Triple Chemoimmunotherapy Regimen Offers Best PFS For Advanced CLL

Fludarabine, cyclophosphamide and rituximab remains the standard of care for physically fit, treatment-naïve patients with advanced chronic lymphocytic leukaemia

medwireNews: Phase III trial results indicate that fludarabine , cyclophosphamide and rituximab is superior to bendamustine plus rituximab for the front-line treatment of physically fit patients with advanced chronic lymphocytic leukaemia (CLL) without deletion 17p.

After a median of 37.1 months, the primary endpoint of progression-free survival (PFS) was 55.2 months for the 282 patients who received the triple chemoimmunotherapy regimen and significantly longer than the 41.7 months for the 279 patients randomly assigned to receive the doublet regimen.

This gave a hazard ratio of 1.643, which exceeded the prespecified value for noninferiority of 1.388, report Barbara Eichhorst, from the University of Cologne in Germany, and co-authors in The Lancet Oncology.

The study included patients aged between 33 and 81 years and subanalysis of those aged 65 years and younger confirmed that triple chemoimmunotherapy was associated with longer PFS at 53.6 versus 38.5 months for the doublet regimen.

However, there was no significant difference in PFS between the two treatment groups for patients aged over 65 years, and there was no difference in overall survival at any age.

Fludarabine, cyclophosphamide and rituximab was associated with more grade 4 toxicity than bendamustine plus rituximab (69 vs 42%). Triple therapy patients were more likely to experience grade 4 haematological side effects (69 vs 39%) and infections (3 vs 2%).

Secondary tumours were reported in 21 and 14 of the triplet and doublet groups, respectively.

The researchers note that participants aged 65 years or older treated with the triple chemoimmunotherapy regimen were at particular risk of infection, with 43% developing grade 3 infections versus 17% of doublet-treated patients.

“Prophylactic use of co-trimoxazole against Pneumocystis jirovecii pneumonia or virostatics against herpes virus infections in patients with previous infections should be considered in patients receiving front-line chemoimmunotherapy”, the authors suggest.

Patients aged over 65 years who were given triple therapy were also significantly less likely to receive all of their planned treatment cycles than those given the doublet regimen (43 vs 24%), they add.

“Higher incidence of adverse events observed with fludarabine, cyclophosphamide, and rituximab in patients older than 65 years and good efficacy with bendamustine and rituximab in this group might support the use of bendamustine and rituximab in fit elderly patients”, the team summarises.

Adrian Wiestner, from theNational Heart, Lung, and Blood Institute in Bethesda, Maryland, USA, notes that in the 5 years since the last enrolment to the CLL10 study treatment options for CLL have “radically changed” with the arrival of ibrutinib, idelalisib, venetoclax and ibrutinib.

“Targeted agents are continued indefinitely raising concerns about long-term toxic effects, compliance, drug resistance, and cost”, he observes. 

“Clarifying the relative risk and benefit of different chemoimmunotherapy regimens is therefore timely and relevant”, he writes, describing the possibility of long-lasting treatment-free remission as a “major attraction”.

The commentator therefore concludes that the “CLL10 study provides information for nuanced discussions about treatment choices tailored to treatment goals, risk–benefit considerations, financial constraints, and personal preferences. A valuable contribution to personalised medicine!”


Eichhorst B, Fink A-M, Bahlo J, et al. First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial. Lancet Oncol 2016; Advance online publication 20 May. DOI:

Wiestner A. Choosing frontline chemoimmunotherapy for CLL. Lancet Oncol 2016; Advance online publication 20 May. DOI:

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