Ibrutinib plus fludarabine, cyclophosphamide, and rituximab as initial therapy in CLL: A 5-year follow-up study

Previously, high rates of undetectable minimal residual disease were observed after ibrutinib plus fludarabine, cyclophosphamide, and rituximab (FCR) in patients with newly diagnosed chronic lymphocytic leukemia (CLL). Here, we summarize a 5-year follow-up outcomes study published by Ahn et al.¹ in Blood Advances.

Study design

• Multicenter, single-arm, phase II trial (NCT02251548) conducted at seven sites in the USA
• Patients with newly diagnosed CLL treated with ibrutinib at 420 mg PO daily for 7 days, followed by up to six cycles of FCR given with continuous daily doses of ibrutinib
• The co-primary endpoints were:
  • Rate of BM-uMRD4 with complete response (including with or without count recovery)
  • Rate of sustained BM-uMRD4 after 2 years ibrutinib maintenance in patients who achieved BM-uMRD4 after ibrutinib plus FCR

Key findings

Baseline

• Overall, 85 patients were enrolled (median age 55 years; 52.9% with unmutated heavy chain variable gene, 47.1% with a Rai stage 3–4)

Efficacy

• With a median follow-up of 63 months, 5-year progression-free survival and overall survival were 94% and 99%, respectively
• No difference in progression-free survival was observed by IGHV status or duration of ibrutinib maintenance
• Patients treated with ibrutinib maintenance had twice the complete response (CR) rate over time compared with after iFCR (79.6% vs 34.7%)
• BM-uMRD4 was achieved by 89.8% including 32.7% of whom achieved CR/ complete remission with incomplete count recovery (CRi) with BM-uMRD4
  • This response was durable and reported in 77.6% after 2 years of ibrutinib maintenance
  • No BTK mutations reported, and only one patient had PLCG2 mutation

Safety

• Thrombocytopenia and neutropenia remained the most commonly reported Grade ≥3 adverse events (31.8% and 40%, respectively)
• Second malignancies were reported in 12.9%
• No additional deaths were reported in the follow up

Key learnings
Treatment with 6 cycles of chemotherapy followed by 2 years of ibrutinib provides durable responses in patients with untreated CLL irrespective of IGHV status Patients with recurrent CLL were not identified with BTK mutations and continued to respond to ibrutinib treatment