Insights Into Advances in CLL Therapies From the ASCO® 2021 Annual Meeting

From June 4 to June 8, 2021, oncologists gathered virtually to discuss the latest research, insights, and innovations in hematologic malignancies, including chronic lymphocytic leukemia (CLL), at the 2021 American Society of Clinical Oncology (ASCO®) Annual Meeting. This year’s meeting featured a robust program, including a “practice-changing” plenary session, ASCO award lectures, hundreds of abstracts, and more.
 
Daniel O. Persky, MD, Associate Director of Clinical Investigations, Director of the Clinical Trial Office of the University of Arizona Cancer Center, and professor of medicine at the University of Arizona College of Medicine, shared his insights from this year’s ASCO Annual Meeting.

This year’s ASCO Annual Meeting covered a large number of posters and presentations on CLL. Were there any abstracts in particular that stood out to you as clinically interesting?

I think the 2 most impactful CLL abstracts were 7500¹ and 7501.² Abstract 7500¹ reported on ELEVATE-RR (ClinicalTrials.gov Identifier: NCT02477696), which was a phase 3 study of 533 patients randomly assigned to either the Bruton tyrosine kinase (BTK) inhibitor, acalabrutinib — which was more recently approved — or the first-approved BTK inhibitor, ibrutinib.¹ Patients had been previously treated for CLL, were a median age of 66 years, and had received 2 prior lines of therapy. These patients had an unfavorable risk profile, including del(17p) in 45% or del(11q) in 64% of the patients.
 
The primary endpoint was progression-free survival as defined by an independent review committee. The interesting point about this trial was that it was actually a noninferiority trial, which is generally harder to do because it needs to be larger. There was a median follow-up of almost 41 months, and acalabrutinib was found to be noninferior. The median progression-free survival for both arms was 38.4 months.¹
 
The secondary endpoints had to do with toxicity. In that regard, acalabrutinib had some points of superiority. In regard to atrial fibrillation, a known side effect of BTK inhibitors, the all-grade atrial fibrillation rate was 9.4% with acalabrutinib vs 16% in the ibrutinib arm. For serious infections, outcomes were comparable. Overall, if you look at all adverse events that were more common, acalabrutinib had a lower incidence of hypertension, diarrhea, and arthralgias but a higher incidence of headache and cough.¹
 
I do like looking at the percentage of patients who discontinue treatment due to adverse events, because to me, that is the best indicator of how truly tolerable the drug is. Toxicity that led to drug discontinuation occurred in 14.7% of patients treated with acalabrutinib vs 21.3% of patients treated with ibrutinib.¹ To me that says that with equivalent outcomes and probably a somewhat better toxicity profile, acalabrutinib is continuing to penetrate the treatment of CLL into the first line of therapy.
 
Results from the phase 2 CAPTIVATE study (ClinicalTrials.gov Identifier: NCT02910583) were presented in abstract 7501.² The study tested fixed-duration combination ibrutinib plus venetoclax in previously untreated patients with CLL who were younger. Patients received 3 cycles of ibrutinib and then went on to receive 12 cycles of combination ibrutinib plus venetoclax, both of which are oral targeted therapies.²
 
The primary endpoint was complete response rate. There were 159 patients enrolled, 17% with a del(17p)/TP53 mutation, 19% with a complex karyotype, and 56% with unmutated IgHV. The complete response rate was 55%, which is very reasonable; overall response was 96%. Undetectable minimal residual disease, which is a more stringent kind of complete response rate, was seen in peripheral blood in 77% of patients and in bone marrow biopsy in 60% of patients at 24 months. The progression-free survival rate at 2 years was 84%. Adverse events leading to treatment discontinuation were low: 4% with ibrutinib and 2% with venetoclax.²
 
This was a very effective treatment, and a lot of us are trying to see if we could actually administer fixed-duration therapy. In the past in CLL, when we asked patients to commit to treatment, it usually meant chemoimmunotherapy for about 6 months, after which patients went back to surveillance. Oral targeted agents changed this paradigm because of the way that they’ve been approved: continuously until progression or intolerance. So, we have patients in, for example, the RESONATE-2 trial³ (ClinicalTrials.gov Identifier:NCT01722487) who are still on treatment 7 years later — 47% of patients.  That’s a lot of years of treatment and commitment for the patient. The ability to achieve a really great response without having patients commit to so many years of therapy is really beneficial. Plus, there are obviously financial savings to the system because a lot of the oral targeted agents are very expensive.

Your team used the Surveillance, Epidemiology, and End Results Program (SEER) database to study outcomes in patients with CLL during the era of oral targeted therapies, finding that survival was significantly improved among patients diagnosed after 2004.⁴ Can you discuss the results of this investigation and future next steps for these data?

We wanted to take a look at the impact of novel therapies in patients with CLL, understanding that it’s still early for their impact on outcomes to fully play out. The first oral targeted therapy for CLL was ibrutinib, and it was approved by the US Food and Drug Administration (FDA)] in 2013.
 
I want to point out that the critical work has been performed by Neda Alrawashdh (of the University of Arizona Center for Health Outcomes and PharmacoEconomic Research), with the help of Ivo Abraham (PhD, RN, Professor of Pharmacy Practice and Science at the University of Arizona College of Pharmacy), Ali McBride (PharmD, MS, Clinical Coordinator of Hematology/Oncology at the University of Arizona Cancer Center), and others like myself.
 
This was a look at the SEER database to estimate 5- and 10-year relative survival rates for patients diagnosed with CLL from 1985 to 2015. There were 2 critical findings. One, the relative survival rate clearly improved during this time. The 5-year relative survival rate was 77% among women diagnosed with CLL from 1985 to 1989 compared with 91% for those diagnosed from 2010 to 2014, when oral targeted agents started to make an impact. For men, those rates were 72% and 88%, respectively. The 10-year relative survival rate improved from 58.2% to 78.7% for women and from 47.3% to 72.5% for men.
 
The proportion of long-term survival was improved. We used mixed-cure models; cure here does not imply a cure for the disease but means really long-term survival. Even clinically, this concept is relevant for CLL because we very well know — and occasionally some of us will say to patients — that you may die with CLL, and not from CLL.
 
There were 2 cohorts that were compared: one that was diagnosed from 2004 to 2007 and followed until 2015. That’s the “new” cohort, where you have some approval of oral targeted agents. And this was compared vs the other cohort diagnosed from 2000 to 2003 and followed until 2012.
 
You could see that hazard ratios were clearly improved across the age categories. They were statistically significant for all, except for those at the age of 85 years, and they were clinically meaningful. The hazard ratio of 0.57 to 0.58 was for patients between the ages of 45 and 74 years.
 
For future studies we would need to tease out whether outcome improvement differed by treatment type; for example, BTK inhibitors or B-cell lymphoma 2 (BCL-2) inhibitors, or by CLL disease characteristics such as TP53 alterations or unmutated IgHV. These kinds of analyses are hard to do with databases, which often don’t contain so much detail.
 
Treatment for CLL has been revolutionized with oral targeted drugs. Chemoimmunotherapy (traditional treatment) maintains a very fragile foothold in CLL, primarily among younger patients with favorable CLL features. For these patients, we do consider a regimen called FCR (fludarabine, cyclophosphamide, rituximab), but even then, a lot of us do it with reluctance.

Results from a first-in-human study of lisaftoclax⁵ (APG-2575) were promising for patients with relapsed/refractory CLL, with researchers concluding that lisaftoclax is a treatment alternative for this patient population (ClinicalTrials.gov Identifier: NCT03537482). Do you see these results changing the treatment paradigm for patients with relapsed/refractory CLL, and if so, how?

Lisaftoclax is a novel BCL-2 inhibitor. One of the touted benefits is that it has a fast daily ramp-up compared with a weekly ramp-up over 5 weeks for venetoclax, the only FDA-approved BCL-2 inhibitor, which also requires hospitalization for the first and second doses if patients are at high risk for tumor lysis syndrome (TLS), a key side effect and the reason for the ramp-up. Hospitalization is something that we’ve been trying to avoid doing during the COVID-19 pandemic.
 
This is a first-in-human study, which by its nature is never definitive; first-in-human studies seek to establish the safety and the maximum tolerated dose. This was a study of 35 patients with a median 2 prior lines of therapy. Of these, 15 of the 35 patients had CLL or small lymphocytic lymphoma (SLL), 6 had multiple myeloma, 5 had follicular lymphoma, and 4 patients had Waldenstrom macroglobulinemia.
 
The maximum tolerated dose was not reached; the highest dose was 1200 mg/d, and they did not see any tumor lysis syndrome, either laboratory or clinical. In terms of major grade 3 toxicities, there were 14.3% who had neutropenia, and there was a bit of thrombocytopenia as well.
 
Among 12 of the 14 evaluable patients with relapsed/refractory CLL or SLL, the drug caused partial response. With oral targeted agents, especially early in the treatment course, most of the responses are expected to be partial, not complete. It’s curious that we’ve had so many new drugs developed in other oral targeted therapy drug classes — like BTK inhibitors, for example — but venetoclax remains the only BCL-2 inhibitor available. So, the development of new BCL-2 inhibitors such as lisaftoclax is most welcome. Any first-in-human study will require a longer follow-up for toxicity monitoring, with plans for further phase 2 studies of specific malignancies where BCL-2 inhibition is biologically relevant. They would also include assessment for complete remission and minimal residual disease status. Thus, this study is very promising, but preliminary.

In a study of genetic markers associated with ibrutinib-related cardiovascular toxicity, researchers found that 20% of patients who received frontline ibrutinib monotherapy experienced cardiovascular side effects.⁶ In particular, patients with at least 2 single nucleotide polymorphisms (SNPs) had a 12-fold increase in the risk of experiencing these side effects.
 
Do these data give you pause in prescribing an ibrutinib monotherapy regimen? How can physicians individualize ibrutinib treatment in order to provide the most efficacy with the fewest negative outcomes?

This kind of study falls into the field of pharmacogenomics because we’re talking about people who have certain genetic predispositions for developing side effects to certain drugs.
 
This was a study of 50 patients treated within 1 year with ibrutinib. Half of them were treated frontline, and the other half were patients who had relapsed CLL/SLL. Patients had buccal swabs that were genotyped for 40 SNPs using a custom next-generation sequencing panel. They found 3 SNPs — GATA4, KCNQ1, and KCNA5 — that predicted an increase in toxicity. These genes have previously been implicated in the pathogenesis of atrial fibrillation.⁶
 
It’s a small study; it would need to be replicated in the larger population, but eventually it could lead to us using this information for patients to guide therapy further. Pharmacogenomics is a nascent but extremely promising field that has still made a significant impact in the treatment of hematologic malignancies and with some solid tumors.
 
We continue tailoring our treatment based on disease and patient characteristics, but at this point, this study doesn’t really give me pause. I still prescribe ibrutinib, and I still prescribe other BTK inhibitors, for which this score may not be as relevant. We just discussed acalabrutinib and its noninferiority to ibrutinib. How would acalabrutinib do with this? Would this score be similarly predictive? We don’t know.

Seven-year follow-up data from the RESONATE-2 study³ (ClinicalTrials.gov identifier NCT01722487) showed that ibrutinib is associated with sustained progression-free and overall survival, including for those with high-risk genomic features. Are there any genomic features in particular that would give you concern about prescribing ibrutinib therapy for a patient, or do the benefits of ibrutinib outweigh the potential risks?

Generally speaking, ibrutinib still remains a drug with a very favorable toxicity profile. The question is, has it been challenged by newer BTK inhibitors with an even better safety profile? It’s not truly like it is in RESONATE-2, with ibrutinib vs chlorambucil. Chlorambucil was the FDA-approved therapy; it still is, and this, by necessity, is the drug that pharmaceutical companies and sponsors use for their randomized studies. It’s a drug that’s been seldom used in the United States for many years.
 
RESONATE-2 is a phase 3 study of older patients, older than 65 years, with previously untreated CLL/SLL without del(17p). Patients were randomly assigned to either ibrutinib or chlorambucil. Ibrutinib was used until disease progression or unacceptable toxicity, and chlorambucil was used for 12 cycles. There was a drastic difference in progression-free survival: 61% progression-free survival with ibrutinib at 6.5 years vs 9% with chlorambucil. The value of this additional reporting — and RESONATE-2 has now been reported on several times — is to serve as a check on ongoing side effects.
 
They reported that the side effects remained fairly low; hypertension was 5% at 5 to 6 years and another 4% at 6 to 7 years, atrial fibrillation was 1% at the 5- to 6-year mark and another 1% at the 6- to 7-year mark. There were no major hemorrhages that were grade 3 or higher, and dose reductions were needed in only 1 patient. Most drug discontinuation was due to progression, as you’d expect. The side effects that led to discontinuation were only 3%. Over 7 years of follow-up, 47% of patients are still taking single-agent ibrutinib, which I consider great. The whole BTK drug class is an unqualified success, and ibrutinib was the flagship drug that started it all. It’s really about the newer BTK inhibitors; there was also a study reported on zanubrutinib and at the European Hematologic Association, the ALPINE trial⁷ (ClinicalTrials.gov Identifier: NCT03734016), which actually shows superior progression-free survival compared with ibrutinib.

One abstract⁸ discussed the use of bioengineered Engineered Leukocyte Immunostimulatory (ENLIST) and SUPLEXA cell lines as an autologous immune cell therapy for cancer, comparing SUPLEXA cells generated from patients with CLL and healthy volunteers. The results are the first to show that peripheral blood mononuclear cells (PBMCs) from patients with CLL can be converted into SUPLEXA cells, which then acquire “potent tumor killing activity.” Are you optimistic about these results in terms of future treatment options for patients with CLL? What questions do you hope that next-steps research will answer?

I was interested in learning about this new technology. We are also in the age of immunotherapy, after many years of failure. Immunotherapy is a field that has blossomed in the last 10 years. And this is cellular immunotherapy, which is using patients’ own cells to fight their cancer. The interesting part here is that it’s using cells from the patient with CLL, which is often hard in CLL and in other indolent lymphoid cancers where the cancer significantly suppresses a patient’s own immune cells and makes it difficult to stimulate them to attack the cancer cells.
 
These authors reported that they use technology called engineered leukocyte immunostimulatory cell lines, called ENLIST cells, done with melanoma cell lines. These were used to activate and expand the population of tumor-killing effector cells from PBMCs. What kind of cells are these? These are natural killer cells, cytotoxic T lymphocytes, natural killer T-cells, and T-cell receptor gamma delta T cells. It’s a 300-fold expansion of this cocktail of effector cells called SUPLEXA cells. The researchers looked at what percentage of killing occurred of tumor cells by these SUPLEXA cells taken from patients with CLL vs cells taken from normal healthy volunteers, who presumably have no immunosuppressive component.
 
They found them to be similar; for percent killing, it was 77.8% from patients with CLL vs 81.5% from healthy volunteers, which is a very general measure of effectiveness.⁸
 
This is fascinating technology, but certainly not ready for practical use yet. One caveat that the authors mentioned was the population of non-T/non-B cells that was detected in SUPLEXA cells from CLL patients, which requires further characterization. The technology itself probably needs to be refined, and the safety needs to be described. This is very preliminary, because we’re talking about a very powerful cocktail of very powerful effector cells. As we know, when immune systems get activated; chimeric antigen receptor (CAR)-T cells, for example, we have cytokine release syndrome. You can have an immune storm, basically a cytokine storm that could be potentially very dangerous. That kind of technology needs to be described very carefully, and methods to control for an overly active immune response need to be developed, just like there were for CAR-T cells. Only then, with further clinical studies, can we see if this kind of technology pans out.
 
There’s so much interesting work being done with different cells in CLL and other hematologic malignancies, such as immune redirecting therapies and off-the-shelf CAR-T cell approaches.

Are there any final thoughts you’d like to add about this year’s ASCO Annual Meeting?

There is a lot of work in different venues: drug development, real-world experience, immunotherapy, fixed-duration therapy, and better disease assessment with minimal residual disease. The field has transformed during the past few years and will continue its rapid evolution.