This is my report from ASH 2021, the 63rd American Society of Hematology Annual Conference and Exhibition, this year a hybrid meeting held in Atlanta, Georgia, and virtually around the world.
I will only be reporting from the oral presentations and will cover the relevant poster presentations later.
Keep in mind that there are only 12 oral presentations covering the clinical aspects of CLL, while there were over 300 poster abstracts on CLL that were accepted. The oral presentations are what the ASH committee deemed the most important.
Six talks were scheduled today, and I will briefly point out some of the highlights of all six. It won’t be difficult to quickly recognize some recurring themes.
This year, in a break with the past few years, there are no exciting late-breaking abstracts on CLL, the most exclusive category, with only six slots for all topics in hematology.
Also, there is no conference-stopping plenary session on CLL this year.
Overall, it was not a breakthrough year for CLL, no big new surprising findings, but there were some very important moves forward in CLL management that could soon inform how CLL patients are better cared for.
That makes it even more disappointing when the ASH technical folks blew it with no audio and video for the first two “oral” abstracts, and it appears that these sessions were not recorded.
No worries. I will rely on the written abstracts. Though they will not contain the latest information, they will help set the stage and I will do a more in-depth analysis later in video reports and interviews.
On another day, I will also share some news from other oral presentations including COVID-19 in blood cancers in general and in CLL in particular, some encouraging studies in cellular therapies related to CLL, as well as the disturbing findings from research on issues about how race affects CLL care. And finally, at another time, I plan to proudly share some of the slides presented at a major medical education presentation yesterday at ASH, that featured CLL Society.
The first abstract I’ll cover from today, Dec. 11. 2021, was supposed to be presented virtually at 6:30 AM PT: Zanubrutinib in Combination with Venetoclax for Patients with Treatment-Naïve (TN) Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL) with del(17p): Early Results from Arm D of the SEQUOIA (BGB-3111-304) Trial. I instead rely on the written abstract.
Zanubrutinib is a next-generation, more selective BTKi that is not yet approved in CLL. But that approval should be coming soon.
This trial builds on the data showing that the combination of a BTKi and venetoclax can lead to uMRD (undetectable minimal/measurable residual disease), and allows finite duration therapy with continued disease control post-drug discontinuation. We will hear more about those other combinations soon.
This arm of the SEQUOIA study looked only at those patients with the poor prognostic marker del17p and found that a remarkable 30 of 31 people responded with no new safety signals seen for the combination.
Encouraging results, for sure. And reassuring to see that the overall result of this logical and well-tolerated combination works in this high-risk population. We must wait to see how durable the responses are and how this combination compares to others, but there is reason to be optimistic.
The next oral presentation was also not presented virtually, so again I rely on the abstract. It used a similar combination: First-Line Treatment with Ibrutinib (Ibr) Plus Venetoclax (Ven) for Chronic Lymphocytic Leukemia (CLL): 2-Year Post-Randomization Disease-Free Survival (DFS) Results from the Minimal Residual Disease (MRD) Cohort of the Phase 2 Captivate Study.
Here we have longer data, and they are good. With an additional year of follow-up with frontline ibrutinib + venetoclax, we learn that those who had reached uMRD had no new MRD relapses, no progressive disease, and there were no deaths. The 3-year PFS (progression-free survival) rates in all arms of the trial were ≥95%.
Next: Time-Limited Venetoclax and Ibrutinib for Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia (R/R CLL) Who Have Undetectable MRD – Primary Analysis from the Randomized Phase II Vision HO141 was another ibrutinib + venetoclax trial, this time in patients who had progressed after frontline chemo-immunotherapy (CIT).
The study proved several things:
- This time-limited combination is an excellent “salvage” therapy after progressing post chemoimmunotherapy (CIT) with an overall response rate of 86%.
- 98% of patients had PFS one year after treatment cessation.
- All patients who did become MRD positive were able to successfully reinitiate therapy to control their CLL.
- MRD levels remained stable in the first year for those who stayed on single-agent ibrutinib after finishing the fixed duration course of the combination.
- No difference in blood uMRD at cycle 15 was seen in those with or without TP53.
While I don’t generally agree with the approach of CIT used as a frontline therapy followed by novel agents, it’s important to know there is an excellent fixed-duration, all-oral, novel therapy option for the many who are so treated, whose disease either remains stable or can be retreated if it becomes apparent again.
This trial also hints at a possible emerging new trend: Treat when the disease becomes MRD positive, instead of waiting until it clinically progresses and meets the usual criteria for treatment.
Ready for yet another BTKi and Venetoclax trial focusing on MRD? First Prospective Data on Minimal Residual Disease (MRD) Outcomes after Fixed-Duration Ibrutinib Plus Venetoclax (Ibr+Ven) Versus Chlorambucil Plus Obinutuzumab (Clb+O) for First-Line Treatment of CLL in Elderly or Unfit Patients: The Glow Study Do you see a theme here?
No surprise: The rate of uMRD was significantly higher for ibrutinib plus venetoclax versus Chlorambucil plus Obinutuzumab in the bone marrow (51.9% vs 17.1%) and in the blood (54.7% vs 39.0%).
But there was more to this trial:
- Deep remissions down to 10-5 by NGS (next-generation sequencing) were achieved by ibrutinib plus venetoclax and were predictive of longer remissions.
- Relapses were less common in the ibrutinib plus venetoclax arm.
- Even those patients who didn’t achieve uMRD with ibrutinib plus venetoclax had a 90% PFS one year after therapy.
A Randomized Phase III Study of Venetoclax-Based Time-Limited Combination Treatments (RVe, GVe, GIVe) Vs Standard Chemoimmunotherapy (CIT: FCR/BR) in Frontline Chronic Lymphocytic Leukemia (CLL) of Fit Patients: The First Co-Primary Endpoint Analysis of the International Intergroup GAIA (CLL13) trial added obinutuzumab (Gazyva) to the mix in the comparisons of different combinations.
Guess what? The novel therapies won again. In particular, the time-limited therapies of obinutuzumab and venetoclax and the combination of obinutuzumab, ibrutinib, and venetoclax provided superior uMRD rates in the blood compared to CIT. In addition, uMRD rates in the bone marrow and complete response rates were higher with obinutuzumab and venetoclax, and with obinutuzumab, ibrutinib, and venetoclax than with CIT.
The same trial was reported again, this time looking specifically at the data on deeper measurements of MRD using NGS (next-generation sequencing): High-Resolution Assessment of Minimal Residual Disease (MRD) By Next-Generation Sequencing (NGS) and High-Sensitivity Flow Cytometry (hsFCM) in the Phase 3 GAIA (CLL13) Trial.
Here’s is some of what they found:
- Treatment with either the combination of obinutuzumab and venetoclax or the combination of obinutuzumab, ibrutinib, and venetoclax allowed more than half the patients to reach uMRD (undetectable measurable residual disease) at 10-6 in the peripheral blood at 15 months and predicted better odds of reaching uMRD-6.
- Females were more likely to reach uMRD-6.
- With the novel therapy combinations, there was a high concordance between the MRD findings in the blood and marrow. If this finding is confirmed, it could obviate the need for some bone marrow biopsies in trials and in the clinic.
- NGS is the best way to measure MRD.
- It is not yet known if a deeper MRD of 10-6 is predictive of better PFS (progression-free survival) and OS (overall survival), but my bet is that deeper remissions will prove to be better and that NGS (next-generation sequencing) will become the new standard for measuring residual disease.
So, there you have it for the six CLL talks on day one of ASH.
The themes seem to be:
- CIT is an inferior therapy in almost all comparisons to novel agents.
- Limited duration therapy using combinations of novel agents will be a big player in the future management of CLL / SLL.
- Drugs with complementary, non-overlapping mechanisms of controlling CLL seem to be the most logical combinations. That usually means a BTKi and venetoclax with or without a monoclonal antibody.
- MRD-guided therapy is becoming increasingly important.
- NGS is the best way to measure MRD, though its clinical utility is only starting to be proven.
Overall, a great first day of ASH 2021. More tomorrow.
Thanks for reading and listening.
Here’s my video summary of day one.
Stay strong. We are all in this together.
Brian Koffman MDCM (retired) MS Ed
Co-Founder, Executive VP and Chief Medical Officer
CLL Society, Inc.
