I am currently receiving Bendamustine/Gazyva for del 11q CLL. My response to BG has been very good and four cycles could be sufficient for initial therapy. What lab tests are needed to indicate CR, PR MRD(-) etc.. My absolute lymphocyte count (ALC) was less than 1 after the 3rd cycle. Also, when to you assess possible clonal evolution, Richter’s transformation and what tests are needed?
The response assessment should include a CBC, CT scan, and a bone marrow biopsy if no evidence of disease in the peripheral blood or lymph nodes. I often don’t perform the bone marrow biopsy unless it would change therapy. The use of MRD is a surrogate that could be used, but it has to be remembered that it is possible to have MRD negativity in the peripheral blood, but still have disease in the marrow.
The assessment of clonal evolution would occur at the time of relapse, when the relapsing cells are assessed for changes in their characteristics. The same is true for Richter’s syndrome, where we will see clinical progression that is unexpected for CLL.
What does remission look like in the bone marrow, via CT scan and in the results of a complete blood count (CBC)? What determines PR, CR and/or MRD(-)?
Remission is when there is no evidence of CLL in the bone marrow, CBC, and CT scans. The review of the bone marrow would be normal, with no aggregates of CLL. This is what we would call a complete response (CR). Anything more, but less than when you started, would be a partial response (PR). MRD negativity means that using very sensitive techniques, they were unable to find any CLL. This means a level of 1 out of 10,000 cells, which is far lower than what we might see with standard techniques.
You have said in a video interview that you prefers ibrutinib frontline unless high-risk CLL is present. Would young and fit unmutated gene 11q del relapse from BR 2year+ be considered to need more than mono therapy ibrutinib?
In general, I would consider deletion 11q, deletion 17p, NOTCH1 mutations, and any response to chemotherapy that is short as high risk. I would still use ibrutinib in these circumstances. The issue is that the Progression Free Survival falls to 40% and 20% at five years for del11q and del17p patients who are relapsed and treated with ibrutinib. I currently use venetoclax plus ibrutinib on trial or might use ibrutinib plus obinutuzumab.
Can you explain why a person with CLL who develops diffuse large B-Cell lymphoma (DLBCL) is diagnosed with “Richter’s Transformation”, even if it is not clonally related? Why wouldn’t this person be considered “de novo DLBCL” and thus have more a more favorable prognosis?
The term Richter’s transformation was coined long before we had the knowledge of clonal relatedness or the ability to test for it. Richter’s transformation does mean the presence of a large cell lymphoma developing in a patient who had pre-existing CLL. We now know that some of these large cell lymphoma develop from the CLL cells (clonally related), while others develop from B cells that are not CLL B cells (clonally unrelated). The clonally unrelated and large cell lymphoma developing in someone without prior CLL could both be called de novo diffuse large B cell lymphoma. De novo diffuse large cell lymphoma likely has the same prognosis when they arise in a patient with CLL or a patient without CLL. There are other factors which will impact upon prognosis, not related to the large cell clone itself. Most significantly is the ability of the patient to receive chemotherapy for the large cell lymphoma. If a CLL patient has a great deal of marrow involvement with CLL or has received prior chemotherapy, their ability to receive the treatment for the large cell lymphoma might be lessened, and this would impact on outcome.
Can you tell me what the experience has been with progression from CLL to Richter’s to aggressive lymphoma and the prognosis using a mini stem cell transplant vs Ibrutinib?
Ibrutinib does not have significant activity in Richter’s transformation, while mini-allogeneic transplants are effective in eligible patients.
I have been taking ibrutinib and have bruising on my arms, I know this may seem minor but I find it very distressing. Can anything be done about skin issues associated with ibrutinib?
Unfortunately, there is not much that can be done to alleviate the bruising except avoiding other agents that impact platelet function. There is some data that the bruising is dose related, but it would be extremely important to not be under dosed and lose effectiveness. There are also data suggesting that as the CLL diminishes, the bone marrow is able to compensate and generate larger platelets which are more active.
Richard Furman, MD is Director of the CLL Research Center at Weill Cornell Medical College and a member of the Lymphoma/Myeloma Service in the Division of Hematology/Oncology. He is a member of the Medical Advisory Board for the CLL Society.