection consists of the unambiguity of each diagnosis, providing a reference framework for any further classification and diagnosis especially in difficult cases.
Therefore, SIRIUS will compare the diagnostic superiority of WGS or WTS to the combined approach with gold standard results and by matching the obtained results to the nearest "digital sibling" within our reference cohort of more than 5,500 WGS and WTS (both in 93% of cases). To this end, the investigators will use an inhouse developed matching algorithm, which is able to match genomic or transcriptomic profiles to a group of similar cases and gold standard results from timepoint of this study. Current workflows intended to generate WTS/WGS data from patient samples - all while fulfilling state of the art accreditation (ISO 15189) - require up to 5 - 7 days. This is largely comparable to classical methods but holds the promise to replace error prone and arduous iterations in the methodological work up. The objective is to test whether WTS and/or WGS based approaches can surpass classical methods regarding diagnostic precision and routine reliability. Here the investigators will test this hypothesis in a prospective real-world setting under diagnostically difficult circumstances.
Study design
- Observational model
- Case only
- Time perspective
- Prospective
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Unclear diagnosis via conventional methods | – | Diagnostic Test: Next Generation SequencingThe study population consists of carefully chosen patients with potential hematological malignancy, for which current diagnostic methods were not sufficient to provide clear-cut diagnosis and definitive clinical guidance. SIRIUS will be conducted for a total number of 110 patients with inconclusive diagnosis by gold standard techniques for a total of up to nine months after the first enrollment. |
Who may qualify
- Ages
- 18 to 99 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- SIRIUS is conducted as a monocentric prospective case-control study. The study population consists of carefully chosen patients with potential hematological malignancy, for which current diagnostic methods were not sufficient to provide clear-cut diagnosis and definitive clinical guidance. SIRIUS is entirely a non-interventional study without therapeutic consequences for direct patient care.
Key inclusion criteria (10 listed)
- Patients having been investigated with a suspected hematological disorder and:
- Having unclear diagnosis after internal routine diagnosis
- Unusual clinical course
- Unusual r/r status or non-responder
- Multiple parallel hematological conditions
Key exclusion criteria (2 listed)
- Sample is not fit for state-of-the-art diagnosis, fails initial quality control. For quality insurance we will exclude samples with wrong anticoagulant sent. Samples with damage due to meteorological reasons (freeze-thaw damage or elevated temperature) will be excluded.
- Samples with to scarce material jeopardizing routine gold-standard diagnosis will be excluded (tumor content < 20 %).
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Next Generation SequencingAlso: NGS, Whole genome SequencingNON-Interventional Observation only study comparing sequencing-only approaches to classical diagnostic methods | Diagnostic test | Unclear diagnosis via conventional methods |
Primary outcome
sequencing only versus gold standard diagnosis
Time frame: Time Frame of Outcome: At diagnosis for each case/patient throughout the complete duration of study for approximately 1 year.
The primary endpoint will be assessed as follows: unclear cases will be subjected to three diagnostic algorithms: 1. Inhouse at referring site by histopathological diagnosis in the context of a hematological tumor board according to current standards 2. Current gold-standard diagnostic workup as performed routinely by the MLL 3. WGS and WTS sequencing plus matching to nearest digital sibling in 5,5k cohort We will compare the accuracy for approach #3 for each patient/case by comparing the sequencing results with the therapy guiding approach in domo and Current gold-standard diagnostic workup as performed routinely by the MLL. Accuracy and overlap or discordance will be measured in percentage (%) of total cohort. Time Frame of Outcome: At diagnosis for each case/patient throughout the complete duration of study for approximately 1 year.
4 secondary outcomes
turnaround time
Time frame: The time frame will be consisting of an assessment at diagnosis for next 14 days per case/patient.
actionable targets
Time frame: This outcome will be measured one year after diagnosis. (1 year after diagnosis)
disease stage
Time frame: This outcome will be measured one year after diagnosis. (1 year after diagnosis)
Micro-cost analysis
Time frame: The estimated timeframe for this outcome will be the timepoint of diagnosis for each patient (approximately 5 days)
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 9 Oct 2026.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Leukemia and Hematologic Malignancy, run by Munich Leukemia Laboratory at 1 site in Germany.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 10 inclusion and 2 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 9 Oct 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Germany. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Torsten Haferlach, MD (+49 (0)89 99017-100, torsten.haferlach@mll.com), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
sequencing only versus gold standard diagnosis (time frame: Time Frame of Outcome: At diagnosis for each case/patient throughout the complete duration of study for approximately 1 year.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 Oct 2026; AzTrials last refreshed its copy on 26 Oct 2026.