LymphomaNCT05702502
Assessing the Presence of CT-DNA in Lymphoma Associated HLH
An observational study of Lymphoma and Haemophagocytic Lymphohistiocytosis, run by Nottingham University Hospitals NHS Trust at 1 site in United Kingdom.
Trial summary
Haemophagocytic lymphohistiocytosis (HLH) is a rare life-threatening blood disease which causes severe inflammation with symptoms similar to severe sepsis. It is hard to diagnose. The most common cause of HLH in adults is lymphoma (blood cancer). Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Lymphoma, Haemophagocytic Lymphohistiocytosis
- How many people
- 12 participants
- Where
- 1 siteUnited Kingdom
- Study dates
- 30 Jun 2023to 1 Jan 2026
- 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 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Study population: Patients with HLH are usually unwell and hospitalised. Patients will be identified by the clinical (direct care) teams following a clinical diagnosis of HLH as part of routine clinical practice.
Who may be able to join
- Informed consent.
- Age ≥18 years.
- Clinically confirmed HLH.
- High dose steroids and/or systemic anti-cancer therapy (SACT) for <72 hours for the current episode of HLH (anakinra is not considered SACT). Prior steroid use >14 days at the time of consent is permitted.
- Patients with recurrent HLH may be included.
- Patients already known to have underlying lymphoma, or have relapsed lymphoma may be included.
Who cannot join
- Cause of HLH already known to be due to a non-malignant cause.
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
United Kingdom1 site, 1 recruiting
- Recruiting
Nottingham Univeristy Hospitals NHS Trust
Nottingham, Nottinghamshire, NG7 2UH
Mark Bishton, 0115 924 9924 ext. 80755, markbishton@nhs.net
About this study
Official title: Liquid Biopsy for the Identification of Malignancy Associated Haemophagocytic Lymphohistiocytosis (HLH)
Haemophagocytic lymphohistiocytosis (HLH) is a rare life-threatening blood disease which causes severe inflammation with symptoms similar to severe sepsis. It is hard to diagnose. The most common cause of HLH in adults is lymphoma (blood cancer). Outcomes for adults with HLH and cancer are serious, and most die after days or weeks because they have been diagnosed or treated too late. It is likely that many cases where patients died of HLH with no underlying cause actually had cancer.
Recently it has been found that patients with certain types of lymphoma have DNA which comes directly from their cancer (circulating tumour DNA; ctDNA). Aggressive lymphomas release a lot of ctDNA which can be detected in the blood of patients. This study will look for ctDNA in patients with HLH, and see if it is possible to use it to diagnose lymphoma earlier. Patients will provide a small additional blood sample for analysis. Diagnosing lymphoma more rapidly would mean more people could get the correct treatment for the lymphoma which has caused their HLH. They could receive the correct treatment sooner. Earlier diagnosis and treatment could improve survival for these patients.
Read the detailed description
A variety of constitutive and acquired risks trigger HLH. In general, infants have inherited T- and NK-cell defects impairing cytotoxic function, while adults are most likely to suffer from lymphoma, most commonly diffuse large B cell lymphoma (DLBCL), Hodgkin lymphoma and T-cell lymphoma. Patients with underlying lymphoma have the worst survival rates (West et al J Intern Med 2021). Diagnosis of lymphoma is challenging due to severe sepsis-like presentation, meaning CT-PET and early biopsy may not be possible. Patients with delayed/no diagnosis frequently receive empirical chemotherapy, delaying diagnosis, inadequately treating underlying lymphoma and potentially worsening infections. Epidemiological studies have failed to show improvements in survival in patients with HLH, whilst also confirming a significant increase in the number of diagnoses (West et al J Intern Med 2021). Improvements in rapidly diagnosing cases of lymphoma driving HLH would result in better outcomes due more rapid (immuno-)chemotherapy administration.
Circulating tumour DNA (ctDNA) are DNA isolated from blood, originating from the apoptosis/necrosis of cancerous cells. ctDNA reflects the entire tumour genome and is referred to as a "liquid biopsy". These techniques are under investigation in several lymphomas, and DLBCL-specific mutations can be detected and quantified using ctDNA, with studies using quantification as a strategy to monitor response to therapy (Kurtz et al J Clin Onc 2018). Similarly, ctDNA mutations can be identified in Hodgkin lymphoma (Spina et al Blood 2018) and T-cell lymphoma (Ottolini et al Blood advances 2020).
Capitalising on the success of the DLBCL Interim Response Evaluation for Customised Therapy (DIRECT) study, existing infrastructure in Cambridge will be used to conduct a feasibility study assessing whether ctDNA from patients with HLH with underlying lymphoma is viable in contributing to diagnoses. Blood samples from patients with HLH will have ctDNA and granulocytes extracted and stored. Once lymphoma is confirmed, the biopsy will be requested and ctDNA, granulocytes and biopsy from each patient will be interrogated using shallow whole genome sequencing (WGS; 0.1x) and a high-sensitivity, targeted sequencing panel termed LyVE-Seq (~2000x). This panel includes coding regions of 122 genes implicated as drivers of DLBCL, in addition to translocation hotspots for BCL6/MYC. For non-DLBCL, the existing panel will be modified to include 150 genes recurrently mutated across all lymphoma subtypes, ordered as a focused panel from Twist Bioscience.
Demographic/laboratory data will be requested and will be integrated with information from clinical risk scores, tumour genotype, and radiology (CT/PET-CT). These invaluable clinical samples will be stored and may be used for future research as, to date, there is no data for ctDNA in the context of malignancy associated HLH and the study is highly exploratory.
- Conditions
- Lymphoma, Haemophagocytic Lymphohistiocytosis
- Medical subject headings
- Lymphoma, Lymphohistiocytosis, Hemophagocytic
What is being measured
The primary outcome is the main question the study is designed to answer.
Identification of lymphoma-specific mutations in ctDNA from patients with lymphoma driven HLH.
For those patients found to have lymphoma driven haemophagocytic syndrome we will assess whether we can find the presence of cell free tumour DNA in blood.
Measured: Up to 2 years
Secondary outcomes (2)
Assess the utility of integrated data from clinical risk factors (IPI), up-front genotype, and radiological assessment (CT or PET-CT) with ctDNA findings.
We will use clinical, radiological and tumour mutation status to see if there is any correlation with the detection of cell free tumour DNA.
Measured: Up to 2 years
Assessing the feasibility of returning central laboratory data in a clinically useful timeframe.
Provided the primary outcome is successful we will see if the finding of cell free tumour DNA can be used as a clinical test to identify lymphoma in patients with HLH,
Measured: Up to 2 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 Jan 2023
- Study start30 Jun 2023
- Primary completion1 Jan 2026 (estimated)
- Study completion1 Jan 2026 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for LymphomaStudies 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
- 12 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Nottingham University Hospitals NHS Trust
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05702502
- Sponsor's protocol ID
- 22CH022
- Status last verified
- Apr 2025
- First submitted
- 28 Sep 2022
- Last updated
- 8 Apr 2025
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 8 Apr 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Liquid Biopsy for the Identification of Malignancy Associated Haemophagocytic Lymphohistiocytosis (HLH)
- ClinicalTrials.gov ID
- NCT05702502
- Acronym / sponsor ID
- 22CH022
- Conditions
- Lymphoma, Haemophagocytic Lymphohistiocytosis
- Study type
- Observational
- Recruitment status
- Recruiting
- Enrolment
- 12 participants (estimated)
- Lead sponsor
- Nottingham University Hospitals NHS TrustUniversity, hospital or other
- Study start
- 30 Jun 2023 (actual)
- Primary completion
- 1 Jan 2026 (estimated)
- Study completion
- 1 Jan 2026 (estimated)
- First posted
- 27 Jan 2023 (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.
Haemophagocytic lymphohistiocytosis (HLH) is a rare life-threatening blood disease which causes severe inflammation with symptoms similar to severe sepsis. It is hard to diagnose. The most common cause of HLH in adults is lymphoma (blood cancer). Outcomes for adults with HLH and cancer are serious, and most die after days or weeks because they have been diagnosed or treated too late. It is likely that many cases where patients died of HLH with no underlying cause actually had cancer.
Recently it has been found that patients with certain types of lymphoma have DNA which comes directly from their cancer (circulating tumour DNA; ctDNA). Aggressive lymphomas release a lot of ctDNA which can be detected in the blood of patients. This study will look for ctDNA in patients with HLH, and see if it is possible to use it to diagnose lymphoma earlier. Patients will provide a small additional blood sample for analysis. Diagnosing lymphoma more rapidly would mean more people could get the correct treatment for the lymphoma which has caused their HLH. They could receive the correct treatment sooner. Earlier diagnosis and treatment could improve survival for these patients.
Detailed description
A variety of constitutive and acquired risks trigger HLH. In general, infants have inherited T- and NK-cell defects impairing cytotoxic function, while adults are most likely to suffer from lymphoma, most commonly diffuse large B cell lymphoma (DLBCL), Hodgkin lymphoma and T-cell lymphoma. Patients with underlying lymphoma have the worst survival rates (West et al J Intern Med 2021). Diagnosis of lymphoma is challenging due to severe sepsis-like presentation, meaning CT-PET and early biopsy may not be possible. Patients with delayed/no diagnosis frequently receive empirical chemotherapy, delaying diagnosis, inadequately treating underlying lymphoma and potentially worsening infections. Epidemiological studies have failed to show improvements in survival in patients with HLH, whilst also confirming a significant increase in the number of diagnoses (West et al J Intern Med 2021). Improvements in rapidly diagnosing cases of lymphoma driving HLH would result in better outcomes due more rapid (immuno-)chemotherapy administration.
Circulating tumour DNA (ctDNA) are DNA isolated from blood, originating from the apoptosis/necrosis of cancerous cells. ctDNA reflects the entire tumour genome and is referred to as a "liquid biopsy". These techniques are under investigation in several lymphomas, and DLBCL-specific mutations can be detected and quantified using ctDNA, with studies using quantification as a strategy to monitor response to therapy (Kurtz et al J Clin Onc 2018). Similarly, ctDNA mutations can be identified in Hodgkin lymphoma (Spina et al Blood 2018) and T-cell lymphoma (Ottolini et al Blood advances 2020).
Capitalising on the success of the DLBCL Interim Response Evaluation for Customised Therapy (DIRECT) study, existing infrastructure in Cambridge will be used to conduct a feasibility study assessing whether ctDNA from patients with HLH with underlying lymphoma is viable in contributing to diagnoses. Blood samples from patients with HLH will have ctDNA and granulocytes extracted and stored. Once lymphoma is confirmed, the biopsy will be requested and ctDNA, granulocytes and biopsy from each patient will be interrogated using shallow whole genome sequencing (WGS; 0.1x) and a high-sensitivity, targeted sequencing panel termed LyVE-Seq (~2000x). This panel includes coding regions of 122 genes implicated as drivers of DLBCL, in addition to translocation hotspots for BCL6/MYC. For non-DLBCL, the existing panel will be modified to include 150 genes recurrently mutated across all lymphoma subtypes, ordered as a focused panel from Twist Bioscience.
Demographic/laboratory data will be requested and will be integrated with information from clinical risk scores, tumour genotype, and radiology (CT/PET-CT). These invaluable clinical samples will be stored and may be used for future research as, to date, there is no data for ctDNA in the context of malignancy associated HLH and the study is highly exploratory.
Study design
- Observational model
- Case only
- Time perspective
- Prospective
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- Patients with HLH are usually unwell and hospitalised. Patients will be identified by the clinical (direct care) teams following a clinical diagnosis of HLH as part of routine clinical practice.
Key inclusion criteria (6 listed)
- Informed consent.
- Age ≥18 years.
- Clinically confirmed HLH.
- High dose steroids and/or systemic anti-cancer therapy (SACT) for <72 hours for the current episode of HLH (anakinra is not considered SACT). Prior steroid use >14 days at the time of consent is permitted.
- Patients with recurrent HLH may be included.
Key exclusion criteria (1 listed)
- Cause of HLH already known to be due to a non-malignant cause.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
Identification of lymphoma-specific mutations in ctDNA from patients with lymphoma driven HLH.
Time frame: Up to 2 years
For those patients found to have lymphoma driven haemophagocytic syndrome we will assess whether we can find the presence of cell free tumour DNA in blood.
2 secondary outcomes
Assess the utility of integrated data from clinical risk factors (IPI), up-front genotype, and radiological assessment (CT or PET-CT) with ctDNA findings.
Time frame: Up to 2 years
Assessing the feasibility of returning central laboratory data in a clinically useful timeframe.
Time frame: Up to 2 years
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 8 Apr 2025.
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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.
Nottingham Univeristy Hospitals NHS Trust
Nottingham, United Kingdom
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 Lymphoma and Haemophagocytic Lymphohistiocytosis, run by Nottingham University Hospitals NHS Trust at 1 site in United Kingdom.
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 6 inclusion and 1 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 8 Apr 2025. 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 United Kingdom. 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?
Each site lists its own contact: choose the nearest one under Trial locations. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Identification of lymphoma-specific mutations in ctDNA from patients with lymphoma driven HLH. (time frame: Up to 2 years). 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 8 Apr 2025.