US real-world analysis of ibrutinib in CLL

On the 1^st February 2018, Antony R Mato, from the Division of Hematology and Oncology at the  University of Pennsylvania, Philadelphia, PA and colleagues, had an article published online ahead of print in Haematologica which reported a real-world retrospective analysis of the safety of ibrutinib in chronic lymphocytic leukemia (CLL) patients treated at nine US cancer centers registered in the Connect^TM CLL Registry.

Clinically approved ibrutinib—a Bruton’s tyrosine kinase (BTK) inhibitor—has demonstrated differential side effects to traditional chemotherapy, which have restricted its clinical use, following accumulating evidence from phase III trials, like RESONATE, RESONATE 2 and HELIOS. The aim of this multicenter, retrospective study was to compare the type and frequency of reported ibrutinib-mediated toxicities in CLL patients. The primary endpoint of this study was progression-free survival (PFS) and secondary endpoints included overall survival (OS) and reasons for discontinuation.

Patient characteristics

• N = 621 patients (536 R/R and 80 ibrutinib front line)
• N = 399 (64%) patients treated in academic cancer centers
• N = 222 (36%) treated in community sites
• N = 546 (88%) treated with commercial ibrutinib (outside clinical trials)
• Clinical trial patients vs off-trial patients:
  • Mean age: 58 vs 61 years (P = 0.01)
  • Time from diagnosis to treatment: 85 vs 87 months (P = 0.8)
  • Daily ibrutinib initiation at 420 mg: 100% vs 89%

Key findings

• Median follow-up = 17 months
• Median PFS = 35 months
• Median OS = not reached
• No significant difference in PFS by front-line or R/R ibrutinib treatment (P = 0.27)
• No significant difference in PFS at first, second or third relapse (P = 0.45)
• No significant difference in PFS between clinical trial and commercial ibrutinib treatment (P = 0.14)
• Longer PFS and OS for patients discontinuing due to toxicity than those due to disease progression (P = 0.01; P = 0.02)
• PFS of R/R CLL patients with 17q deletion status or complex karyotype (≥3 abnormalities):
  • Not significantly different in patients with 17q deletion status (P= 0.70)
  • Significantly shorter in patients with complex karyotype (HR = 1.8; [95% CI (1.1-3.0)]; P = 0.01)

Reasons for discontinuation

• At 17-months median follow-up:
  • 42% patients discontinued ibrutinib
  • Median time to discontinuation due to intolerance = 6 months
  • Median time to discontinuation due to disease progression = 10 months
• Patients on ibrutinib monotherapy = 41.9% discontinued
• Patients on ibrutinib-based combination therapy = 43.9% discontinued
• Ibrutinib daily starting dose (420 mg vs < 420 mg) did not correlate with either toxicity or disease progression discontinuation
• Main reasons for ibrutinib discontinuation (% front-line patients; % R/R patients):
  • Toxicity (63.1%; 50.2%)
  • Disease progression (15.8%; 20.9%)
  • Other/unrelated death (5.3%; 12.1%)
  • Physician/patient preference (10.5%; 6.7%)
  • Richter’s transformation to DLBCL or HL (5.3%; 4.6%)
  • CAR-T cell treatment (0%; 3.3%)

Toxicities

• Most common discontinuation-leading toxicities:
• In front-line CLL patients:
  • Arthralgia (41.6%)
  • Atrial fibrillation (25%)
  • Rash (16.7%)
• In R/R CLL patients:
  • Atrial fibrillation (12.3%)
  • Infection (10.7%)
  • Pneumonitis (9.9%)
  • Bleeding (9%)
  • Diarrhea (6.6%)
• Median time to discontinuation varied by toxicity:
  • Rash (3.5 months)
  • Pneumonitis (4.5 months)
  • Arthralgia (5 months)
  • Bleeding (6 months)
  • Infection (6 months)
  • Atrial fibrillation (7 months)
  • Diarrhea (7.5 months)

The results of this study provided a detailed account on the main reasons for ibrutinib discontinuation in both clinical trial and community treatment settings and established a discontinuation timeline for all toxicity types reported. According to the authors, the main limitation of this study is its retrospective and multicentric nature, that might affect data consistency. Nevertheless, this work provides a valuable tool for the development of future management strategies to alleviate ibrutinib intolerance and to maximize its treatment efficacy for CLL.