Welcome back to day two of 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.
Today there were no technical difficulties, and I will briefly cover the six oral CLL clinical presentations.
There was a stimulating Q+A session with Drs. Con Tam, Deborah Stephens, and Florence Cymbalista moderated by Dr. Susan O’Brien. There was some more research on cellular therapies that I will cover another day.
Dr. Mato started the morning with an update on the reversible noncovalently binding BTKi (Bruton’s Tyrosine Kinase inhibitor) pirtobrutinib, formerly known as LOXO-305: Pirtobrutinib, A Next Generation, Highly Selective, Non-Covalent BTK Inhibitor in Previously Treated CLL / SLL: Updated Results from the Phase 1/2 BRUIN Study.
By reversibly binding BTK to block the B-cell receptor which promotes the CLL cells’ drive to stay alive and active, there is good reason to believe pirtobrutinib can continue to work when the irreversible binding BTKis are no longer working due to mutations in C481, their binding site.
There were 618 patients studied, and 296 had CLL. Of those with CLL, 256 had prior BTKi exposure, and 75% of those had progressed on that BTKi therapy. This was a difficult to treat cohort with poor prognostics.
That makes the overall response rate (ORR) of 68% for patients who had been previously treated with a BTKi even more impressive. The ORR was similar regardless of whether they had progressed on their prior BTKi, had the C481 mutation that confers resistance to the irreversible BTKi, or even if they had also failed venetoclax. Responses looked to be durable with the median progression-free survival (PFS) not yet reached after more than nine months. Responses appear to deepen over time. Adverse events were manageable, with only 1% of patients stopping the treatment due to side effects.
In summary, pirtobrutinib is an effective option for patients who have previously failed a BTKi, and possibly even more therapies. Hopefully, this trial and others will lead to its swift approval.
Next up Dr. Jennifer Woyach shared results on another reversible BTKi that has been mostly missing in action for the last year of hematology meetings until this ASH, MK-1026, which was formerly known as ARQ-531: Preliminary Efficacy and Safety of MK-1026, a Non-Covalent Inhibitor of Wild-Type and C481S Mutated Bruton Tyrosine Kinase, in B-Cell Malignancies: A Phase 2 Dose Expansion Study.
There were 51 CLL patients who were studied. Of them, 43 had been treated with prior BTKis. The ORR was 58%.
Similar to pirtobrutinib, the reversibly binding MK-1026 has promising anti-tumor activity. It also has a manageable safety profile in participants with CLL / SLL who have been exposed to multiple lines of therapy, including in those who had progression of disease with the prior covalent or irreversibly binding BTKi.
The trial, Three-Year Follow-up of the Ascend Trial: Acalabrutinib Vs Rituximab Plus Idelalisib or Bendamustine in Relapsed/Refractory Chronic Lymphocytic Leukemia, is important because it is one of the very few that compares two novel agents in different arms. Namely, the BTKi acalabrutib versus rituximab, plus the approved PI3K inhibitor (PI3Ki) idelalisib, for treatment after relapsing/not responding to chemoimmunotherapy (CIT) which is the usual frontline therapy in Europe where the trial was started.
After three years, acalabrutinib was well tolerated and had better progression-free survival than rituximab combined with idelalisib or bendamustine. Clearly for most patients, where appropriate, acalabrutinib or another BTKi would be the smarter choice for second-line treatment after CIT. How applicable this is in today’s era of diminished use of CIT even in the frontline setting is less clear.
Retrospective Single-Institution Analysis of Patients with Chronic Lymphocytic Leukemia with TP53 alterations Treated First-Line with Bruton’s Tyrosine Kinase Inhibitor-Based Therapy was conducted at MD Anderson Cancer Center.
We know that del 17p and TP53 mutations are associated with worse outcomes, especially when CIT is used, and to a lesser extent when BTKis are used in the frontline setting.
The questions this trial asked included:
- Does the prevalence of the deletion, mutation, or whether both exist together affect outcomes?
- Do other prognostic factors influence the responses?
- Do the BTKis work better when combined with venetoclax in these circumstances?
It seems that whether one had a lot or a little of the del 17p and/or TP53 mutation, or if both chromosomal arms were involved (called a double or multi-hit), it didn’t make much difference in the outcomes. Neither did the other biomarkers, such as IgHV mutation status or complex karyotype.
Adding venetoclax did improve PFS, but not OS as that was already high.
For the entire group, the four-year PFS was an impressive 73%, and the OS was 84.4%.
This paper is worth digging into if you want a more nuanced understanding of del 17p and TP53. But the bottom line is, even a small subclonal prevalence of the problem is significant.
A Phase 2 Study Evaluating the Addition of Ublituximab and Umbralisib (U2) to Ibrutinib in Patients with Chronic Lymphocytic Leukemia (CLL): A Minimal Residual Disease (MRD)-Driven, Time-Limited Approach presented by Dr. Lindsey Roeker explores the concept of using enough medication to knock back the CLL, but to avoid using more than is needed.
In this tailored approach, more drug was added if undetectable measurable disease (uMRD) was not reached in the hope of getting to the point where the disease is no longer detectable and treatment can be stopped. This has been more commonly done with venetoclax based therapies, but this trial looks at adding U2, the combination of ublituximab, an experimental anti-CD20 monoclonal antibody (similar to rituximab and obinutuzumab) and umbralisib which is an experimental PI3K inhibitor (similar to idelalisib and duvleisib, but with a better safety profile).
After adding U2, treatment is stopped either when patients reach uMRD or after 24 months. Patients are re-treated if they become MRD positive.
With this approach, an impressive 77% reached uMRD.
I like this approach because it gives CLL patients a strong alternative pathway to an MRD-based time-limited therapy besides the ones using venetoclax. It offers the possibility of not over or under-treating patients but instead guiding treatment by their MRD status.
Future studies will look at adding U2 to acalabrutinib and venetoclax in similar trials.
ASH also revisited SEQUOIA: Results of a Phase 3 Randomized Study of Zanubrutinib versus Bendamustine + Rituximab (BR) in Patients with Treatment-Naïve (TN) Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL / SLL) presented by Dr. Con Tam.
This study looked at the arm of the SEQUOIA trial where frontline patients without del 17p who were unfit for FCR (fludarabine, cyclophosphamide, rituximab) CIT were randomized to either the BTKi zanubrutinib, or a different “milder” CIT of bendamustine plus rituximab (BR).
The adverse events were as expected with zanubrutinib, again showing a lower rate of atrial fibrillation of 3.3% compared to ibrutinib. Other side effects were similar to those seen with ibrutinib.
PFS was 85.5% at two years in the zanubrutinib arm compared to only 65.5% in the BR arm.
No surprise. So once again, a novel agent proves its superiority to CIT.
In summary, at the end of day two at ASH 2021 we’ve learned there is more to CLL treatment than the approved BTKi and venetoclax:
- Two promising reversibly binding BTKis offer good responses for patients who have failed ibrutinib or acalabrutinib.
- U2, ublituximab and umbralisib, are powerful partners with ibrutinib, and will probably be with other therapies too.
- Zanubrutinib is another BTKi that appears equally effective, but with fewer cardiac side effects than ibrutinib.
We also learned that del 17p and/or TP53 is equally bad no matter how little or how much of the clone is involved, but this can largely be overcome with the use of novel agents. That trial offered important details in understanding these critical prognostic markers.
We learned that acalabrutinib worked better after CIT than did rituximab plus either idelalisib or bendamustine. Although I doubt that this news will have hardly any practical impact, as it was very much expected.
And we were again reminded that using MRD as a tool to guide therapy in being able to stop and start treatment is rapidly evolving as an important treatment option.
Tomorrow is another day. We will report on CLL sessions addressing CLL and COVID-19, additional sessions comparing novel agents to CIT, and a lot more!
Stay strong. We are all in this together.
Brian Koffman, MDCM (retired), MSEd (he, him, his)
Co-Founder, Executive VP and Chief Medical Officer
