This is my report from the third day of ASH 2021, the 63rd American Society of Hematology Annual Conference and Exhibition. This year is a hybrid meeting being held live in Atlanta, Georgia, and streamed virtually around the world.
Today there were another six oral/clinical CLL abstracts. This will be the “Cliff’s Notes” version of what we have learned. The first two abstracts were on CLL patients’ responses to the mRNA vaccines for COVID-19.
The first abstract from France showed that our COVID-19 antibody responses were mostly suboptimal, and zero if treated with anti-CD20 monoclonal antibodies (such as rituximab or obinutuzumab). Of all the treatments, venetoclax had the least impact on COVID-19 antibody responses in those with CLL.
The only sure way that someone with CLL can make antibodies was to become infected with COVID-19 and then get vaccinated. Every patient with this scenario mounted an antibody response to the vaccine. A third dose was helpful to those who had any measurable response to the first two doses (even if the response was a weak one). However, if there was zero antibody response after the first two doses of the vaccine, getting a third dose only resulted in one out of five (20%) having an antibody response.
From the Israel abstract, we learned that the T cell response (cellular immunity) to COVID-19 mRNA vaccines was also not great. And the T cell response to the vaccine was correlated with the antibody response (humoral immunity). Less than one-third of CLL patients had a positive T cell response. The good news was that one in four patients who had zero detectable COVID-19 antibodies did have some T cell response after being vaccinated. So vaccines may still provide some level of protection to 25% of those who get their antibodies checked and find that the results are zero.
The Alliance trial updated its results and offered no surprises when comparing bendamustine and rituximab (BR) to ibrutinib-based therapy in frontline therapy for patients over 65 years old.
- Ibrutinib with or without rituximab still had more favorable PFS (progression-free survival) than BR in all subgroups.
- Adding rituximab to ibrutinib added no benefit.
- Rates of hypertension and atrial fibrillation rose over time in the ibrutinib arms.
- BR patients had more secondary cancers.
Next: Adding ibrutinib to Fludarabine, Cyclophosphamide, Rituximab (iFCR) in fit young patients for 40 months lead to impressive results: PFS in 97%, and OS (overall survival) in 99%.
Remarkably, 84% reached uMRD (undetectable measurable disease) in the bone marrow. The downside: Other secondary blood cancers arose in 2.4%, likely due to the FCR.
The preliminary results of a trial comparing ibrutinib + venetoclax (IV) to FCR at nine months showed a largely meaningless result of higher uMRD in the FCR arm. But that will likely change over time as responses deepen in the IV arm, and wane in the FCR arm. Again, FCR was associated with higher rates of second blood cancers.
Finally, the FLAIR trial showed that IR was superior to FCR as a frontline therapy for patients. FCR was associated with more second cancers and ibrutinib with more cardiac events.
Are we seeing a theme?
- Vaccines offer unpredictable efficacy for CLL patients both in terms of antibodies and T cells. We will either need a fourth dose, pre-exposure prophylaxis (PrEP) with anti- SARS-CoV-2 monoclonal antibodies, or both.
- iFCR is a potent fixed-duration combination therapy for some young and fit patients.
- Long-term use of ibrutinib can result in an increased risk of developing cardiac issues including atrial fibrillation, hypertension, and even sudden death.
- Chemo-immunotherapy (CIT), especially FCR, is associated with a small but significant risk of developing second blood cancers which can be very bad news.
- And finally, the time for trials comparing novel agents to CIT has long passed.
Here are the links to the six ASH abstracts:
- Humoral Response to mRNA Vaccines BNT162b2 and mRNA-1273 COVID-19 in Chronic Lymphocytic Leukemia Patients
- Cellular Immune Responses to BNT162b2 mRNA COVID-19 Vaccine in Patients with Chronic Lymphocytic Leukemia
- Long-Term Results of Alliance A041202 Show Continued Advantage of Ibrutinib-Based Regimens Compared with Bendamustine Plus Rituximab (BR) Chemoimmunotherapy
- Longer-Term Follow-up of a Multicenter, Phase 2 Study of Ibrutinib Plus Fludarabine, Cyclophosphamide, Rituximab (iFCR) As Initial Therapy for Younger Patients with Chronic Lymphocytic Leukemia
- Preliminary Results of the Filo Phase 2 Trial for Untreated Fit Patients with Intermediate Risk Chronic Lymphocytic Leukemia Comparing Ibrutinib Plus Venetoclax (IV) Versus FCR
- Ibrutinib Plus Rituximab Is Superior to FCR in Previously Untreated CLL: Results of the Phase III NCRI FLAIR Trial
Please enjoy the ASH 2021 Day 3 Highlights video.
Tomorrow I will cover some of the non-CLL sessions that have a CLL focus.
Stay strong. We are all in this together.
Brian Koffman MDCM (retired) MS Ed (he, him, his)
Co-Founder, Executive VP, and Chief Medical Officer
CLL Society, Inc.