The Importance of Shared Decision-Making in the Frontline Setting

Presentation

A 76-year-old male with known CLL that has never been treated returns for follow-up with worsening fatigue and increasing lymph nodes as well as unintentional weight loss of 10% of his total body weight over the past 6 months. Past medical history is significant for hypertension, and type 2 diabetes mellitus with diabetic nephropathy, currently managed by angiotensin-converting enzyme (ACE) inhibitor and SGLT2 inhibitor, in addition to diet. Upon physical examination, symmetric, nontender progressive adenopathy is detected in the cervical, axillary, and inguinal regions. A complete blood cell count also demonstrates anemia (9.8 g/dL) and thrombocytopenia (110,000/µL).

Work-up and Shared Therapeutic Decision-Making

You recognize that you patient now meets criteria for therapy based on the presence of B symptoms and anemia (hemoglobin <10 g/dL).¹ You therefore order a CT scan of the chest, abdomen, and pelvis (CT C/A/P) and a bone marrow biopsy for baseline staging prior to initiation of therapy. You also order fluorescence in situ hybridization (FISH) testing to detect chromosomal abnormalities in addition to testing for TP53 somatic mutation and IGHV genes as these will help inform your treatment recommendation.

The CT C/A/P demonstrates bulky adenopathy throughout the lymphatic system, including conglomerate retroperitoneal nodes measuring up to 7 cm. Additional baseline workup demonstrates del17p by FISH, positive TP53 somatic mutation, and unmutated IGHV, consistent with high risk CLL.

You discuss what this means for therapeutic selection with the patient. You explain that patients with high-risk features such as del17p by FISH and positive TP53 somatic mutation testing should not be treated with chemoimmunotherapy regimens. In general, treatment will consist of either indefinite therapy with a Bruton’s tyrosine kinase (BTK) inhibitor, or time-limited therapy with a venetoclax-based regimen. You explain that venetoclax plus obinutuzumab would offer him the option of time-limited therapy for 1 year, although patients with these high-risk features do have shorter progression free survival (PFS) time compared to those without del17p/TP53 mutation. The median PFS for frontline therapy with venetoclax plus obinutuzumab for patients with del17p/TP53 mutation is 49 months from initiation of therapy.² Additionally, his baseline renal dysfunction and bulky disease will put him at increased risk for tumor lysis syndrome.

Alternatively, he could consider indefinite therapy with a BTK inhibitor. His primary cardiac comorbidity is hypertension; he has no known history of atrial fibrillation. In alignment with the NCCN guidelines and comparative studies between BTK inhibitors, you suggest against ibrutinib. In terms of BTK inhibitors, his best options would include acalabrutinib, which demonstrates similar efficacy and fewer cardiac side effects including hypertension and atrial fibrillation compared to ibrutinib, or zanubrutinib, which has demonstrated superior PFS and decreased rates of atrial fibrillation compared to ibrutinib but similar to slightly higher rates of hypertension.^3-5

You explain that given his renal dysfunction, bulky disease, and high-risk features, you would lean toward indefinite therapy with a BTK inhibitor. Both acalabrutinib and zanubrutinib are typically dosed twice daily, although zanubrutinib does also have a once-daily formulation. To help decide between acalabrutinib and zanubrutinib, you ask the patient his goals for therapy, and he stressed that he wants to focus on quality of life and experience as few side effects as possible. He is very concerned about his hypertension and the possibility of it worsening with therapy as he does not want to start another antihypertensive medication. He has a large support network and noted that he would be open to indefinite therapy versus a fixed duration. Based on all of these factors, he elects to begin therapy with acalabrutinib.

Discussion

Although CLL comprises 25%-30% of leukemias in the United States, only approximately 5%- 10% of patients with CLL are symptomatic with early satiety, unintentional weight loss over the past 6 months (≥ 10% of body weight), and fever (>100.5°F for > 2 weeks) and/or drenching night sweats with no evidence of infection. Up to 90% of patient with CLL present with lymphadenopathy, and CT scans can help define the extent of enlarged lymph nodes throughout the chest, abdomen, and pelvis that cannot be easily palpated on physical exam.⁶

Both del17p by FISH and positive TP53 mutation status are associated with the most aggressive disease course, correlating with shorter remissions even with novel agents such as BTK inhibitors or venetoclax-based therapy. Although more common in patients with relapsed/refractory disease, it can also be seen in up to 10% of newly diagnosed patients. Because of loss of heterozygosity, almost 80% of patients with del(17p) will have a mutation in the remaining allele of the TP53 gene.⁷

Although the International Workshop on Chronic Lymphocytic Leukemia (iwCLL)¹ published revised guidelines for the diagnosis, staging, and management of CLL in 2018, numerous trials have been published and presented since that time, which have served to better inform frontline management decisions in light of additional therapeutic approvals since 2018; the NCCN guidelines have been updated accordingly, last revised in January 2023. Although these are only cross-trial comparisons, this data can help CLL healthcare providers determine the safest, most effective treatment based on a patient’s genomic profile and comorbid conditions.

Although representative of a relapsed patient population, the ELEVATE-RR trial comparing ibrutinib to acalabrutinib for patients with CLL who demonstrated del17p or del11q22 by FISH, the consensus is that these results are generalizable to the frontline setting and, therefore, help inform treatment decisions for this patient. With almost 4 years of follow up, rates of PFS were similar for both agents (median PFS, 38.4 months for both; 95% CI for acalabrutinib: 33.0 to 38.6 and ibrutinib: 33.0 to 41.6; hazard ratio: 1.00; 95% CI: 0.79 to 1.27), but acalabrutinib demonstrated decreased rates of grade 3 or higher adverse events compared to ibrutinib (68.8% vs. 74.9%), as well as fewer treatment discontinuations due to adverse events (14.7% vs. 21.3%, respectively).³ The ASCEND trial, also in relapsed/refractory disease, reported similar safety data for acalabrutinib and showed a low rate of atrial fibrillation for those patients with an ongoing history of hypertension (5%) compared with idelalisib/rituximab and bendamustine/rituximab (3% combined).⁸

In terms of frontline data for acalabrutinib, data from the ELEVATE-TN trial led to the 2019 US FDA frontline approval of acalabrutinib. ELEVATE-TN demonstrated continued efficacy with a median follow-up of 4 years, with the median PFS not reached for acalabrutinib plus obinutuzumab (vs. 22.6 months for obinutuzumab-chlorambucil (range, 20.2-27.6 months). Although there were two arms in this trial containing acalabrutinib (one with, and one without, the addition of obinutuzumab), it was not statistically powered to detect a difference between the acalabrutinib arms. It remains to be seen how the addition of a monoclonal antibody such as obinutuzumab to BTK inhibitors in the frontline setting may impact outcomes. For those patients with del(17p) and TP53 mutations, 88% (61%-97%) and 95% (70%-99%), respectively, of patients who received acalabrutinib-obinutuzumab had not experienced disease progression at a median of 2 years (vs. 22% [5%-45%] and 19% [5%-41%], respectively). Of those patients with bulky disease at study entry, 90% were progression free at a median of 2 years vs. 28% of patients who received obinutuzumab-chlorambucil. Tolerability was consistent with other studies, and acalabrutinib-containing treatment was associated with a low incidence of cardiovascular AEs (atrial fibrillation/flutter and hypertension) despite the longer duration of therapy. Rates of ≥ grade 3 hypertension were similar among the treatment groups.⁹

Additional important data to consider include the recently published ALPINE trial, a phase 3 trial comparing zanubrutinib to ibrutinib in patients with relapsed/refractory CLL. Again, although this trial was performed in the relapsed setting, one can consider the generalizability of the results to the frontline setting. This trial was the first to demonstrate increased PFS with a newer BTK inhibitor, zanubrutinib, compared to ibrutinib. At a median follow-up of 29.6 months, there were 87 vs. 118 occurrences of disease progression or death with zanubrutinib compared to ibrutinib, respectively (hazard ratio (HR): 0.65, 95% confidence interval, 0.49 – 0.86; p=0.002). Additionally, estimated PFS at 24 months was 78.4% (95% CI, 73.3 – 82.7) with zanubrutinib compared to 65.9% (95% CI, 60.1-71.1) with ibrutinib. In patients with del17p and/or TP53 mutation, such as the patient in our case, these differences in PFS persisted. Slightly higher rates of all grade and grade > 3 adverse events including neutropenia, hypertension, and COVID-19 were observed with zanubrutinib, although lower rates of all grade and grade >3 atrial fibrillation were noted with zanubrutinib compared to ibrutinib (4.6% vs. 12.3% all grade atrial fibrillation and 1.9% vs. 3.7% grade >3 atrial fibrillation, respectively).⁴

Ultimately, in this case, based on the patient’s risk factors, preferences, and comorbidities including hypertension, and in light of this data and cross-trial comparisons, he elected to proceed with acalabrutinib monotherapy in the frontline setting.

References

1. Hallek M, Cheson BD, Catovsky D, et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood. 2018;131:2745-2760.
2. Al-Sawaf O, Zhang C, Robrecht S, et al. Venetoclax-obinutuzumab for previously untreated chronic lymphocytic leukemia: 5-year results of the randomized CLL14 study. Presented at the European Hematology Association 2022 meeting; June 10-June 12, 2022. Abstract S148. https://library.ehaweb.org/eha/2022/eha2022-congress/357012/othman.al-sawaf.venetoclax-obinutuzumab.for.previously.untreated.chronic.html. Accessed April 13, 2023.
3. 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;39:3441-3452.
4. Brown JR, Eichhorst B, Hillmen P, et al. Zanubrutinib or ibrutinib in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2023;388:319-332.
5. Wierda WG, Brown J, Abramson JS, et al. NCCN Clinical Practice Guidelines in Oncology: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1478. Accessed April 13, 2023.
6. Mukkamalla SKR, Taneja A, Malipeddi D, Master SR. Chronic Lymphocytic Leukemia. StatPearls Publishing LLC, 2022. Accessed March 20, 2023. https://www.ncbi.nlm.nih.gov/books/NBK470433/
7. Camp E, Cymbalista F, Gia P, et al. TP53 aberrations in chronic lymphocytic leukemia: an overview of the clinical implications of improved diagnostics. Haematologica. 2018;103:1956-1968.
8. Ghia P, Pluta A, Wach M, Lysak D, Kozak T, Simkovic M. ASCEND: Phase III, randomized trial of acalabrutinib versus idelalisib plus rituximab or bendamustine plus rituximab in relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol. 2020;38:2849-2861.
9. Sharman JP, Egyed M, Jurczak W, et al. Efficacy and safety in a 4-year follow-up of the ELEVATE-TN study comparing acalabrutinib with or without obinutuzumab versus obinutuzumab plus chlorambucil in treatment-naïve chronic lymphocytic leukemia. Leukemia. 2022;36:1171-1175.