ASH 2020: Day 2 Updates
The CLL specific oral sessions today were on the biology and, frankly, while extremely important, were often complex, requiring a significant background in cell biology, pharmacology, and immunology
There were also two interesting oral sessions on “outcome results”, one specific to CLL that showed that ibrutinib outperformed CIT (chemoimmunotherapy) in the real world and not just in clinical trials, and one on phase I trials across multiple blood cancers that documented how unusual it was to have such high response rates as was seen with the BTKis such as ibrutinib.
And of course, these sessions overlapped each other.
There were also several extremely interesting posters, including at least 3 on frontline use of ibrutinib in high-risk CLL- bottom line, it works well, but we need to find ways to do even better, and 2 more on combinations of I+V (ibrutinib + venetoclax), this time, with one trial that used venetoclax first, followed by ibrutinib, and the other that did it in the reverse order, both with very significant success.
These news snapshots are meant to whet your appetite. More details in the days and weeks to follow.
Let’s start with some posters.
Here is one that caught my interest, presented by a radiologist and not a hematologist, Jayant Narang, MD: The Clinical Relevance of Residual, Persistent and Elongated Abnormal Sized Nodes By Longest Diameter (LDi) in Patients (pts) with Chronic Lymphocytic Leukemia (CLL), Otherwise in a Complete Remission (CR).
I am part of the 13.8% of patients that are classified as having a partial remission after my CAR-T treatment because one of my lymph nodes never shrank back to normal, as its longest axis stayed > 15 mm, creating a skinny, but by stringent criteria, abnormal node. He argues that these patients with everything else normal should be classified as having a complete remission (CR) and I agree. And the data support us.
Another poster was from the ICICLE trial (Ibrutinib and Obinutuzumab in CLL: MRD (measurable or minimal residual disease) Responses Sustained for Several Years with Deepest MRD Depletion in Patients with 1 Year Prior Ibrutinib Exposure) by Andy Rawstron from Leeds showing that adding obinutuzumab to patients taking ibrutinib not only deepened remissions but lead to durable uMRD (undetectable MRD) remissions lasting several years in some cases, especially when the obinutuzumab is added in after one year on ibrutinib. This may be because ibrutinib is great at getting the CLL out of the nodes into the blood, while obinutuzumab is particularly good at cleaning out the CLL that is in the blood and marrow, and does even better when the disease burden has been diminished by a year of taking ibrutinib.
Now let’s cover some basic science highlights from Saturday’s 1st oral session:
CLL: Biology and Pathophysiology, excluding Therapy: Treatment Resistance and Prognosis
Hold onto your hats. This gets complicated.
The first talk was by Dr. Aaron Lipsky from Weill Cornell Medical titled Single-Cell Multi-Omics Reveals Distinct Paths to Survival of Admixed BTK C481 Mutant Vs. Wild-Type Cells in Clinically Progressing Chronic Lymphocytic Leukemia.
Here is the problem he set out to solve. Folks on ibrutinib have CLL progress when less than 10% of the cancer cells have the mutation at C481 that prevents ibrutinib from binding and blocking the B cell receptor (BCR). On its surface, that makes no sense.
First the technical challenges in studying this were enormous. His lab developed tools that allowed him to interrogate single cells so that he could separately measure gene expression in the resistant cancer cells with mutated C481 and from the majority of cells that were “wild type”, meaning they were not mutated. Only with this sophisticated lab technology, was it possible to begin to tease out the answers. It’s complicated, but it appears that the 10% are a bad influence on the 90% (please note in the video monologue I mistakenly said 80%) making them less sensitive to ibrutinib.
Now it really gets interesting. The research suggests that they do this, not by preventing ibrutinib interrupting B cell signaling, but by their effects on the micro-environment that engages other pro-survival signals (NOTCH-1 and IL-4) that make up for the lack of B cell signaling.
Another biology talk was B-CLL Mediated Resistance to CAR T Cell Therapy Via Insufficient Activation Is CAR-Independent from McKensie Collins, BS at U Penn who showed the reason for CAR-T failure is not only from our “exhausted” T cell profile, but the CLL cells themselves may insufficiently stimulate CAR-T cells to expand and attack. This has important implications on how to rev up the response rate for CAR-T cell therapy.
The final one I will discuss was presented by Dr. Clive Zent from Wilmot Cancer Center U. of Rochester: Ibrutinib Off-Target Inhibition Inhibits Antibody-Dependent Cellular Phagocytosis but Not Efferocytosis of CLL Cells.
Don’t run away. I will keep it simple: Dr. Zent explains why ibrutinib therapy does not seem to benefit from the addition of rituximab, which does work to deepen responses when added to venetoclax. He believes it is due to the “off-target” effects of ibrutinib on other kinases or enzymes besides BTK that interfere with not just rituximab, but many other monoclonal antibodies. In other words, ibrutinib blocks more than BTK and this has some risks and benefits associated with it. The take-away is that this may not be the case with newer generation BTKis such as acalabrutinib and zanabrutinib.
Tomorrow there will be less basic science and more clinical results.
Thanks for listening.
Stay strong. We are all in this together.
Brian Koffman, MD