What is the prognosis of Chronic Lymphocytic Leukemia (CLL) with a modified Rai stage IV if treated with Acalabrutinib (Bruton's tyrosine kinase inhibitor)?

From the Guidelines

The prognosis for patients with Chronic Lymphocytic Leukemia (CLL) modified Rai stage IV treated with acalabrutinib is generally favorable, with significant improvements in survival outcomes compared to traditional chemotherapy, as evidenced by the 5-year follow-up analysis of ELEVATE-TN, which showed superior efficacy for acalabrutinib-obinutuzumab versus chlorambucil-obinutuzumab 1.

Key Considerations

• Acalabrutinib, a second-generation Bruton's tyrosine kinase (BTK) inhibitor, typically produces overall response rates of 85-95% in this advanced disease stage, with progression-free survival often exceeding 3-4 years 1.
• The standard dosing is 100 mg twice daily, taken orally, and treatment is typically continued until disease progression or unacceptable toxicity occurs.
• Patients with modified Rai stage IV disease who receive acalabrutinib often experience normalization of blood counts within 2-3 months of starting therapy.

Side Effects and Monitoring

• The medication is generally well-tolerated with fewer off-target effects than first-generation BTK inhibitors like ibrutinib.
• Common side effects include headache (often resolving after the first few weeks), mild bruising, diarrhea, and upper respiratory infections.
• Regular monitoring should include complete blood counts, liver function tests, and assessment for atrial fibrillation, though the cardiac risk is lower than with ibrutinib 1.

Mechanism of Action

• Acalabrutinib works by blocking the BTK signaling pathway, which is crucial for B-cell receptor signaling and malignant B-cell survival, effectively disrupting the proliferation and survival of CLL cells.

Treatment Recommendations

• Acalabrutinib should be considered as a first-line treatment option for patients with CLL modified Rai stage IV, given its favorable efficacy and safety profile, as supported by the ELEVATE-TN trial 1.
• Pre-treatment evaluation should include assessment of IGHV and TP53 status, deletions in chromosome 17p, and patient-related factors such as comedication, comorbidities, and preference 1.

From the FDA Drug Label

The efficacy of CALQUENCE in patients with CLL was demonstrated in two randomized, controlled trials. The indication for CALQUENCE includes patients with SLL because it is the same disease ELEVATE-TN The efficacy of CALQUENCE was evaluated in the ELEVATE-TN trial, a randomized, multicenter, open-label, actively controlled, 3 arm trial of CALQUENCE in combination with obinutuzumab, CALQUENCE monotherapy, and obinutuzumab in combination with chlorambucil in 535 patients with previously untreated chronic lymphocytic leukemia (NCT02475681) Patients 65 years of age or older or between 18 and 65 years of age with a total Cumulative Illness Rating Scale (CIRS) > 6 or creatinine clearance of 30 to 69 mL/min were enrolled. The trial also required hepatic transaminases ≤ 3 times upper limit of normal (ULN) and total bilirubin ≤ 1. 5 times ULN, and excluded patients with Richter’s transformation. A total of 535 patients were randomized, 179 to CALQUENCE+G, 179 to CALQUENCE monotherapy, and 177 to GClb The overall median age was 70 years (range: 41 to 91 years), 47% had Rai stage III or IV disease, 14% had 17p deletion or TP53 mutation, 63% of patients had an unmutated IGVH, and 18% had 11q deletion. Baseline demographic and disease characteristics were similar between treatment arms. Efficacy was based on progression-free survival (PFS) as assessed by an Independent Review Committee (IRC). The median duration of follow-up was 28. 3 months (range: 0.0 to 40. 8 months). Efficacy results are presented in Table 14. The Kaplan-Meier curves for PFS are shown in Figure 2. Table 14: Efficacy Results per IRC in Patients with CLL ‒ ITT population (ELEVATE-TN)

• Per 2008 International Workshop on CLL (IWCLL) criteria. † Kaplan-Meier estimate. ‡ Based on a stratified Cox-Proportional-Hazards model Both hazard ratios are compared with the obinutuzumab and chlorambucil arm. § Based on a stratified log-rank test, with an alpha level of 0. 012 derived from alpha spending function by the O’Brien-Fleming method. ¶ Based on a stratified Cochran–Mantel–Haenszel test, for the comparison with the obinutuzumab and chlorambucil arm CALQUENCE plus Obinutuzumab N=179 CALQUENCE Monotherapy N=179 Obinutuzumab plus Chlorambucil N=177 Progression-Free Survival* Number of events (%) 14 (8) 26 (15) 93 (53) PD, n (%) 9 (5) 20 (11) 82 (46) Death events, n (%) 5 (3) 6 (3) 11 (6) Median (95% CI), months† NE NE (34, NE) 22.6 (20,28) HR‡ (95% CI) 0.10 (0.06,0.17) 0.20 (0.13,0.30) - p-value§ < 0.0001 < 0. 0001 - Overall Response Rate* (CR + CRi + nPR + PR) ORR, n (%) 168 (94) 153 (86) 139 (79) (95% CI) (89,97) (80,90) (72,84) p-value¶ < 0.0001 0. 0763 - CR, n (%) 23 (13) 1 (1) 8 (5) CRi, n (%) 1 (1) 0 0 nPR, n (%) 1 (1) 2 (1) 3 (2) PR, n (%) 143 (80) 150 (84) 128 (72)

The prognosis of Chronic Lymphocytic Leukemia (CLL) with a modified Rai stage IV if treated with Acalabrutinib (Bruton's tyrosine kinase inhibitor) is as follows:

• Progression-Free Survival (PFS): The median PFS was not reached in the CALQUENCE monotherapy arm, with a hazard ratio of 0.20 (0.13,0.30) compared to the obinutuzumab and chlorambucil arm 2.
• Overall Response Rate (ORR): The ORR was 86% (80,90) in the CALQUENCE monotherapy arm, with a complete response rate of 1% (1) and a partial response rate of 84% (80,90) 2.
• Key points:
  • The trial included patients with Rai stage III or IV disease (47% of patients).
  • The median age was 70 years, and 63% of patients had an unmutated IGVH.
  • The median follow-up was 28.3 months. It is essential to note that the modified Rai stage IV is not explicitly mentioned in the provided text, but the results for Rai stage III or IV disease are presented. Therefore, the prognosis for CLL with a modified Rai stage IV treated with Acalabrutinib can be inferred from the available data, but the exact prognosis for this specific subgroup is not directly stated.

From the Research

Prognosis of Chronic Lymphocytic Leukemia (CLL) with Modified Rai Stage IV

The prognosis of CLL with a modified Rai stage IV can be favorable when treated with Acalabrutinib, a Bruton's tyrosine kinase inhibitor.

• A study published in 2021 3 demonstrated significant efficacy and safety of acalabrutinib monotherapy in treatment-naive CLL patients, including those with Rai stage III/IV disease.
• The overall response rate was 97%, with a median duration of response not reached and a 48-month duration of response rate of 97% (95% confidence interval, 90-99).
• Another study published in 2023 4 reported a survival rate of approximately 88% at 4 years for acalabrutinib, indicating a favorable prognosis for CLL patients treated with this medication.

Treatment Outcomes with Acalabrutinib

Treatment outcomes with acalabrutinib in CLL patients with modified Rai stage IV are promising, with:

• High overall response rates, including complete and partial responses 3, 5, 6
• Durable responses, with median duration of response not reached in some studies 3, 5
• Manageable adverse events, with grade 3/4 events occurring in a subset of patients 3, 4, 5, 6

Comparison with Other Therapies

Acalabrutinib has been compared to other therapies in CLL, including:

• Ibrutinib, another Bruton's tyrosine kinase inhibitor, which has a similar mechanism of action but may have different adverse event profiles 4, 5
• Venetoclax, a B-cell leukemia/lymphoma 2 (BCL2) inhibitor, which may be used in combination with obinutuzumab in first-line treatment for CLL 4, 6