Solving Riddles Through Sequencing

NCT05046444 | Recruiting DMC

• 1 other identifier: MLL_002
• Study Type: observational
• Target: 100
• Locations: 1 country
• Sites: 1

Brief 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. 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.

Conditions

Leukemia; Hematologic Malignancy; Rare Diseases; Refractory Leukemia; Refractory Lymphoma; Unknown Primary Tumors

Outcome Measures

Primary Outcomes (1)

• sequencing only versus gold standard diagnosis

  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.

  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

  The time frame will be consisting of an assessment at diagnosis for next 14 days per case/patient.

• actionable targets

  This outcome will be measured one year after diagnosis. (1 year after diagnosis)

• disease stage

  This outcome will be measured one year after diagnosis. (1 year after diagnosis)

• Micro-cost analysis

  The estimated timeframe for this outcome will be the timepoint of diagnosis for each patient (approximately 5 days)

Study Arms (1)

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.

Diagnostic Test: Next Generation Sequencing

Interventions

Next Generation Sequencing DIAGNOSTIC_TEST

NON-Interventional Observation only study comparing sequencing-only approaches to classical diagnostic methods

Also known as: NGS, Whole genome Sequencing

Unclear diagnosis via conventional methods

Eligibility Criteria

• Age: 18 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

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.

You may qualify if:

• 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
• 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

You may not qualify if:

• 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 %).

Sponsors & Collaborators

• Munich Leukemia Laboratory: lead
• Illumina, Inc.: collaborator

Study Sites (1)

MLL Munich Leukemia Laboratory

Munich, Germany

RECRUITING

Biospecimen

Retention: SAMPLES WITH DNA

Peripheral blood smears for morphology and/or peripheral blood or bone marrow for immunophenotyping from all hematological malignancies recognized by current WHO classification (Swerdlow et al. 2017)

MeSH Terms

Conditions

Leukemia; Hematologic Neoplasms; Rare Diseases; Lymphoma; Neoplasms, Unknown Primary

Condition Hierarchy (Ancestors)

Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Neoplasms by Site; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Neoplasm Metastasis; Neoplastic Processes

Central Study Contacts

Torsten Haferlach, MD

CONTACT

+49 (0)89 99017-100; torsten.haferlach@mll.com

Adam Wahida, MD

CONTACT

004917664982845; adam.wahida@tum.de

Study Design

• Study Type: observational
• Observational Model: CASE ONLY
• Time Perspective: PROSPECTIVE
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 22, 2021
• First Posted: September 16, 2021
• Study Start: January 19, 2022
• Primary Completion: August 31, 2025
• Study Completion (Estimated): October 1, 2026
• Last Updated: December 17, 2024

Record last verified: 2024-12

Data Sharing

• IPD Sharing: Will not share

Locations

DE (1)