"Ibrutinib–Rituximab or Chemoimmunotherapy for CLL". The New England Journal of Medicine. 2019.

Clinical Question

In patients 70 years of age or younger with previously untreated chronic lymphocytic leukemia (CLL), how does treatment with ibrutinib-rituximab compare with standard chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab?

Bottom Line

In patients 70 years of age or younger with previously untreated CLL, ibrutinib-rituximab therapy led to superior progression-free survival and overall survival compared with chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab.

Major Points

Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab has been the standard first-line treatment for younger, fit patients with CLL. Ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, has shown efficacy in patients with relapsed/refractory and untreated CLL. This phase 3 trial demonstrated that ibrutinib in combination with rituximab was superior to standard chemoimmunotherapy in progression-free and overall survival in previously untreated patients younger than 70 years old with CLL.

Guidelines

Current guidelines for CLL treatment reflect earlier data and may not yet include the combination of ibrutinib and rituximab as a frontline therapy in fit patients aged 70 or younger. These guidelines will likely be updated following the publication of this trial's results.

Design

- Multicenter, open-label, randomized, phase 3 trial
- N=529
- Ibrutinib-rituximab (n=354)
- Chemoimmunotherapy with fludarabine-cyclophosphamide-rituximab (FCR) (n=175)
- Median follow-up: 33.6 months

Population

- Inclusion Criteria: Previously untreated patients with CLL/SLL, ≤70 years old, appropriate for FCR treatment, no chromosome 17p13 deletion
- Exclusion Criteria: Details within Supplementary Appendix
- Baseline Characteristics: Median age 58 years, majority were male, Rai stage I-II in majority

Interventions

- Ibrutinib-rituximab: Ibrutinib (420 mg/day) until disease progression + rituximab for 6 cycles
- Chemoimmunotherapy: Fludarabine + cyclophosphamide + rituximab for 6 cycles

Outcomes

- Primary Outcome: Progression-free survival
- 3-year survival: 89.4% ibrutinib-rituximab vs. 72.9% FCR, HR 0.35, 95% CI [0.22-0.56], P<0.001
- Secondary Outcome: Overall survival
- 3-year survival: 98.8% ibrutinib-rituximab vs 91.5% FCR, HR 0.17, 95% CI [0.05-0.54], P<0.001

Criticisms

- Indefinite therapy with ibrutinib has potential long-term side effects and cost implications.
- FCR has a proven long-term efficacy, particularly in patients with IGHV-mutated CLL.

Funding

- National Cancer Institute and Pharmacyclics (a subsidiary of AbbVie).

Further Reading

- ClinicalTrials.gov number, NCT02048813
- Full NEJM article with supplementary material