CLL Decisions
While the choice of therapy is rightly the major decision chronic lymphocytic leukemia (CLL) patients face, a close second might be about when to treat. A third, more “experimental” decision concerns what data should be used and when to stop treatment.
MRD Status to Guide CLL Therapy
Many clinical trials and new possible therapeutic approaches are challenging how we might use limited duration therapies based on MRD (measurable residual disease) status and other factors to decide best when to start, stop, continue, intensify, or change therapy by closely monitoring the disease. Some examples include:
- Clinical trials using limited-duration therapies based on MRD status are currently mostly venetoclax-based, but new BCL-2 inhibitors such as sonrotoclax are starting to be studied.
- In some trial designs, MRD is being studied to assess if it can guide when to stop, continue, or intensify these therapies.
- Early trials with bispecific T-cell engagers (BiTE), like the one I’m on with epcoritamab.
“The wheel’s still in spin,” but MRD testing increasingly influences our decisions.
I want to share my decision process in deciding when to start treatment and how biomarker testing helped me. To be clear, this is my approach. It is my N of 1 and not meant as a clinical guideline. It is based on a little data and more conjecture. It is also not the most common way MRD testing is being used today, namely guiding when to stop therapy.
My Last Two CLL Treatment Timing Decisions
I have already blogged extensively on my decision to have a first remission allogeneic (from a donor) hematopoietic (bone marrow) stem cell transplant in 2008 and my going to Columbus, Ohio State University for a Phase 1 trial of PCI-32765 (later named ibrutinib) in 2012 for my CLL. I won’t discuss that decision further here.
I will instead discuss how I decided it was time to switch from PCI-32765 to a CAR-T trial and later from CAR-T to epcoritamab.
In both cases, I was guided by next-generation sequencing (NGS) and MRD testing, not symptoms.
In the case of my relapse on ibrutinib, long before my CLL was clinically apparent, let alone clinically significant, I was found to have both a PCLƔ2 mutation that confers resistance to ibrutinib and a tiny but growing number of monoclonal CLL cells seen my flow cytometry in my still very average blood counts. This was not welcome news, but it did give me time to prepare and research my next move, my subsequent clinical trial. It also allowed me to monitor and plot the velocity of my malignant clone’s growth and its doubling time long before my absolute lymphocyte count was to rise. Graphing my counts proved surprisingly accurate in predicting when my cancer was starting to take off. It allowed me to get ahead of the curve, ready to jump quickly to CAR-T with the experimental JCAR-014, the grandparent to the recently approved liso-cel. I do believe one of the reasons I did so well with JCAR-014 is that I hit my CLL just as it started to accelerate. Immunotherapies do better when there is a lower disease burden.
NGS testing with clonoSEQ for uMRD Status
My response to my CAR-T was dramatic. Using a new NGS test, clonoSEQ (still experimental at that time, but subsequently approved), I was found at one month post-infusion of the modified T cells to have no CLL in my blood or bone marrow down to the level of one in a million cells or uMRD-6 (undetectable measurable residual disease). It stayed like that for more than two years on repeated clonoSEQ testing in both my blood and bone marrow. I was beyond thrilled and even entertained the idea that this might be the last therapy I would ever need.
But CAR-T, like nearly all other treatments for CLL, proved not to be curative for the vast majority of patients, me included.
My clonoSEQ graphed the story of my relapse. My CLL clone went from undetected to <1 per million, then 1 per million, then 4, then 17, then 50, then 123, then 422, then 1,877, and then it was time to treat. My CLL relapse was picking up speed. My lymphocyte count was still average, but it wouldn’t last long. It was clear what was happening. My CLL was taking off like a freight train heading down the mountain with no brakes.
If I was going to opt for an immune therapy, where the higher the ratio of the amount of drugs to the amount of cancer, the better, it was time to move.
Surprisingly, my flow cytometry tests remained negative until my count on clonocSEQ hit 1,888/1,000,000 or almost 1 in 500. It should be positive at anything over 1 in 10,000, so the two prior readings should have been positive. They weren’t, and I don’t know why.
One might argue I could have continued blissfully unaware, believing the dream that my CLL was not coming back for longer, remaining ignorant of the oncoming tsunami for almost two more years if I checked for MRD by only using flow cytometry, and for more than three years if I just followed my lymphocyte count. I understand that might be the right and perfectly acceptable choice for some, but not for me. The more data, the better. Knowing the velocity of my CLL’s growth gave me a heads-up that it was time to start planning my next move. I am driven by data and grateful that I track my cancer so tightly. Keep your friends close and your enemies closer.
As those who’ve read my blog know, I did opt early for a clinical trial of immune therapy, an experimental bispecific T cell engaging antibody (BiTE), epcoritamab, so once more, not waiting until my disease burden had exploded probably improved my odds of my excellent response. Six months into my trial, I am essentially uMRD-6 by clonoSEQ again in the peripheral blood. Thrilled but also wise to my hard-earned reality that uMRD is not the same as a cure. I am now waiting to see what my recent bone marrow biopsy shows in terms of MRD. While epcoritamab is usually taken continuously until disease progression or intolerance, it would be reassuring to know if I did need to stop for any reason that my disease had been driven below and stayed below the level of detection for a long time.
I have no doubts that MRD testing, especially MRD testing down to finding one in a million cancer cells, will emerge from its limited use in clinical trials and by the odd data-hungry patient like me into the clinic for general use in guiding CLL management at multiple decision points in the patient journey. It is already happening.
Stay strong. We are all in this together.
Brian
Brian Koffman MDCM (retired) MS Ed (he, him, his)
Co-founder, Executive VP, and Chief Medical Officer
CLL Society, Inc.
1: Bob Dylan: The times they are a changing.
