Transcript: Matthew S. Davids, MD, MMSc: So we’ve been fortunate in CLL to have had effective therapies over the last several decades, including chemotherapy initially and then chemoimmunotherapy. But what’s really changed in CLL over the last 5 or so years is an increased understanding of the biology of the disease. This has actually led to the development of several new drugs that are targeted agents that actually attack the disease at various functional nodes including the B-cell receptor pathway, as well as the BCL2 pathway, as well as the development of newer CD20 monoclonal antibodies. So I think this new understanding of the disease has led to major therapeutic advances and actually allowed us to treat patients more effectively with less toxic agents.
So the indications for CLL have actually been developed over the last few decades and in the recently updated International Workshop guidelines have not changed. Those treatment indications broadly include patients who are having progressive cytopenias, either anemia or thrombocytopenia, due to bone marrow infiltration by CLL; patients who have bulky organ-threatening lymphadenopathy; or patients who are having significant progressive constitutional symptoms, including B symptoms—and the key for that is that they have to be attributed to CLL. So often we have patients who have fatigue but don’t have other signs of progressive disease, and often we can identify another cause of fatigue, and so that’s not usually a reason on its own to treat CLL.
The most important factor that we consider when deciding on initial therapy for CLL patients is the mutational status of TP53. Either deletion 17p by FISH [fluorescence in situ hybridization] or a TP53 mutation by sequencing leads us to recommend novel agent therapy and, in particular, ibrutinib. Outside of the 17p setting, there are a number of different options that we have for our patients, including chemoimmunotherapy; we have ibrutinib, and then we have more gentle chemotherapy regimens like chlorambucil with obinutuzumab. And to make those decisions, we think about a number of different factors, including the age of the patient, what their specific medical comorbidities might be, and then, importantly, the IGHV mutation status.
And when patients have a mutated IGHV gene, they can often enjoy very long remissions after chemotherapy, and so we often will think about that approach for the mutated IGHV patients. However, patients with the unmutated IGHV gene typically have a very short remission from chemoimmunotherapy, and those are patients now where we consider ibrutinib as a new standard of care.
So clearly, for patients with high-risk cytogenetics—meaning deletion 17p or TP53—ibrutinib is the current standard of care. I think that for patients with unmutated IGHV, based on the data that we’ve seen now at the ASH [American Society of Hematology] meeting from both the Alliance trial and the ECOG[-ACRIN] trial, in both older patients and younger patients with that subgroup…the ibrutinib therapy should now be considered a new standard of care. I think where there still is some controversy is for patients with the mutated IGHV gene, where they also can do very well with ibrutinib, but it requires ongoing continuous therapy, and we know that patients who get chemoimmunotherapy who have mutated IGHV can also do quite well, often with just a 6-month course of therapy.
Transcript Edited for Clarity