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Dr. Bill Wierda out of MDACC leads their chronic lymphocytic leukemia team in Houston TX.
At ASH 2018 in San Diego, we talked about the re-emergence of the importance of U-MRD (undetectable minimal residual disease) as a tool in CLL care.
- U-MRD is defined as not finding any CLL cells down to a level of one in 10,000 cells (U-MRD4)
- This is usually done by flow cytometry (FC). That is the same method used to diagnose CLL. It looks for markers on the surface of the cells that say it is a CLL cell.
- MRD testing by FC is a well standardized test in the community now.
- There are other methods to look for even lower levels of cancer using PCR (polymerase chain reaction) and NGS (next generation sequencing) that looks for cancer specific DNA that can find one cell in 100,000 (U-MRD5) or even one in a million (U-MRD6). These are generally not clinical available and mostly used in clinical trials.
- U-MRD used to called MRD negative, but that name was confusing and might falsely imply there was no cancer left. There may or may not be cancer, but whatever is left is below our ability to detect it.
- With chemo-immunotherapy (CIT), especially FCR (fludarabine, cyclophosphamide and rituximab), achieving U-MRD for chronic lymphocytic leukemia patients is associated with better outcomes. This is important in making more accurate predictions for the 70% of patients that achieve CR (complete remission) with FCR when used frontline. It’s true with other CITs too. This is well illustrated in references linked below.
- With the advent of ibrutinib and other BCR blockers, it became possible to well manage CLL very long term without ever reaching U-MRD, so it became less important, but this necessitates taking the meds until progression or intolerance.
- The pendulum is swinging back with the new oral BCL2 inhibitor, venetoclax, alone or in combination that can achieve very deep remissions and be stopped. It turns out those with the deepest remissions do the best.
- MRD can be used several ways (thanks to Deborah Stephens for organizing this:
- It’s as already a prognostic marker that predicts how long the remission might last.
- It’s as a biomarker for decisions about therapy. In the future will MRD status direct when we start and stop therapy?
- It’s a possible replacement for assessing clinical or radiologic responses. CRs can be subjective when measuring lymph nodes. Imaging and palpation techniques can vary. The difference between a 1.6 cm. and a 1.5 cm. lymph node can be the difference between being in a partial (PR) versus a complete remission (CR). U-MRD might be more objective, and more important in planning for and understanding disease progression.
- And finally, while it is too early to make this claim, there is accumulating evidence that MRD could be used as a surrogate marker for progression free and overall survival.
MRD is not important if you are taking ibrutinib but it has been proven to be very important for those choosing CIT and probably also for venetoclax alone and in combinations. U-MRD is also predictive of duration remission for CLL patients such as me who have had CAR-T therapy.
I have always said that you can get to cure without first passing U-MRD. That is increasingly looking to be the case.
Here is my Interview with Dr. Wierda from ASH 2018.
There are many abstracts that address MRD status in chronic lymphocytic leukemia.
Here are three on CIT in CLL:
Undetectable-Minimal Residual Disease (U-MRD6) (10-6 sensitivity) Is Associated with Best Progression-Free Survival for Patients Who Achieve Bone Marrow Undetectable MRD4 (10-4sensitivity) with First-Line FCR
Here are a couple on venetoclax including the one that Dr. Wierda references:
I like the direction of this research.