ASH 2018 | Phase III Alliance A041202 results on ibrutinib alone or with rituximab as front-line therapy in older CLL patients

On Sunday 2 December 2018, a Plenary Scientific Session took place at the 60^th American Society of Hematology (ASH) Annual Meeting, San Diego, CA. During that session (Abstract #6), results from the phase III Alliance A041202 (NCT01886872) study were presented by Jennifer Woyach from the Ohio State University Comprehensive Cancer Center, Columbus, OH.

In this multicenter, randomized, NCI National Clinical Trials Network phase III trial bendamustine plus rituximab combination (BR; arm 1) was compared against ibrutinib alone (arm 2) or ibrutinib plus rituximab (IR; arm 3), in older untreated patients with chronic lymphocytic leukemia (CLL). This is one of the first studies to prospectively evaluate in this setting the potential benefit of rituximab addition to ibrutinib and the direct comparison of ibrutinib to BR. The primary endpoint of the study was progression-free survival (PFS), while overall survival (OS) was a secondary endpoint. The results of this trial have also been recently published in the New England Journal of Medicine.

Study design & baseline characteristics

• N = 547 previously-untreated CLL patients ≥ 65 years with Eastern Cooperative Oncology Group (ECOG) performance status 0−2, were randomized 1:1:1 to BR (n = 183), IR (n = 182) or ibrutinib alone (n = 182)
• Median age (range) = 71 (65−89)
• Dosing (28-day cycles):
  • BR: Six cycles of 90 mg/cm² bendamustine on Day 1 and 2 plus 375 mg/m² rituximab on Day -1 and then 500 mg/m² on Day 1 of cycle 2 to 6
  • IR: Six cycles of 420 mg of ibrutinib daily plus 375 mg/m² rituximab weekly for 4 weeks on Day 1 of cycle 2 and then on Day 1 of cycles 3−6
  • Ibrutinib: 420 mg daily until disease progression or unacceptable toxicity
• Data from December 2013 to May 2016, with data locked on 4 October 2018
• All basic patient demographics were similar between arms (age, sex, high-risk disease according to modified Rai stage, ECOG score, TP53 mutation, unmutated IGVH rate) except for a higher percentage of patients with complex karyotype in the IR group when compares to the other two arms (P = 0.04)
• No significant differences were detected among treatment arms in terms of baseline geriatric assessment scores (daily living activities, number of coexisting conditions and number of falls in past six months)
• Forty-six percent of patient across arms had intermediate-risk disease and 54% had high-risk CLL based on modified Rai scoring

Results

• Median PFS was reached only in the BR arm
• Two-year PFS estimates:
  • BR: 74% (95% CI, 66−80) from n = 176 patients
  • IR: 88% (95% CI, 81−92) from n = 170 patients
  • Ibrutinib: 87% (95% CI, 81−92) from n = 178 patients
  • Statistical 2-year PFS comparisons:
    • Ibrutinib vs BR: HR = 0.39; 95% CI, 0.26−0.58; one-sided P < 0.001
    • IR vs BR: HR = 0.38; 95% CI, 0.25−0.59; one-sided P < 0.001
    • IR vs ibrutinib: HR = 1.00; 95% CI, 0.62−1.62; one-sided P = 0.49
  • In subgroup analyses according to risk and cytogenetic factors for CLL (complex karyotype, del[17p13.1], ZAP70 methylation, etc.) PFS was longer with ibrutinib-containing regimens when compared to BR in all risk factor subgroups, except for patients with ZAP70-methylated disease, where there was no significant difference
  • PFS was longer among patients with IGVH mutated disease than those without (HR = 0.51; 95% CI, 0.32−81)
  • At data cut-off, 66 deaths had occurred
  • Two-year OS estimates:
    • BR: 95% (95% CI, 91−98) from n = 183 patients
    • IR: 94% (95% CI, 89−97) from n = 182 patients
    • Ibrutinib: 90% (95% CI, 85−94) from n = 183 patients
    • Statistical 2-year OS comparisons:
      • There was no statistical difference in 2-year OS rates among the three arms (P ≥ 0.65 for all pairwise comparisons)
    • Overall response rates (ORR):
      • BR: 81% (95% CI, 75−87)
      • IR: 94% (95% CI, 89−97)
      • Ibrutinib: 93% (95% CI, 88−96)
    • Complete response (CR) rates:
      • BR: 26% (95% CI, 20−33)
      • IR: 12% (95% CI, 8−18)
      • Ibrutinib: 7% (95% CI, 4−12)
    • Minimal residual disease (MRD) negative in bone marrow at 9 months:
    • Overall response rates (ORR):
      • BR: 8% (95% CI, 5−13)
      • IR: 4% (95% CI, 2−8)
      • Ibrutinib: 1% (95% CI, <1−3)

Safety

• The rate of grade 3,4 or 5 hematological adverse events (AEs) was statistically higher in the BR group (61%) than in the IR (39%) or ibrutinib arm (41%)
• The rate of grade 3,4 or 5 non-hematological AEs was lower in the BR arm (63%) than with the ibrutinib-containing regimens (74% for IR and ibrutinib alone)
• Infections occurred in all three arms, with respiratory tract, urinary tract, sepsis and abdominal infections being the most common
• Atrial fibrillation of any grade occurred in 3% of patients in the BR arm, 17% of patients in the ibrutinib group, and 14% of patients in the IR arm
• Grade 3 hypertension occurred in 14% of patients in the BR arm, 29% of patients in the ibrutinig group, and in 34% of patients in the IR arm

Conclusions

• Ibrutinib alone or IR significantly prolonged PFS when compared to BR as front-line regimen for older CLL patients
• Rituximab did not improve PFS over ibrutinib alone
• The use of ibrutinib is not without significant toxicity in older patients, thus close monitoring is required
• Further clinical trials for this patient population are of great clinical interest and are required