Episode 098: Understanding MRD Testing in CLL

Apr 3

Written By TheFellowOnCall HemeOncPodcast

With multiple options for frontline therapy in CLL, MRD has the potential to emerge as a factor that could be considered in our decision-making algorithm for sequencing treatment options.

In this week’s episode, we dive into a deeper understanding of the role of MRD testing in CLL.

What is MRD and role in CLL?

Traditionally referred to as “minimal” residual disease, but “measurable” residual disease is a more accurate term.
In patients with clinically undetectable disease, identification of a tiny clonal population of cancer cells through highly sensitive techniques.
Surrogate for depth of remission
Depth of remission can inform early treatment discontinuation in patients with CLL and inform prognosis.
Under investigation, and not validated to be used as a clinical decision-making tool for CLL.
Sustained MRD negative remission is more informative than a single time point of MRD results.
Possible role for general prognostication, but not validated.

What are the techniques to determine MRD?

Flow cytometry

First international consensus published in 2007.
Multi parametric flow cytometry assay
Must be ordered in real-time (not on archived samples- need live cells)
Looks for CD markers on CLL cells (can be performed any time during disease course), so original (diagnostic) samples not needed.
Sensitivity: MRD4 for 10^-4 (1 cell in 10,000) and MRD5 for 10^-5 (1 cell in 100,000)
In comparison, conventional cytology offers sensitivity of ~ 1/100.
European Research Initiative on CLL (ERIC) has validated reliable detection of CLL to MRD5 (2016).

Allele specific oligonucleotide (ASO) PCR: looks at uniquely rearranged immunoglobulin genes.
Since it’s a molecular technique, it requires patient specific primers and a representative pathologic sample for set up.
Not widely used in clinical practice.

Ultra-deep next generation sequencing is commonly used (ClonoSeq).
Amplifies V(D)J sequences from a single sample.
Need to have the CDR3 sequence expressed by the original CLL clone (need to send both diagnostic sample and post treatment sample)
Sensitivity of MRD5 or MRD6 (1 in a million)
Not standardized yet.
Expensive, send-out tests.

Ideal sample for MRD testing: Peripheral blood versus Bone marrow?

Concordance of about 85% between MRD4 for peripheral blood and bone marrow.
Peripheral blood testing is most used, more convenient, and saves patients a procedure (don’t typically need to perform bone marrow biopsy on a patient with CLL for diagnosis or even treatment response).
Some evidence suggests that concordance of MRD negativity between blood and bone marrow may be determined by type of treatment exposure. E.g., Rituximab can have higher rates of MRD positivity in bone marrow, despite being negative in blood. Obinutuzumab has more concordance.

What is the prognostic role of MRD testing?

Study from group in Leeds: all patients with MRD negative bone marrow had MRD negativity in blood, but nor vice versa. Also suggested that bone marrow MRD negativity is “more prognostic” than peripheral blood. These patients were naïve to treatment with novel agents such as BTK inhibitors or Venetoclax.

The same group also showed that MRD negativity in bone marrow, ameliorates the negative prognostic significance of adverse cytogenetics such as del17p, since these patients had improved survival compared to MRD positive without adverse cytogenetics.
Bottom line is that peripheral blood MRD negative testing has a very good prognosis and is more convenient to perform and spares our patients a procedure.

The paradigm of treatment selection based on MRD testing.

BTK inhibitors

Traditionally thought to work well, but don’t eradicate disease or put into deep remission.
MRD negativity in roughly 10 % patients.
For most patients on BTKi monotherapy, disease will progress after treatment discontinuation.
FLAIR study: suggests that subset of patients could be off treatment despite MRD status at end of treatment.

FLAIR study: FCR vs IR, FCR vs I alone, FCR vs IV

FCR was the continuously enrolled control arm, and 3 comparator arms were opened at different time periods.
FCR vs IR (Ibrutinib + Rituximab): IR for fixed duration of 6 years. Early data presented at iwCLL 2023 suggested that patients off therapy (IR) may do fine for at least 12 months regardless of MRD positivity.
Many of these patients will be enrolled on STATIC trial (phase 3 trial) to study intermittent versus continuous ibrutinib.
1. An important substudy randomization introduced in 2018 was randomization to I vs IV (Ibrutinib vs Ibrutinib+Venetoclax) for patients with del17p and/or TP53 mutation (important modifier since it does not make sense to give FCR to patients with these adverse risk factors).
In summary, patients on BTL inhibitor monotherapy may do well without achieving MRD negativity for the prolonged period. Need more data to demonstrate disease kinetics over time, and to see whether intermittent therapy approach may work.

There is an off-shoot of this study called the STATIC study where patients who completed 6 years of ibrutinib + venetoclax are being followed to understand if intermittent treatment with ibrutinib can be used to keep disease under control (as opposed to continuous therapy)

When looking at these patients off of therapy, there was early data presented at the international workshop on CLL in 2023 that showed many patients may do fine for at least 12 months off of therapy if if they are MRD4 positive

For MRD adapted treatment durations, these were not compared to simple fixed duration of therapy so we again don’t know if that fancy extra step of MRD testing actually matters

In the GAIA CLL 13 study, the authors tried to understand if adding more agents up-front results in better outcomes, with primary endpoint being MRD-negativity and PFS. In this study, the ventoclax+obinituzumab+/- ibrutinib arm had better PFS and MRD compared to chemoimmunotherapy (FCR), but with more toxicity.
In the modern era where FCR is not really used, hard to know how to interpret this data and implement MRD

Available data to guide dual combination regimen of BTKi and Venetoclax

Unanswered questions/Limitations:

Unclear whether combination vs. sequential therapies have different outcomes.
Many trials continue to use historical/outdated control arms e.g., FCR regimen.
Unclear if MRD adapted treatment durations offer benefit in terms of survival over fixed duration of treatment (not compared).
No evidence to guide re treatment based on MRD positivity.
MRD testing is still not standardized, not universally available, and not ready for prime time yet.

References:

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)60329-9/fulltext: Study comparing MRD negativity in bone marrow vs. peripheral blood specimens

https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(23)00144-4/fulltext: FLAIR study suggesting that BTKi are effective even if MRD is not achieved

https://cllsociety.org/2023/11/is-it-safe-to-stop-ibrutinib-therapy-for-cll-after-multiple-years/: Commentary on stopping ibrutinib after 6 years

https://www.nejm.org/doi/full/10.1056/NEJMoa2213093: GAIA CLL13 study looking at MRD and PFS

The crew behind the magic: