Treatment with acalabrutinib (Calquence) does not increase the risk for developing new or worsening hypertension in patients with chronic lymphocytic leukemia (CLL), according to Alessandra Ferrajoli, MD, who emphasized the importance of recognizing the baseline rate of hypertension and other comorbidities in patients with this disease. 

“As we gain experience with BTK inhibitors, we gain experience with their activity, and we are learning more about their unique toxicities,” Ferrajoli said in an interview with 

. “This helps us decide which BTK inhibitor is best for each patient.”

At the meeting, Ferrajoli and colleagues presented findings from a cumulative study investigating the prevalence of hypertension in patients with CLL and other hematologic malignancies who received acalabrutinib. This study demonstrated that the incidence of hypertension in patients with CLL treated with acalabrutinib was similar to that in patients with CLL who had not yet been treated.

In the interview, Ferrajoli discussed the research needs for describing the risk of hypertension associated with the various BTK inhibitors, key findings from the cumulative review presented at the 2023 ASH Annual Meeting, and the importance of involving patients in shared decision making when determining their treatment plans.

Ferrajoli is the associate medical director and a professor in the Department of Leukemia, in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston.

: What was the rationale for conducting a cumulative review of hypertension in patients with CLL who received acalabrutinib? What did this study find?

: We wanted to conduct a cumulative review of hypertension in patients treated with acalabrutinib because there are indications from prior studies that acalabrutinib may not influence blood pressure as much as other TKIs or BTK inhibitors. [Using data from a large database], we compared both the incidence and prevalence of hypertension [in patients with CLL who received acalabrutinib with that in patients before they] started any kind of therapy [for CLL]. We also compared the incidence of hypertension in the whole database [of patients with CLL who received acalabrutinib with that in] patients who were part of randomized trials where they received ibrutinib [Imbruvica].

Our review confirmed what we suspected: that the incidence of hypertension in patients treated with acalabrutinib is superimposable to the incidence of hypertension in this [CLL] population, which is mostly made up of older male adults.

What factors might influence your decision to prescribe acalabrutinib vs other BTK inhibitors for patients with CLL who have hypertension?

[In] a patient with CLL who has particularly difficult-to-control hypertension or hypertension that already needs multiple agents to achieve control, I would prefer acalabrutinib so I would not anticipate any additional needs in the management of that patient’s hypertension. [I would also consider acalabrutinib] if [a patient has] other [risk] factors for hypertension, such [obesity, a smoking history], or any other factor that makes me think hypertension is a potential problem, mostly based on the patient’s medical history.

How do you weigh the potential benefits of acalabrutinib against the risks associated with this drug for patients with CLL and hypertension?

BTK inhibitors revolutionized the treatment of patients with CLL. The potential benefit [of acalabrutinib] is that as we [achieve] control of the disease, the overall health status of the patient will also improve. Obtaining control of the disease [is worth taking] a small risk of cardiovascular toxicities that are a class effect of these drugs. Overall, it’s a small price to pay compared with the toxicities of treatments in the past, such as chemoimmunotherapy, which is what we used to treat patients with CLL 20 years ago. However, with BTK inhibitors, treatment often needs to be prolonged. [Since these agents are] given over time, we have now become attuned and attentive to chronic toxicities [associated with these drugs].

What is the importance of understanding the findings from this study of hypertension in CLL in the context of common baseline characteristics in this patient population?

Regarding the cardiovascular toxicities, as well as other toxicities, such as other cancers, that are relatively common in patients with CLL, we need to [take] a global view of these patients. These patients are older and tend to be White. They have a lot of comorbidities by the time they require treatment for CLL. They may have had other cancers, some cardiovascular events, stents, and maybe even a degree of renal insufficiency.

It’s important to know the baseline in this population. This was reported previously for atrial fibrillation. We can’t expect this population to have a rate of atrial fibrillation of 0. There is a baseline rate of those comorbidities, and adding a BTK inhibitor increases the risk for [developing them].

How do you involve patients in shared decision making when considering the decision to use acalabrutinib or other BTK inhibitors?

This is important. I sit with my patients and have long discussions [with them] regarding what toxicities are [possible] and what monitoring they should do. For example, regarding hypertension, I ask my patients to keep a log of their blood pressure at home, so they can have an idea of what their blood pressure is in real life. I practice in Houston, which is a large city with a lot of traffic. When patients come to my clinic, they tend to justify non-optimal control of their blood pressure [by saying it is] related to the [events of the day, such as] fighting traffic, coming to clinic, and the anxiety of seeing the doctor and finding out what’s going on with their disease. I engage them and tell them I want them to monitor themselves, [because] I need to know what they do on a regular basis. I ask them to check their blood pressure and keep a log maybe once a week or twice a week, it depends. Of course, if there is uncontrolled hypertension, I will ask them to do it daily.

Then, depending on the situation, I engage either their primary care physician or their cardiologist if they have one. If the patients have multiple risk factors, that’s when I will call in our cardio oncologists, who are the cardiologists at [MD Anderson] who have a lot of experience treating patients on targeted therapy. [I will ask the cardio oncologists to] clear patients for specific treatments or for advice on how to best manage [patients’ disease].

Is there ongoing research in CLL that you would like to highlight?

There is a lot of research going on in patients who receive BTK inhibitors. This research sometimes focuses on more in-depth monitoring, such as continuous monitoring of blood pressure, but also continuous monitoring for arrhythmias. We will learn much more once these data can be reported and published.

We will see what happens during the therapy once the therapy is initiated. What changes do we see in the cardiovascular function of patients? We have the luxury to do this because [BTK inhibitors] are extremely effective and well tolerated. Because of how effective and well tolerated they are in general, we now have an interest in investigating what can be considered the fine-tuning of treatment of patients with BTK inhibitors.

What else were you excited to see at the 2023 ASH Annual Meeting?

The [2023 ASH Annual Meeting] was encouraging and positive regarding the outlook of patients with CLL. We saw many trials reporting efficacy and long-term results of therapy with targeted agents. It was exciting, and it gave us a lot of data to reassure our population about the outlook for patients with CLL.

Dr Ferrajoli has disclosed receiving research funding from Beigene, AstraZeneca, AbbVie, and GenMab; and receiving honoraria from AstraZeneca, AbbVie, Janssen, and Genentech.

Ferrajoli A, Follows G, Marmor Y, et al. Cumulative review of hypertension in patients with chronic lymphocytic leukemia (CLL) and other hematologic malignancies treated with acalabrutinib. 

2023;142(suppl 1):1917. doi:10.1182/blood-2023-174727

Articles

Alessandra Ferrajoli, MD, discusses the research needs for describing the risk of hypertension linked with BTK inhibitors in chronic lymphocytic leukemia.

Acalabrutinib Is Not Associated With Increased Hypertension Risk in CLL

Dr Wiestner on an Extended Follow-Up Study of Resistance Mutations With Acalabrutinib in CLL

Adrian Wiestner, MD, PhD, senior investigator, Lymphoid Malignancies, lead, Laboratory of Lymphoid Malignancies, Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, discusses an extended follow-up investigation into resistance mutations in patients with chronic lymphocytic leukemia (CLL) who were treated with acalabrutinib (Calquence). 

. This trial investigated the use of acalabrutinib in patients with treatment-naive CLL or small lymphocytic lymphoma (SLL) who presented with 17p deletion, 

mutations, as well as those with relapsed/refractory CLL/SLL.

This phase 2 clinical trial was a single-center exploration that studied the efficacy of acalabrutinib—a second-generation BTK inhibitor that offers a potentially favorable adverse effect (AE) profile, Wiestner begins. Notably, with a median follow-up of 6.5 years, the trial demonstrates treatment adherence, he states. The primary objective of this study is to determine the reasons for patient progression, Wiestner elucidates.

BTK inhibitor resistance often correlates with mutations in BTK that affect the cysteine residue that is crucial for drug attachment, or downstream mutations in 

—an immediate signaling molecule, he expands. The study revealed that these mutations are present in approximately 80% of patients with CLL who progress, underscoring the dominant mechanism of resistance to BTK inhibitors, Wiestner explains. This clinical insight sheds light on potential CLL management strategies, he notes.

The findings from the phase 2 trial indicate a need to retarget the same signaling pathway affected by these mutations, Wiestner continues. Noncovalent BTK inhibitors, exemplified by pirtobrutinib (Jaypirca), have emerged as viable treatment options for patients with disease harboring 17p deletions, 

 mutations, he states. Additionally, BTKdegraders utilizing the cellular proteasome system to degrade BTK are under investigation, Wiestner adds.

Understanding mechanisms of BTK inhibitor resistance, especially through comprehensive sequencing approaches, is important for informing the development of targeted and effective treatment strategies for patients with CLL, he concludes.

Videos

Adrian Wiestner, MD, PhD, sheds light on resistance mutations in patients with chronic lymphocytic leukemia who were treated with acalabrutinib.

Dr Ferrajoli on the Incidence of Hypertension in Patients With CLL Receiving Acalabrutinib

Alessandra Ferrajoli, MD, associate medical director, professor, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discusses the rationale for, and findings from, a cumulative review of hypertension in patients with chronic lymphocytic leukemia (CLL) and other hematologic malignancies who received acalabrutinib (Calquence).

As the clinical use of BTK inhibitors increases, oncologists are learning more about their activity and unique toxicity profiles, Ferrajoli says. Information on the toxicities associated with these agents can help oncologists choose the optimal BTK inhibitors for individual patients, Ferrajoli explains.

CLL is associated with a high rate of comorbidities, such as cardiovascular disease, of which hypertension is the most common. Previous studies have demonstrated that hypertension can develop or worsen in patients with CLL who receive the BTK inhibitors ibrutinib (Imbruvica) and zanubrutinib (Brukinsa). However, the phase 3 ELEVATE-RR trial (NCT02477696) indicated that the selective, second-generation BTK inhibitor acalabrutinib induced a lower rate of hypertension vs ibrutinib at a median follow-up of 40.9 months in patients with previously treated CLL.

Ferrajoli and coinvestigators determined the incidence of new or worsening hypertension in patients from the acalabrutinib global development program and compared this rate with the prevalence of hypertension in a real-world population of patients with CLL who had yet to initiate treatment. Investigators obtained safety reports of new or worsening hypertension from 11 clinical trials evaluating the efficacy and safety of acalabrutinib monotherapy, including ELEVATE-RR and the phase 3 ELEVATE-TN (NCT02475681) and ASCEND (NCT02970318) trials. Furthermore, ibrutinib hypertension data were obtained from ELEVATE-RR, and hypertension data with other comparator agents were obtained from ELEVATE-TN and ASCEND.

This study confirmed that the prevalence of hypertension in patients with CLL who received acalabrutinib monotherapy across all 11 clinical trials was similar to that in patients with CLL who had not yet received treatment, Ferrajoli concludes. 

Alessandra Ferrajoli, MD, discusses the rationale for, and findings from, a cumulative review of hypertension in patients with chronic lymphocytic leukemia and other hematologic malignancies who received acalabrutinib. 

Acalabrutinib (Calquence), as monotherapy or in combination with obinutuzumab (Gazyva), continued to improve progression-free survival (PFS) vs obinutuzumab and chemotherapy in patients with chronic lymphocytic leukemia (CLL), regardless of genomic marker status, according to 6-year follow-up data from the phase 3 ELEVATE-TN trial (NCT02475681) presented during the 

“Acalabrutinib-containing regimens led to improved PFS over controlled obinutuzumab plus chlorambucil. The addition of obinutuzumab to acalabrutinib resulted in improved response rates and PFS compared to acalabrutinib monotherapy,” Jeff P. Sharman, MD, who is the director of research at Willamette Valley Cancer Institute in Oregon, as well as the medical director of hematology research at The US Oncology Network, said during a presentation of the data.

“Obtaining a complete response with acalabrutinib-containing regimens leads to improved PFS and the safety of acalabrutinib regimens in treatment naive-CLL remains consistent with prior reports.”

Compared with the obinutuzumab-chlorambucil regimen, acalabrutinib plus obinutuzumab (median PFS, not reached [NR]); HR, 0.14; 95% CI, 0.10-0.20; 

 < .001) and acalabrutinib monotherapy (median PFS, NR; HR, 0.24; 95% CI, 0.17-0.32; 

Similarly, the use of acalabrutinib, in combination and monotherapy, induced significantly higher overall response rates (ORRs; difference, 6.1%; 95% CI, 0.9%-11.4%; 

 = .022) and complete response (CR) rates (difference, 17.9%; 95% CI, 8.8%-27.0%; 

 = .022). Patients treated with acalabrutinib who experienced CR/complete remission with incomplete count recovery (CRi) had reduced risk for disease progression by 77% (HR, 0.23; 95% CI, 0.12-0.42; 

 status, the addition of acalabrutinib to obinutuzumab (median PFS, NR; HR, 0.08; 95% CI, 0.05-0.12; 

 < .001) as well as the monotherapy (median PFS, NR; HR, 0.12; 95% CI, 0.08-0.18; 

 < .001), continued to show superior PFS compared with the obinutuzumab-chlorambucil regimen (median PFS, 22.2 months).

 mutation status, the 6-year PFS rates for the acalabrutinib-obinutuzumab and acalabrutinib monotherapy arms were 56% (HR, 0.28, 95% CI, 0.13-0.59; 

 = .0009) and 56% (HR, 0.23; 95% CI, 0.10-0.52; P = .0002), respectively, compared with 18% in the obinutuzumab-chlorambucil arm.

In the crossover portion of the study, those in the acalabrutinib monotherapy group who went on to receive acalabrutinib plus obinutuzumab demonstrated a 6-year PFS rate of 62% (median PFS, NR), while the obinutuzumab-chlorambucil arm who crossed over achieved a 6-year PFS rate of 54% (median PFS, NR).

Overall survival was not reached in any treatment arm; however, the combination use of acalabrutinib plus obinutuzumab reduced the risk for death by 38% compared with obinutuzumab plus chlorambucil (HR, 0.62; 95% CI, 0.39-0.97; 

Adverse events (AEs) of interest were similar in both acalabrutinib-containing arms, Sharman noted, adding that the incidence of cardiac-related AEs remained low at the 6-year follow-up.

The most common grade 3 or higher AEs in the acalabrutinib-obinutuzumab and acalabrutinib monotherapy arms were diarrhea (6.2% vs 0.6%, respectively), headache (1.1% vs 1.1%), arthralgia (2.2% vs 1.1%), neutropenia (30.9% vs 11.7%), fatigue (2.2% vs 1.1%), cough (0.6% vs 0.6%), COVID-19 (9.0% vs 7.3%), thrombocytopenia (8.4% vs 3.4%), pneumonia (7.3% vs 6.1%), hypertension (4.5% vs 5.0%), and syncope (5.1% vs 2.2%).

In the randomized, controlled phase 3 trial, patients were randomized 1:1:1 to receive either 100 mg acalabrutinib twice daily plus a fixed duration of obinutuzumab for 6 cycles, 100 mg acalabrutinib monotherapy twice daily, or a fixed duration of obinutuzumab for 6 cycles plus a fixed duration of chlorambucil. Crossover from the obinutuzumab-plus-chlorambucil arm was allowed after independent review committee-confirmed progression.

Key inclusion criteria were comprised of age 65 years or older, or patients aged 18 to 65 who had a creatinine clearance of 30 to 60 mL/min and a CIRS-G score of more than 6; treatment-naive CLL requiring treatment per the iwCLL 2008 criteria; and an ECOG performance status score of 2 or less. Patients were excluded from the trial if they had significant cardiovascular disease.

Patients in the trial were stratified by del(17p) status, ECOG performance score, and geographic region.

Comparing PFS of both combination regimens served as the primary end point of the trial. Secondary end points included comparing PFS of acalabrutinib monotherapy vs obinutuzumab plus chlorambucil, investigator-assessed PFS, ORR, time to next treatment, undetected minimal residual disease, and safety.

Patients in the acalabrutinib-obinutuzumab, acalabrutinib monotherapy, and obinutuzumab-chlorambucil arms were a median age of 70 (range, 41-88), 70 (range, 44-87), and 71 (range, 46-91), respectively; the majority had an ECOG performance score of 0 to 1 (94.4% vs 92.2% vs 94.4%); and 9.5%, 8.9%, and 9.6% had del(17p).

Previous long-term follow-ups at 28.3 months, 46.9 months, and 58.2 months also demonstrated superior efficacy and acceptable tolerability with acalabrutinib plus obinutuzumab compared with obinutuzumab plus chlorambucil, Sharman said.

In the 6-year follow-up, median study follow-up in the acalabrutinib-obinutuzumab, acalabrutinib monotherapy, and obinutuzumab-chlorambucil arms was 74.6 months (range, 1.7-89.0), 74.5 months (range, 0.1-88.8), and 73.3 months (range, 0.0-88.8), respectively. Overall, 96 patients in the acalabrutinib-obinutuzumab group (53.6%) and 84 patients in the acalabrutinib monotherapy group (46.9%) are ongoing with treatment, while no patients are receiving the obinutuzumab-chlorambucil regimen. Seventy-nine patients (44.6%) crossed over from receiving obinutuzumab plus chlorambucil to the acalabrutinib-obinutuzumab combination.

Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib ± Obinutuzumab Vs Obinutuzumab + Chlorambucil in Treatment-Naive Chronic Lymphocytic Leukemia: 6-Year Follow-up of Elevate-TN. 

. 2023; 142(1):636. doi:10.1182/blood-2023-174750

Acalabrutinib, as monotherapy or in combination with obinutuzumab, continued to improve progression-free survival vs obinutuzumab and chemotherapy in patients with treatment-naive chronic lymphocytic leukemia, regardless of genomic marker status. 

Navigating New Data With Next-Generation BTK Inhibitors in CLL | Supplements and Featured Publications

Acalabrutinib Is Not Associated With Increased Hypertension Risk in CLL

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Acalabrutinib With or Without Obinutuzumab Provides Sustained PFS Benefit in Previously Untreated CLL