Taking a Patient-First Approach to Treatment in Chronic Lymphocytic Leukemia

John M. Pagel, MD, PhD, Chief of Hematologic Malignancies, Director of Stem Cell Transplantation, Swedish Cancer Institute

As a hematologist-oncologist, I frequently treat people living with chronic lymphocytic leukemia (CLL), the most common type of adult leukemia affecting more than 20,000 new patients in the US per year.^1,2 While there is currently no cure, the number of people living with CLL is anticipated to keep growing, as newer treatments are helping patients to live longer with the disease and other comorbidities.^3-6 With this also grows a need to consider the overall patient experience when determining treatment.

As a healthcare provider, I aim to continuously educate and push myself to find effective treatment options for my patients. For CLL patients, tolerability is every bit as important as efficacy.⁷ The results of some recent clinical trials, such as the ELEVATE-RR and ELEVATE-TN trials, presented at this year’s virtual American Society of Clinical Oncology (ASCO) and European Hematology Association (EHA) annual meetings, underscore that there may be treatment options for patients with CLL that can help address their medical needs while also offering good tolerability.^8-11

New data provide context to physicians and patients

In final results from the phase 3 head-to-head ELEVATE-RR trial, at a median follow-up of 40.9 months (range 0-59.1 months), independent review committee-assessed progression-free survival (PFS) for acalabrutinib vs ibrutinib had a hazard ratio (HR) of 1.0, 95% CI: 0.79-1.27 in patients with previously treated CLL and presence of 17p or 11q deletion.¹² The most common adverse events (≥20%) of any grade in patients with acalabrutinib (n=266) were infections (78%), bleeding (38%), diarrhea (35%), headache (35%), cough (29%), upper respiratory tract infection (27%), neutropenia (21%), pyrexia (23%), anemia (22%) and fatigue (20%). The most common adverse events (≥20%) of any grade in patients with ibrutinib (n=263) were infections (81%), bleeding (51%), diarrhea (46%), upper respiratory tract infection (25%), neutropenia (25%), arthralgia (23%), hypertension (23%), cough (21%) and headache (20%).^12,13

Acalabrutinib had a 9% (n=25/266) incidence of all-grade atrial fibrillation/flutter, and ibrutinib had a 16% (n=42/263) incidence of all-grade atrial fibrillation/flutter.¹² Incidences of grade ≥3 atrial fibrillation/flutter were reported in 4.9% of patients in the acalabrutinib arm (n=13/266) and 3.8% of patients in the ibrutinib arm (n=10/263). Grade ≥3 infections were reported in 31% of patients in the acalabrutinib arm (n=82/266) and 30% of patients in the ibrutinib arm (n=79/263), and Richter transformation occurred in 3.8% (n=10/266) of acalabrutinib patients and 4.9% (n=13/263) of ibrutinib patients. The median treatment exposure duration was 38.3 months (range, 0.3-55.9 months) with acalabrutinib and 35.5 months (range, 0.2-57.7 months) with ibrutinib.¹²

This adds to the knowledge we obtained from the pivotal phase 3 ASCEND trial evaluating the safety and efficacy of acalabrutinib alone vs idelalisib plus rituximab or bendamustine plus rituximab in patients with relapsed or refractory CLL, in which acalabrutinib showed a 73% risk reduction in disease progression or death by investigator assessment vs comparators (HR=0.27 [95% CI: 0.18-0.40], P<0.0001) at a median follow-up of approximately 22 months.¹⁴ The most common adverse events (≥20%) of any grade in patients with acalabrutinib (n=154) were headache, neutropenia, diarrhea and upper respiratory tract infection.¹⁴ The median duration of exposure with acalabrutinib was 21.9 months (range 1.1-27.9).¹⁴ The safety and tolerability of acalabrutinib was consistent with its established profile.¹⁴

What we learned from the phase 3 frontline ELEVATE-TN trial, with a median follow-up of 46.9 months (range 0.0-59.4 months), is that acalabrutinib resulted in a high response rate and consistent long-term tolerability. The trial evaluated acalabrutinib in combination with obinutuzumab and as a monotherapy vs chlorambucil and obinutuzumab in patients with previously untreated CLL.⁹ The high response rate and consistent tolerability were seen when acalabrutinib was given both alone and as a combination with obinutuzumab, with a 13% rate (23/179) of discontinuation due to adverse events in the combination arm and 12% rate (22/179) in the monotherapy arm.¹⁵ The median duration of exposure was 46.6 months for the acalabrutinib and obinutuzumab arm and 45.7 months for the acalabrutinib monotherapy arm.⁹ Patients remained alive and progression free with a 90% (HR 0.10, 95% CI: 0.07-0.17) and 81% (HR 0.19, 95% CI: 0.13-0.28) reduction in risk of disease progression or death by investigator assessment in the acalabrutinib combination and monotherapy arms, respectively, vs obinutuzumab plus chlorambucil. These rates of risk reduction were consistent with those reported by independent review committee-assessed PFS in the interim analysis at median follow-up of 28.3 months (range: 0.0-40.8 months).^16,17 Additionally, 75% of patients treated with acalabrutinib and obinutuzumab and 69% of patients treated with acalabrutinib monotherapy remained on treatment at median four-year follow-up.⁹

ELEVATE-TN Investigator-assessed PFS Overall⁹

^aHazard ratio was based on stratified Cox-Proportional-Hazards model; ^bP-value was based on stratified log-rank test.
A, acalabrutinib; CI, confidence interval; Clb, chlorambucil; HR, hazard ratio; NR, not reached; O, obinutuzumab; PFS, progression-free survival.

Importantly, in ELEVATE-TN, the adverse event profile in the frontline setting was as we would expect with longer follow-up. There were no new safety signals. The most common AEs of any grade (≥25%) of patients in the acalabrutinib and obinutuzumab arm (n=178) were infections (75%), bleeding (47%), diarrhea (41%), headache (40%), neutropenia (34%), fatigue (28%), arthralgia (26%) and cough (26%). The most common AEs of any grade (≥25%) of patients in the acalabrutinib monotherapy arm (n=179) were infections (74%), bleeding (42%), diarrhea (40%), headache (38%) and upper respiratory tract infection (26%)^.9,10,15 There were low rates of all-grade atrial fibrillation in patients treated with acalabrutinib and obinutuzumab and acalabrutinib monotherapy (3.9% and 6%, respectively).⁹ The rates of Grade ≥3 atrial fibrillation were 0.6% in patients in the acalabrutinib combination arm and 1.1% in patients in the monotherapy arm. The incidence of all-grade hypertension in patients treated with the acalabrutinib combination and monotherapy was 8% and 7%, respectively, and the incidence of any serious or Grade ≥3 hemorrhagic events, or any grade hemorrhagic event in the central nervous system, was 3.9% in both treatment arms, which was consistent with patients treated in this study’s initial read out at the 2019 American Society of Hematology annual meeting.^9,10,17

Overall, these long-term follow-up results of ELEVATE-TN demonstrate a consistent tolerability profile for acalabrutinib for the treatment of CLL over a prolonged period of time.^9,10 Together with the ASCEND trial, these data can help physicians when making treatment decisions and add to the growing body of evidence supporting that acalabrutinib really fits the bill for an important patient population, where efficacy and tolerability are important.^9,10,14

Looking to the future of CLL treatment

This is promising for those of us who treat CLL patients, as tolerability is an important factor for patients with other comorbidities who are receiving long-term treatment for CLL.^6,7 The long-term tolerability profile of acalabrutinib and the patients’ willingness to stay on it have the potential to change the treatment landscape of CLL. I encourage patients to feel empowered to discuss with their healthcare providers and loved ones a treatment option that could not only be effective but could also be tolerable for long-term use. I look forward to further data emerging over time using acalabrutinib as a monotherapy and in combinations.

CLL is a complicated, chronic condition, but I continue to be inspired by the strength of the patients and their loved ones and by the recent progress in the treatment landscape, even during these difficult times. The data presented at ASCO and EHA this year are a testament to the blood cancer community’s collective dedication to identifying and advancing the science to improve the health outcomes of those living with blood cancer around the world.

INDICATION AND USAGE

CALQUENCE is indicated for the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

IMPORTANT SAFETY INFORMATION ABOUT CALQUENCE^® (acalabrutinib) capsules

Serious and Opportunistic Infections
Fatal and serious infections, including opportunistic infections, have occurred in patients with hematologic malignancies treated with CALQUENCE.

Serious or Grade 3 or higher infections (bacterial, viral, or fungal) occurred in 19% of 1029 patients exposed to CALQUENCE in clinical trials, most often due to respiratory tract infections (11% of all patients, including pneumonia in 6%). These infections predominantly occurred in the absence of Grade 3 or 4 neutropenia, with neutropenic infection reported in 1.9% of all patients. Opportunistic infections in recipients of CALQUENCE have included, but are not limited to, hepatitis B virus reactivation, fungal pneumonia, Pneumocystis jiroveci pneumonia, Epstein-Barr virus reactivation, cytomegalovirus, and progressive multifocal leukoencephalopathy (PML). Consider prophylaxis in patients who are at increased risk for opportunistic infections. Monitor patients for signs and symptoms of infection and treat promptly.

Hemorrhage
Fatal and serious hemorrhagic events have occurred in patients with hematologic malignancies treated with CALQUENCE. Major hemorrhage (serious or Grade 3 or higher bleeding or any central nervous system bleeding) occurred in 3.0% of patients, with fatal hemorrhage occurring in 0.1% of 1029 patients exposed to CALQUENCE in clinical trials. Bleeding events of any grade, excluding bruising and petechiae, occurred in 22% of patients.

Use of antithrombotic agents concomitantly with CALQUENCE may further increase the risk of hemorrhage. In clinical trials, major hemorrhage occurred in 2.7% of patients taking CALQUENCE without antithrombotic agents and 3.6% of patients taking CALQUENCE with antithrombotic agents. Consider the risks and benefits of antithrombotic agents when co-administered with CALQUENCE. Monitor patients for signs of bleeding.

Consider the benefit-risk of withholding CALQUENCE for 3-7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.

Cytopenias
Grade 3 or 4 cytopenias, including neutropenia (23%), anemia (8%), thrombocytopenia (7%), and lymphopenia (7%), developed in patients with hematologic malignancies treated with CALQUENCE. Grade 4 neutropenia developed in 12% of patients. Monitor complete blood counts regularly during treatment. Interrupt treatment, reduce the dose, or discontinue treatment as warranted.

Second Primary Malignancies
Second primary malignancies, including skin cancers and other solid tumors, occurred in 12% of 1029 patients exposed to CALQUENCE in clinical trials. The most frequent second primary malignancy was skin cancer, reported in 6% of patients. Monitor patients for skin cancers and advise protection from sun exposure.

Atrial Fibrillation and Flutter
Grade 3 atrial fibrillation or flutter occurred in 1.1% of 1029 patients treated with CALQUENCE, with all grades of atrial fibrillation or flutter reported in 4.1% of all patients. The risk may be increased in patients with cardiac risk factors, hypertension, previous arrhythmias, and acute infection. Monitor for symptoms of arrhythmia (e.g., palpitations, dizziness, syncope, dyspnea) and manage as appropriate.

ADVERSE REACTIONS
The most common adverse reactions (≥ 30%) of any grade in patients with CLL were anemia,* neutropenia,* thrombocytopenia,* headache, upper respiratory tract infection, and diarrhea.

*Treatment-emergent decreases (all grades) of hemoglobin, platelets, and neutrophils were based on laboratory measurements and adverse reactions.

In patients with previously untreated CLL exposed to CALQUENCE, fatal adverse reactions that occurred in the absence of disease progression and with onset within 30 days of the last study treatment were reported in 2% for each treatment arm, most often from infection. Serious adverse reactions were reported in 39% of patients in the CALQUENCE plus obinutuzumab arm and 32% in the CALQUENCE monotherapy arm, most often due to events of pneumonia (7% and 2.8%, respectively).

Adverse reactions led to CALQUENCE dose reduction in 7% and 4% of patients in the CALQUENCE plus obinutuzumab arm (N=178) and CALQUENCE monotherapy arm (N=179), respectively. Adverse events led to discontinuation in 11% and 10% of patients, respectively. Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 3.9% and 2.8% of patients in the CALQUENCE combination arm and monotherapy arm, respectively.

In patients with relapsed/refractory CLL exposed to CALQUENCE, serious adverse reactions occurred in 29% of patients. Serious adverse reactions in > 5% of patients who received CALQUENCE included lower respiratory tract infection (6%). Fatal adverse reactions within 30 days of the last dose of CALQUENCE occurred in 2.6% of patients, including from second primary malignancies and infection.

Adverse reactions led to CALQUENCE dose reduction in 3.9% of patients (N=154), dose interruptions in 34% of patients, most often due to respiratory tract infections followed by neutropenia, and discontinuation in 10% of patients, most frequently due to second primary malignancies followed by infection. Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 1.3% of patients who received CALQUENCE.

DRUG INTERACTIONS

Strong CYP3A Inhibitors: Avoid co-administration with a strong CYP3A inhibitor. If a strong CYP3A inhibitor will be used short-term, interrupt CALQUENCE.

Moderate CYP3A Inhibitors: When CALQUENCE is co-administered with a moderate CYP3A inhibitor, reduce CALQUENCE dose to 100 mg once daily.

Strong CYP3A Inducers: Avoid co-administration with a strong CYP3A inducer. If a strong CYP3A inducer cannot be avoided, increase the CALQUENCE dose to 200 mg approximately every 12 hours.

Gastric Acid Reducing Agents: If treatment with a gastric acid reducing agent is required, consider using an H2-receptor antagonist or an antacid. Take CALQUENCE 2 hours before taking an H2-receptor antagonist. Separate dosing with an antacid by at least 2 hours.

Avoid co-administration with proton pump inhibitors. Due to the long-lasting effect of proton pump inhibitors, separation of doses may not eliminate the interaction with CALQUENCE.

SPECIFIC POPULATIONS

Based on findings in animals, CALQUENCE may cause fetal harm and dystocia when administered to a pregnant woman. There are no available data in pregnant women to inform the drug-associated risk. Advise pregnant women of the potential risk to a fetus.

Pregnancy testing is recommended for females of reproductive potential prior to initiating CALQUENCE therapy. Advise female patients of reproductive potential to use effective contraception during treatment with CALQUENCE and for at least 1 week following the last dose of CALQUENCE.

It is not known if CALQUENCE is present in human milk. Advise lactating women not to breastfeed while taking CALQUENCE and for at least 2 weeks after the final dose.

Avoid administration of CALQUENCE in patients with severe hepatic impairment. Dose modifications are not required for patients with mild or moderate hepatic impairment.

Please see full Prescribing Information, including Patient Information.

References

1. American Cancer Society. Key statistics for chronic lymphocytic leukemia. https://www.cancer.org/cancer/chronic-lymphocytic-leukemia/about/key-statistics.html. Accessed August 25, 2021.
2. American Cancer Society. What is chronic lymphocytic leukemia? https://www.cancer.org/cancer/chronic-lymphocytic-leukemia/about/what-is-cll.html. Accessed August 25, 2021.
3. Sharma S, Rai KR. Chronic lymphocytic leukemia (CLL) treatment: So many choices, such great options. Cancer. 2019;125(9):1432-1440.
4. Global Burden of Disease Cancer Collaboration. Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 29 cancer groups, 1990 to 2017: a systematic analysis for the Global Burden of Disease Study. JAMA Oncol. 2019;5(12):1749-1768.
5. Chen Q, Jain N, Ayer T, et al. Economic burden of chronic lymphocytic leukemia in the era of oral targeted therapies in the United States. J Clin Oncol. 2017;35(2):166-174.
6. Strati P, Parikh SA, Chaffee KG, et al. Relationship between co-morbidities at diagnosis, survival and ultimate cause of death in patients with chronic lymphocytic leukaemia (CLL): a prospective cohort study. Br J Haematol. 2017;178(3):394-402.
7. Patel K, Pagel JM. Current and future treatment strategies in chronic lymphocytic leukemia. J Hematol Oncol. 2021;14(1):69.
8. Hillmen P, Byrd JC, Ghia P, et al. First results of a head-to-head trial of acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia [presentation]. Presented at: European Hematology Association (EHA) Annual Meeting; June 9-17, 2021 (Virtual Meeting).
9. Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib ± obinutuzumab vs obinutuzumab + chlorambucil in treatment-naïve chronic lymphocytic leukemia: ELEVATE-TN 4-year follow-up [abstract and poster]. Presented at: ASCO Annual Meeting; June 4-8, 2021 (Virtual Meeting); https://meetinglibrary.asco.org/record/196295/poster. Accessed August 25, 2021.
10. Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib ± obinutuzumab vs obinutuzumab + chlorambucil in treatment-naïve chronic lymphocytic leukemia: ELEVATE-TN 4-year follow-up [presentation]. Presented at: EHA Annual Meeting; June 9-17, 2021 (Virtual Meeting).
11. Byrd JC, Hillmen P, Ghia P, et al. First Results of a Head-to-Head Trial of Acalabrutinib versus Ibrutinib in Previously Treated Chronic Lymphocytic Leukemia [presentation]. Presented at: American Society for Clinical Oncology (ASCO) Annual Meeting; June 4-8, 2021 (Virtual Meeting).
12. Byrd JC, Hillmen P, Ghia P, et al. Acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia: results of the first randomized phase III trial. J Clin Oncol. 2021 Jul 26:JCO2101210. doi: 10.1200/JCO.21.01210.
13. Byrd JC, Hillmen P, Ghia P, et al. Acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia: results of the first randomized phase III trial [data supplement]. J Clin Oncol. 2021 Jul 26:JCO2101210.
14. Ghia P, Pluta A, Wach M, et al. Acalabrutinib vs idelalisib plus rituximab or bendamustine plus rituximab in relapsed/refractory chronic lymphocytic leukemia: ASCEND final results [abstract and poster]. Presented at: ASCO Annual Meeting; May 29-31, 2020 (Virtual Meeting); https://meetinglibrary.asco.org/record/187424/poster. Accessed August 25, 2021.
15. Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib ± obinutuzumab vs obinutuzumab + chlorambucil in treatment-naïve chronic lymphocytic leukemia: ELEVATE-TN 4-year follow-up [supplemental information]. Presented at: ASCO Annual Meeting; June 4-8, 2021 (Virtual Meeting).
16. CALQUENCE (acalabrutinib) [U.S. prescribing information]. Wilmington, DE; AstraZeneca Pharmaceuticals LP; 2019.
17. Sharman JP, Egyed M, Jurczak W, et al. ELEVATE TN: Phase 3 study of acalabrutinib combined with obinutuzumab (O) or alone vs O plus chlorambucil (Clb) in patients (Pts) with treatment-naive chronic lymphocytic leukemia (CLL) [presentation]. Presented at: American Society of Hematology (ASH) 2019 Annual Meeting and Exposition; December 7-10, 2019; Orlando, FL.

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US-55914 Last Updated 8/21