Is Fludarabine (FLU), Cyclophosphamide (CYC), and Rituximab (RTX) (FCR) still used in the treatment of Chronic Lymphocytic Leukemia (CLL)?

FCR in Chronic Lymphocytic Leukemia Treatment

FCR (Fludarabine, Cyclophosphamide, and Rituximab) remains a standard first-line therapy for specific subgroups of CLL patients, particularly younger (<65 years), physically fit patients with mutated IGHV status and without del(17p)/TP53 mutations. 1

Current Role of FCR in CLL Treatment

Patient Selection for FCR

• FCR is a category 1 recommendation for first-line therapy in patients <65 years without significant comorbidities and without del(17p)/TP53 mutations 1
• FCR demonstrates superior outcomes in:
  • Physically fit patients under 65 years of age 1
  • Patients with mutated IGHV status 1
• FCR is not recommended for:
  • Patients with del(17p) or TP53 mutations (poor response to chemoimmunotherapy) 1
  • Frail patients or those with significant comorbidities 1
  • Generally avoided in patients >65 years due to increased toxicity 1

Efficacy of FCR

• FCR results in higher complete response rates (40% vs 31%) compared to BR (bendamustine + rituximab) 1
• Achieves higher minimal residual disease (MRD) negativity (59% vs 26% at 12 months) 1
• Provides longer median progression-free survival (PFS) of 55.2 months vs 41.7 months with BR 1
• Particularly effective in patients with mutated IGHV, with some studies showing a plateau in the PFS curve beyond 10 years 1

Alternatives to FCR

For Older/Less Fit Patients

• Bendamustine + rituximab (BR) is preferred for fit elderly patients or those with previous infections 1
• Obinutuzumab + chlorambucil (category 1) for patients ≥65 years with comorbidities 1
• Ibrutinib (category 1) for patients ≥65 years with comorbidities 1
• BR shows similar outcomes to FCR in patients >65 years but with less toxicity 1, 2

For Patients with del(17p)/TP53 Mutations

• Alemtuzumab with corticosteroids is recommended instead of FCR 1, 3
• Consider allogeneic stem cell transplantation for eligible patients after response 1
• Targeted agents acting independently of p53 pathway are preferred 3

Toxicity Considerations with FCR

• Higher incidence of severe neutropenia and infections (39% vs 25%) compared to BR, especially in those >65 years 1
• Increased risk of secondary acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) - 3% with FCR vs 1% with BR 1
• In patients >65 years, secondary neoplasia occurred more frequently after FCR (32.6%) compared to BR (16.8%) 2

Retreatment Considerations

• Patients with long first remission (≥3 years) may benefit from FCR rechallenge at relapse 4
• Patients with short first remission (<3 years) have poor outcomes regardless of salvage therapy and should be considered for novel therapies 4

FDA Indication

• Rituximab, in combination with fludarabine and cyclophosphamide (FC), is indicated for the treatment of adult patients with previously untreated and previously treated CD20-positive CLL 5

FCR remains an important treatment option in CLL, but patient selection is critical to maximize benefit while minimizing toxicity. The treatment landscape continues to evolve with newer targeted therapies, but FCR maintains its place for specific patient populations.