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Clinical

Karen M. Winkfield, MD, PhD; Narjust Florez, MD, FASCO; Gilberto de Lima Lopes Junior, MD, MBA, FASCO; Coral Olazagasti, MD; Vonetta M. Williams, MD, PhD

 Fighting Disparities and Saving Lives: An Exploration of Challenges and Solutions in Cancer Care

PHA-22-TTD0589 - /clinical/cll

Current frontline treatment options for patients with chronic lymphocytic leukemia (CLL) have grown over the past year, specifically with the approval of 2 Bruton’s tyrosine kinase (BTK) inhibitors. Notably, in January 2023, 

 (Brukinsa) for adult patients with CLL or small lymphocytic leukemia (SLL) based on data from 2 phase 3 randomized studies: ALPINE (NCT03734016) and SEQUOIA study (NCT03336333).

In the phase 3 ALPINE trial, investigators assessed treatment with zanubrutinib vs ibrutinib (Imbruvica) in patients with relapsed/refractory CLL.

Of the 415 evaluated patients included in the study, the overall response rate (ORR) among those treated with zanubrutinib was 80% (95% CI, 76-85) vs 73% (95% CI, 68-78) in the ibrutinib arm (HR, 1.10; 95% CI, 1.01-1.20; 

 =.0264). After a median follow-up of 14.1 months, the median duration of response (DOR) was not reached in either arm.

In the SEQUOIA trial, zanubrutinib was compared with bendamustine and rituximab (Rituxan) in treatment of treatment-naïve patients with CLL. Here, the median progression-free survival (PFS) was not reached in the zanubrutinib arm vs 33.7 months (95% CI, 28.1-NE) in the bendamustine and rituximab arm (HR, 0.42; 95% CI, 0.28-0.63; 

 ≤ .0001). The estimated median follow-up was 25.0 months.

A total of 110 patients were given zanubrutinib within a separate non-randomized cohort of the study. Of these patients, all had previously untreated CLL/SLL with 17p deletion. In this cohort, the ORR was 88% (95% CI, 81-94), and the median DOR was not reached after a median follow-up of 25.1 months.

The most frequent adverse events seen in at least 30% of patients who received zanubrutinib included neutrophil count decrease (42%), upper respiratory tract infection (39%), platelet count decrease (34%), hemorrhage (30%), and musculoskeletal pain (30%). Zanubrutinib was generally well-tolerated among patients with CLL, low rates of atrial fibrillation were strong efficacy seen compared [with] ibrutinib and chemoimmunotherapy.

Current frontline treatment options for patients with chronic lymphocytic leukemia have grown over the past year, specifically with the approval of zanubrutinib.

Understanding the Role of Zanubrutinib for the Treatment of CLL

In season 4, episode 7 of Targeted Talks, Cyrus M. Khan, MD, a hematologist at Allegheny Health Network, discusses the latest FDA activity in the chronic lymphocytic leukemia (CLL) space.

Beginning with the early 2023 FDA approval of zanubrutinib (Brukinsa) for the treatment of adult patients with CLL and small lymphocytic leukemia (SLL), Khan explains that the Bruton’s tyrosine kinase (BTK) inhibitor demonstrated non-inferiority compared with the standard-of-care (SoC) combination of bendamustine and rituximab (Rituxan). This approval was granted based on findings from the ALPINE (NCT03734016) and SEQUOIA (NCT03336333) studies.

“Both studies showed that the use of zanubrutinib produced superior results for these patients. In the case of the ALPINE study, the 24-month [progression-free survival] rate was 79.5% with the next generation BTK inhibitor compared with 67.3% for patients on ibrutinib [Imbruvica],” said Khan in the interview with Targeted Talks.

Recently, the FDA Oncologic Drugs Advisory Committee (ODAC) also voted against the approval of duvelisib (Copiktra) for the treatment of relapsed or refractory CLL/SLL. Khan highlights the ODAC discussion on duvelisib and other PI3K inhibitors, as well as the findings from the phase 3 DUO trial (NCT02004522), which support the new drug application.

“The problem with these drugs has been the side effect profile. We’ve had autoimmune problems come up, like pneumonitis, transaminitis, colitis, etc., and infectious complications. Then, in some of the studies, the overall survival has been poorer on PI3 kinase inhibitors rather than the standard of care,” says Khan.

During the discussion, Khan also talks about the tablet formulation of acalabrutinib (Calquence) being approved to improve absorption in patients, and agents newly granted fast track and orphan drug designations by the FDA. According to Khan, an agent to watch is the BTK inhibitor pirtobrutinib (Jaypirca), which is under investigation in the phase 1/2 BRUIN study (NCT03740529).

“Patients do progress on BTK inhibitors…I’m hoping that drug gets approved for patients that progress on the current BTK inhibitors,” Khan says.

In season 4, episode 7 of Targeted Talks, Cyrus M. Khan, MD, discusses the latest FDA activity in the chronic lymphocytic leukemia space.

Exciting Activity in Chronic Lymphocytic Leukemia

In season 3, episode 4 of Targeted Talks, Alexey Danilov, MD, PhD, associate director, Toni Stephenson Lymphoma Center, and professor, Division of Lymphoma, Department of Hematology & Hematopoietic Cell Transplantation, City of Hope Comprehensive Cancer Center, discusses the shift toward utilizing cellular therapy to treat high-risk patients with chronic lymphocytic leukemia (CLL).

The definition of high-risk has changed in CLL based on the emergence of better therapies. Today, patients with 

 mutations, complex karyotype, and patients who have progressed while on targeted therapies are considered to be high risk.

Historically for the high-risk CLL population, allogeneic stem cell transplant and chemoimmunotherapy were the standards of care. The treatment landscape has since expanded to include Bruton’s tyrosine kinase (BTK) inhibitors and BCL-2 inhibitors. These newer drug classes can be used sequentially and in the clinical trial setting, they are being investigated as combinations. PI3K inhibitors are also available and effective for the treatment of high-risk CLL.

The role of transplant is after patients progress on available targeted therapies.

In terms of cellular therapies have been another positive development for high-risk CLL, says Danilov. In studies, responses to chimeric antigen receptor (CAR) T-cell therapy have been observed in patients with deletion 17p and those who are refractory to BTK inhibitors. The next step with CAR T cells is understanding the durability of response and learning better ways to handle severe toxicities like cytokine release syndrome.

The latest treatment strategies being investigated for high-risk CLL include CAR T-cell therapy combined with targeted therapies, novel BTK inhibitors for BTK-refractory patients, and natural killer cells, explains Danilov.

In season 3, episode 4 of Targeted Talks, Alexey Danilov, MD, PhD, discusses the shift toward utilizing cellular therapy to treat high-risk patients with chronic lymphocytic leukemia.

Better Strategies for the Treatment of High-Risk Chronic Lymphocytic Leukemia

MB-105, a first-in-class CD5-targeted CAR T-cell therapy, received FDA orphan drug designation for relapsed/refractory T-cell lymphoma.

FDA Grants Orphan Drug Designation to MB-105 for R/R T-Cell Lymphoma

In an interview, Paolo Ghia, MD, PhD, discussed updated data from the phase 2 CAPTIVATE trial of ibrutinib and venetoclax in chronic lymphocytic leukemia/small lymphocytic lymphoma.

Long-Term Follow-Up of Ibrutinib/Venetoclax Provides Durable Survival in CLL/SLL

During a Case-Based Roundtable® event, Nakhle Saba, MD, and participants discussed treatment for a patient with chronic lymphocytic leukemia who received 1 prior line of therapy in the first article of a 2-part series. 

Deciding on Therapy for a Patient With High-Risk Relapsed CLL

During a Case-Based Roundtable® event, Catherine Coombs, MD, discussed the BRUIN trial and recent NCCN updates on chronic lymphocytic leukemia. 

Coombs Considers Role of BTK Inhibitors in CLL and Treatment Selection

During the 66th American Society of Hematology Annual Meeting and Exposition, investigators revealed early-phase 1 data evaluating various BTK degraders that leverage different strategies to overcome resistance.

Resistance Spurs Evaluation of Early-Phase BTK Degraders

Experts examine the potential role of chimeric antigen receptor (CAR) T-cell therapy in chronic lymphocytic leukemia treatment, incorporating new evidence presented at the 66th American Society of Hematology Annual Meeting and Exposition 2024.

TRANSCEND 004: Highlights from ASH 2024

Videos

Video Series

Key Updates From the CELESTIAL Trial Presented at ASH 2024

Experts discuss the comparative efficacy of sonrotoclax plus zanubrutinib vs venetoclax in chronic lymphocytic leukemia treatment based on updates presented at the 66th American Society of Hematology Annual Meeting and Exposition 2024.

Understanding the Mechanism and Sensitivity of BCL-2 Inhibitors 

John Seymour, MBBS, FRACP, PhD, director of hematology at the Peter MacCallum Cancer Center and the Royal Melbourne Hospital in Melbourne, Australia, explains the mechanism of action of BCL-2 inhibitors.

BCL-2 inhibitors, such as venetoclax (Venclexta) work by targeting the BCL-2 protein, which plays a key role in preventing apoptosis, or programmed cell death. According to John Seymour, MD, overexpression of BCL-2 allows cancer cells to evade apoptosis, leading to uncontrolled growth.

Venetoclax specifically binds to BCL-2, displacing apoptotic activators, which then reinitiate the apoptosis process. Sensitivity to venetoclax depends not only on BCL-2 levels but also on the presence and displacement of apoptotic activators and other factors like MCL-1 that might interfere. Seymour highlights that the drug's potent and rapid induction of apoptosis necessitates a gradual dose ramp-up to manage cytoreduction and mitigate risks of patient morbidity.

BCL-2 inhibitors work by binding to and preventing the action of BCL-2. In the normal cell death pathway, as cells age, they should die by apoptosis. Overexpression of BCL-2 prevents activation of that pathway. Delivering a BCL-2 inhibitor [like] venetoclax binds to BCL-2 and then displaces those apoptotic activators, such as BIM and BID that then bind to and activate that pathway.

 Understanding that it is not solely what level of BCL-2 is present that determines sensitivity, but what are the apoptotic activators that are bound to BCL-2? How will they be displaced? Are there other factors present, such as MCL-1, that can potentially quench those factors, or will they go on to trigger apoptosis? So, it is understanding the dynamic balance between those regulators that determines the sensitivity to venetoclax. But the potency and the rapidity of induction of apoptosis is what leads to the need for that gradual dose ramp-up and cytoreduction and avoid those biochemical issues that can lead to significant patient morbidity.

John Seymour, MBBS, FRACP, PhD, explains the mechanism of action of BCL-2 inhibitors like venetoclax.

News

Exploring Updates on AMPLIFY at ASH 2024

Experts examine both overall survival outcomes and independent review committee–assessed progression-free survival data from the AMPLIFY trial.

SEQUOIA Trial: Updates from ASH 2024 

Experts review the 5-year results of the phase 3 SEQUOIA trial evaluating treatment options for previously untreated chronic lymphocytic leukemia and small lymphocytic lymphoma at the 66th American Society of Hematology Annual Meeting and Exposition 2024.

Insights From the CAPTIVATE Trial on Frontline CLL Treatment Strategies

Paolo Ghia, MD, PhD, deputy director of the Division of Experimental Oncology in San Raffaele Scientific Institute in Milan, Italy, full professor of medical oncology, a group leader in the B-cell Neoplasia Unit, and the head of the Strategic Research Program on CLL at the Università Vita Salute San Raffaele, provides an overview of the CAPTIVATE trial (NCT02910583), uncovering what investigators sought to evaluate.

In the CAPTIVATE trial, ibrutinib (Imbruvica) plus venetoclax (Venclexta) was evaluated for the treatment of patients with chronic lymphocytic leukemia (CLL) and/or small lymphocytic lymphoma (SLL). Patients with previously untreated CLL aged 71 years or younger were included in the study. This included patients with high-risk disease. Two cohorts made up the study.

According to Ghia, the regimen continued to demonstrate a clinically meaningful progression-free survival at 5.5-years of follow-up in both the overall population and in those with high-risk genomic features

The CAPTIVATE trial is a phase 2 international trial where we investigated the combination of ibrutinib, the BTK inhibitor, and venetoclax, a BCL2 inhibitor, in frontline patients with CLL. And in particular, this combination was given with 3 months of debulking with the ibrutinib only, and then 12 months of the combination between ibrutinib and venetoclax. The study involved only young patients below 70 years of age.

There were 2 different cohorts, not arms. They were not randomized to each other. One cohort was MRD driven, so at the end of the 15 months of treatment, patients were randomized based on the level of undetectable MRD. But more importantly, we had the so-called fixed-duration cohort, where patients after 15 months of treatment all stopped the treatment regardless of the level of undetected MRD. And that is actually the regimen that has been approved in Europe, and it can be used now as a standard regimen.

Paolo Ghia, MD, PhD, provides an overview of the CAPTIVATE trial, uncovering what investigators sought to evaluate.

Recommendations and Future Directions of Genetic Testing for CLL

Susan L. Slager, PhD, endowed professor of lymphoma research at Mayo Clinic, discusses some of the recommendations for genetic testing in individuals with a family history of chronic lymphocytic leukemia (CLL).


While genetic testing can identify inherited variants associated with CLL risk, there are currently no preventive strategies available to mitigate these risks. In this interview, Slager highlights the importance of individualizing the decision to undergo genetic testing.

She explains that while some individuals may find the information valuable, others may prefer to avoid potential anxiety or distress. Further, Slager emphasizes the need for careful consideration and discussion with a healthcare provider prior to proceeding with genetic testing.

In addition to her recommendations, Slager emphasizes her interest in identifying factors that contribute to disease progression and in developing strategies to prevent or delay the onset of CLL.

You can get genetic testing, but there is nothing that you can do about it yet and there are no preventive strategies. You can find that you have this genetic score, and you are on the high end, and you have a family history of CLL or lymphoma, but there is nothing you can do about it right at the moment. So, when I talk to the general population and ask the question, “Would you want to know?” it varies by individual. Some people say they do want to know and just be more informed and other people say they are not interested. I think it is still an individualized process. But as far as clinically, I do not recommend getting it tested, or at least have a conversation [before testing].

So, obviously I am more interested in etiology, mostly about the precursors and conditions for monoclonal B-cell lymphocytosis, understanding why people get this precursor condition, and understanding why individuals progress and why a lot of people do not progress. I think that is the active area that excites me.




Susan L. Slager, PhD, discusses some of the recommendations for genetic testing in individuals with a family history of chronic lymphocytic leukemia.


A Deeper Dive Into Polygenic Risk Scoring for CLL

Susan L. Slager, PhD, endowed professor of lymphoma research at Mayo Clinic, discusses the use of polygenic risk scoring to assess individual risk for chronic lymphocytic leukemia (CLL).

According to Slager, this scoring system incorporates over 42 inherited genetic variants, each weighted based on its impact on CLL risk. By summing these weighted variants, researchers can estimate an individual's overall genetic predisposition to the disease. Individuals with higher scores are at increased risk of developing CLL.

These genetic variants are often located in regulatory regions of the genome, such as enhancers, rather than directly within genes. While the precise mechanisms by which these variants influence CLL risk remain under investigation, it is believed that they play a role in gene expression and cellular processes involved in the development of CLL.

It is the 42 inherited variants and each inherited variance, you get 0, 1, or 2 copies, depending on if you get it from both parents or neither parent. Then, the score is weighted by the effect size from the genome wide association studies. For each variant, we determine 0, 1, or 2, and then we weigh it, and then we add it up across the variants, and then that is your score. Everybody has a score, and you can get a clear distribution of the score. Among individuals without CLL, that score is much lower. But among patients with chronic lymphocytic leukemia, the score is much higher.

 The inherited variants are located across the genome. They tend to be not in any particular genes per se, but they are located in regions that regulate downstream gene expression. They are in epigenomic regions and super enhancers. The actual biology of how these individual variants increase your risk of CLL is still under a lot of research, but we just know that they happen to be regulators of gene expression.

Transcription has been edited for clarity with AI.

Susan L. Slager, PhD, discusses the use of polygenic risk scoring to assess individual risk for CLL.

The Clinical Utility of Genetic Risk Scores in Chronic Lymphocytic Leukemia

Susan L. Slager, PhD, endowed professor of lymphoma research at Mayo Clinic, discusses the background of her research on inherited germline genetics for risk of chronic lymphocytic leukemia (CLL).

Susan L. Slager, PhD, discusses the background of her research on inherited germline genetics for risk of chronic lymphocytic leukemia.


Chronic Lymphocytic Leukemia

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