Dr Islam on the Limited Use of Ibrutinib in CLL

Prioty Islam, MD, MSc, attending physician, medical oncologist, Leukemia, Division of Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, discusses the current status of the first-generation BTK inhibitor ibrutinib (Imbruvica) following the FDA approvals of next-generation BTK inhibitors in patients with chronic lymphocytic leukemia (CLL) and expands on the few instances in the clinic where she may lean toward treatment with ibrutinib instead of the next-generation BTK inhibitors zanubrutinib (Brukinsa) or acalabrutinib (Calquence).

Islam details that she rarely sees patients with CLL whose disease profiles are best suited for ibrutinib in place of acalabrutinib or zanubritinib. However, she occasionally sees these patients in her practice, she amends, adding that for certain patient subsets, ibrutinib is the only BTK inhibitor with published safety or efficacy data.

A phase 2 trial (NCT02420912) being led out of the University of Texas MD Anderson Cancer Center is evaluating ibrutinib in 1 of these patient subsets, Islam says. This trial is investigating the use of ibrutinib with nivolumab (Opdivo) in the treatment of patients with relapsed/refractory or high-risk untreated CLL, small lymphocytic lymphoma, or Richter transformation. Findings from this trial indicate that ibrutinib in combination with nivolumab can be an effective treatment approach for patients whose disease displays Richter transformation, Islam expands. Notably, this regimen addresses an unmet need for patients with Richter transformation, as there is a limited amount of safe and effective treatment options for this population. In patients with Richter transformation, Islam says she would not trial a next-generation BTK inhibitor because there are no data to support the use of those agents in that population.

Based on the data from that phase 2 trial and the continued development of next-generation BTK inhibitors, ibrutinib should only be used in subsets of patients with CLL in whom no safety or efficacy data with other agents are available, Islam emphasizes. However, these patients are rare, Islam concludes.

Clinicians referring a patient to MSK can do so by visiting msk.org/refer, emailing referapatient@mskcc.org, or by calling 833-315-2722.

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Prioty Islam, MD, MSc, discusses the current status of the first-generation BTK inhibitor ibrutinib following the FDA approvals of next-generation BTK inhibitors in patients with chronic lymphocytic leukemia and expands on the few instances in the clinic where she may lean toward treatment with ibrutinib instead of the next-generation BTK inhibitors zanubrutinib or acalabrutinib.


Dr Islam on Novel Explorations of BTK Inhibitors in MCL and CLL

Prioty Islam, MD, MSc, attending physician, medical oncologist, Leukemia, Division of Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, discusses the exploration of novel roles for BTK inhibitors in the treatment of patients with mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (MCL).

Due to recent successes derived from treatment with BTK inhibitors in CLL and MCL, there continues to be interest in furthering their utility by harnessing novel combination regimens, targeting mechanisms, and prognostic features, Islam begins.

Many clinical trials are evaluating the addition of BTK inhibitors with BCL2 inhibitors, such as an investigation of frontline acalabrutinib (Calquence) and venetoclax (Venclexta), Islam states. This could provide patients with an all-oral, time-limited treatment alternative to either standard continuous BTK inhibitor therapy or the combination of a BCL2 inhibitor and a monoclonal antibody infusion, Islam explains. The goal of further developing novel combination regimens is to improve upon the convenience, tolerability, and efficacy of currently available strategies, she adds.

Moreover, there is additional interest in if minimal residual disease (MRD) may inform the duration of BTK inhibitor treatment, Islam continues. Any BTK inhibitors that are currently approved for use are approved with continuous administration until disease progression or intolerance, she says. Some patient subsets may benefit more from a truncated or attenuated treatment course, but this population has not yet been identified, Islam notes. To utilize a time-limited treatment strategy with BTK inhibitors, co-administration of an additional novel therapy may be necessary. This could induce deeper remissions, as complete responses with BTK inhibitor monotherapy are typically uncommon, Islam details.

Lastly, an emerging area of research in both MCL and CLL is focused on discovering alternative methods of targeting the BTK protein, Islam says. Current BTK inhibitors are either covalent, in which the agent irreversibly binds to the BTK protein, or noncovalent, in which this bond is reversible.

However, there may be other ways to inhibit BTK mutations. For example, several agents currently in development have been designed to degrade the BTK protein, Islam introduces. Because this approach would blockthe BTK signaling pathway in its entirety, this method could also overcome or prevent the development of BTK inhibitor resistance through its varied mechanisms, Islam concludes.

Dr Islam reports consulting roles with AbbVie, AstraZeneca, BeiGene, DAVA Oncology, and LOXO Oncology; as well as speaking roles with Targeted Oncology and The Video Journal of Hematologic Oncology (VJHemOnc).

Prioty Islam, MD, MSc, discusses the exploration of novel roles for BTK inhibitors in the treatment of patients with mantle cell lymphoma and chronic lymphocytic leukemia. 

Dr Islam on the Current and Expanding Role of Pirtobrutinib in MCL

Prioty Islam, MD, MSc, attending physician, medical oncologist, Leukemia, Division of Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, discusses how the approval of the noncovalent BTK inhibitor pirtobrutinib (Jaypirca) has transformed the treatment of patients with mantle cell lymphoma (MCL), and where this agent fits in to the current treatment armamentarium.

received FDA approval in January, 2023, for the treatment of patients with relapsed/refractory MCL

 who have been previously exposed to at least 2 prior lines of systemic therapy, including a BTK inhibitor. This approval was supported by data from the phase 1/2 BRUIN trial (NCT03740529), in which a subset of patients with MCL achieved a high overall response rate (ORR) with the agent.

Historically, patients with relapsed/refractory MCL experienced poor prognosis and did not respond well to chemoimmunotherapy regimens, Islam begins. However, the introduction of single-agent, oral targeted BTK inhibitors, such as pirtobrutinib, to the treatment armamentarium has improved the durability of patient responses to treatment, Islam states, as well as patients' quality of life. Accordingly, this drug class has significantly affected the treatment of relapsed/refractory MCL, she says.

Much like its activity in chronic lymphocytic leukemia, pirtobrutinib has been shown to successfully restore BTK inhibitor dependency in patients with MCL, as well as induce responses in those who previously progressed on a different BTK inhibitor, Islam continues. Although there is interest in moving pirtobrutinib into earlier lines of therapy in MCL, efforts to accomplish this remain both a challenge and a subject of debate due to a lack of data on patient responses after progression on pirtobrutinib, Islam cautions. 

The ongoing, randomized phase 3 BRUIN-MCL-321 trial (NCT04662255) is investigating pirtobrutinib vs investigator’s choice of BTK inhibitor in patients with pretreated, BTK inhibitor–naïve MCL. Findings from the trial are hoped to illuminate the feasibility of utilizing pirtobrutinib in the frontline, as the current FDA indication for this agent is after progression on or intolerance to a prior covalent BTK inhibitor, Islam says.

Prioty Islam, MD, MSc, discusses how the FDA approval of the noncovalent BTK inhibitor pirtobrutinib has transformed the treatment of patients with mantle cell lymphoma, and where this agent fits in to the current treatment armamentarium.

Dr Islam on Updated Safety and Efficacy Data With FDA-Approved BTK Inhibitors in CLL

Prioty Islam, MD, MSc, attending physician, medical oncologist, Leukemia, Division of Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, discusses the impact of the updated safety and efficacy data seen with FDA-approved BTK inhibitors in patients with chronic lymphocytic leukemia (CLL).

BTK inhibitors are approved across all treatment lines in CLL, Islam begins. As such, these agents can be used in both the frontline and relapsed/refractory settings, Islam explains. Therefore, if a BTK inhibitor is being used in the relapsedsetting, it typically means that the patient’s disease progressed on a frontline treatment, such as venetoclax (Venclexta), Islam explains.

Currently, there are 3 covalent BTK inhibitors available for use in CLL–

, and zanubrutinib (Brukinsa). The most recent BTK inhibitor to be approved was 

zanubrutinib, which received its designation

 for patients with CLL or small lymphocytic lymphoma (SLL) based on data from the phase 3 ALPINE (NCT03734016) and SEQUOIA trials (NCT03336333). Overall, there are now many different treatment options to offer patients with CLL, Islam emphasizes.

However, acalabrutinib and zanubrutinib have become preferred BTK inhibitors due to improved safety data, as well as improved efficacy data, specifically with zanubrutinib, in the relapsed setting, Islam continues. 

In the phase 3 ELEVATE-RR trial (NCT02477696), acalabrutinib met the noninferiority end point of the study vs ibrutinib, whereas in the phase 3 ALPINE trial (NCT03734016) zanubrutinib demonstrated superiority over ibrutinib. For patients who have been on ibrutinib and are responding, it may be beneficial to raise the conversation of switching the patient over to either acalabrutinib or zanubrutinib due to concerns over long-term safety with the first-generation BTK inhibitor. Overall, these are 3 efficacious agents available for patients in all lines, making this an optimaltime to be using BTK inhibitors in CLL, Islam concludes.

Prioty Islam, MD, MSc, discusses the impact of the updated safety and efficacy data seen with FDA-approved BTK inhibitors in patients with chronic lymphocytic leukemia.


Dr Islam on Clinical Decisions Regarding BTK Inhibitor Use in MCL and CLL

Prioty Islam, MD, MSc, attending physician, medical oncologist, Leukemia, Division of Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, discusses the importance of shared decision making between patients and clinicians when selecting among available BTK inhibitors in the treatment of chronic lymphocytic leukemia (CLL) or mantle cell lymphoma (MCL).

BTK inhibitors represent a safe and well-tolerated treatment approach for patientswith CLL and MCL—even for those with high-risk disease, Islam begins. Patients with poor risk markers or relapsed/refractory MCL now have a beneficial option, as these agents are inducing significant responses with improved quality of life, she explains.Notably, BTK inhibitors have been approved across all lines of therapy in CLL, Islam says, adding that in MCL, these agents are appropriate for use in the relapsed/refractory setting.

For example, FDA-approved BTK inhibitors in CLL include 

, and are supported by data from the phase 3 RESONATE-2 (NCT01722487), ALPINE (NCT03734016), and ELEVATE-TN (NCT02475681) trials, respectively. Current FDA-approved BTK inhibitors in MCL include 

BTK inhibitor selection should be a shared decision between the patient and the clinician, according to Islam. Each BTK inhibitor has its own toxicity profile, she notes. Arrythmia, bleeding risk, and hypertension are among some of the most common adverse effects (AEs) that are often experienced with BTK inhibition, Islam says.Reviewing the toxicity profiles and dosing schedules of these agents with patients prior to treatment is vital, Islam concludes.

Prioty Islam, MD, MSc, discusses the importance of shared decision making between patients and clinicians when selecting among available BTK inhibitors in the treatment of chronic lymphocytic leukemia or mantle cell lymphoma.


Prioty Islam, MD, MSc

Articles

Dr Islam on the Limited Use of Ibrutinib in CLL

Dr Islam on Novel Explorations of BTK Inhibitors in MCL and CLL

Dr Islam on the Current and Expanding Role of Pirtobrutinib in MCL

Dr Islam on Updated Safety and Efficacy Data With FDA-Approved BTK Inhibitors in CLL

Dr Islam on Clinical Decisions Regarding BTK Inhibitor Use in MCL and CLL