Leveraging Standardized MRD Assays to Guide CLL Treatment
Investigators from the United Kingdom National Cancer Research Institute published results from FLAIR: Front-Linetherapy in Chronic Lymphocytic Leukemia: Assessment of ibrutinib containing regimens: a randomized controlled
trial. The investigators found ibrutinib in combination with venetoclax induced significantly higher rates ofundetectable measurable residual disease (MRD) compared with fludarabine, cyclophosphamide, and rituximab(FCR) in patients with untreated chronic lymphocytic leukemia (CLL). This abstract was noted in the Best of ASH
2023 presentation and the results were simultaneously published in the New England Journal of Medicine. The
study’s primary outcome was progression-free survival defined as time from randomization to progressive diseaseor death from any cause was longer with ibrutinib-venetoclax (I+V) than with FCR in the overall population and inpatients with unmutated IGHV. These results should change first line therapy, from chemotherapy with anti-CD20
therapy, to a strategy of combining targeted inhibition of B-cell lymphoma 2 (Bcl-2) and Bruton’s tyrosine kinase(BTK) pathways. The four secondary endpoints of the study were: Overall Survival, MRD assessment, Responseto therapy (IWCLL criteria), Safety and Toxicity showed either noninferiority or benefit with the I+V arm. The
most common grade three to five adverse events occurring within one year after randomization were
neutropenia, anemia, and thrombocytopenia with marked lower events in the I+V group compared to theFCR cohort (10.3% vs 47.3%; 0.8% vs 15.5%; 2.0% vs 10.0%.).
Temporary stopping protocols lessen the risk for resistance and adverse events. Stopping interventions were
carefully followed with guided MRD results compared to arbitrary time points. MRD was assessed in theperipheral blood (PB) and bone marrow (BM) by highly sensitive multiparameter flow cytometry with a detection
limit of 1 CLL cell in 100,000 leukocytes (0.001%, 10-5). Following a standardized harmonized diagnostic strategy all
samples from the ninety-six hospitals were sent to a central laboratory (HMDS, Leeds). MRD was deemed to be
detectable if CLL-cells represented at least 0.01% of total blood or BM leukocytes and was undetectable-MRD(uMRD) if CLL cells represented less than 0.01% of 12 total blood or BM leukocytes. The first assessment was 9m
post-randomization (PB and BM) followed by PB assessment at 12m, then every 6m thereafter in I+V and every
12m in FCR (Figure S2, from supplement). 1
Most of the patients had durable remission (Figure 1) suggesting cure while five patients (5/260) restarted I+V andwere alive and progression free at the last follow up.

Ibrutinib and Venetoclax (Treated and Stopped Treatment)
Number of Subjects

300
250
200
150
100
50001215242736

39485160

63

Stopped Treatment

00065

111

126

135

144

145

146

146

Treatment Ongoing

256

243

241

158

106

74

60

251642Months
Figure 1: Estimates for I+V treatment stopping for attaining MRD stopping rules up to five years (+3m) post-randomization.1 This figure wasadapted from Table S7 of the Munir T. et al. publication in the New England Journal of Medicine.

What lessons can we take from the investigation?
This trial represents a triumph for individualized medicine based on knowledge of genomic architecture. CLL cells
proliferate through dysregulated B-cell receptor signaling and resistance to apoptosis due to increased
expression of Bcl-2 leading to accumulation of these cells causing tissue infiltration and resulting immune
dysfunction. Using a BTK inhibitor which blocks BCR signaling combined with venetoclax inhibition results in
profound CLL-cell apoptosis and potential cure.
Beyond the pharmaceutical breakthroughs the MRD sensitive assay guided rational intervention. Individualized
medicine using MRD defined the therapeutic duration which was double the time taken to achieve
undetectable MRD.
The investigators followed a wise strategy of bringing all testing of MRD samples to one institution. It speaks to thepower of standardization to ensure the same highly sensitive assay is performed for all patient’s samples
throughout the time of the study. Unlike many trials, ninety-six hospitals and their primary investigators agreed toparticipate in the trial throughout the UK and to send all the samples to one institution.

Cost Savings
The investigators, like many stakeholders, are keenly aware of the cost of targeted oncologic therapeutics. They
assessed cost-eﬀectiveness by means of the Short-Form 12 and EQ-5D to produce quality adjusted life years.
Health-related quality of life and cost eﬀectiveness is the subject of separate reports in preparation.

Our Solution
As per the American Cancer Society about 18,740 new cases of chronic lymphocytic leukemia (CLL) arediagnosed each year.2 Europe and Asia Pacific have similar newly diagnosed CLL patients. Invivoscribe, throughits wholly owned subsidiary, LabPMM, oﬀers an ultrasensitive MRD CLL assay with sensitivity and specificity
performance comparable to HDMS, Leeds. This assay can be performed throughout the world using an
optimized panel with standardized dried down reagents, artificial intelligence assisted interpretation, and final
interpretation and reporting by the same group of hematopathologists; the same team that worked with the flow
team to develop and validate the assay.

1

Munir T. et al., Chronic Lymphocytic Leukemia Therapy Guided by Measurable Residual Disease. N. Engl. J. Med. 2023. DOI:
10.1056/NEJMoa2310063
2

https://www.cancer.org/cancer/types/chronic-lymphocytic-leukemia/about/key-statistics.html