Clinical Trial Details
— Status: Not yet recruiting
Administrative data
NCT number |
NCT05702502 |
Other study ID # |
22CH022 |
Secondary ID |
|
Status |
Not yet recruiting |
Phase |
|
First received |
|
Last updated |
|
Start date |
April 1, 2023 |
Est. completion date |
January 1, 2026 |
Study information
Verified date |
January 2023 |
Source |
Nottingham University Hospitals NHS Trust |
Contact |
n/a |
Is FDA regulated |
No |
Health authority |
|
Study type |
Observational
|
Clinical 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). 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.
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.