In the German CLL8 study 76% of patients experienced at least one grade 3 or 4 adverse event following chemoimmunotherapy with FCR (table 2). The majority of these events were haematological toxicity (56%) with neutropenia (34%) being most common. Chemoimmunotherapy with FCR was associated with a higher rate of grade 3 or 4 neutropenia compared to FC (34% versus 21% respectively, P<0.0001); however, the rates of severe infections were similar (25% versus 21%, p=0.18).
In the GCLLSG CLL10 study FCR was more toxic than bendamustine-rituximab with increased neutropenia (84% vs. 59%) and severe infections (39% vs. 25%).r In the ECOG-ACRIN E1912 trial grade 3+ infections were higher in the FCR arm (20%) than ibrutinib-rituximab.r
Similar rates of grade 3 or 4 complications were noted in the REACH study (Table 3).r Almost all patients experienced grade 3 or 4 neutropenia during the study with a slightly higher incidence in the FCR arm (FCR 89% vs. FC 84%). Despite this, the overall incidence of infections (FC 51% and FCR 49%) and grade 3 or 4 infections (FC 19% and FCR 18%) did not differ between arms. Fatal adverse events occurred in 10% (FC) and 14% (FCR) of patients, mostly related to serious infections. In the phase 2 MD Anderson trial for relapsed CLL, patients older than 70 years with relapsed CLL were less likely to complete therapy and had a higher incidence of serious infections and myelosuppression.r
This regimen should be used with caution in elderly patients and patients with co-morbidities including reduced creatinine clearance. Landmark trials demonstrating efficacy and survival for the FCR regimen excluded patients with CrCl <70 mL/min.rr Other clinical trials have included patients with creatinine clearance as low as 40 mL/min without dose modification.r There are no clear data on the efficacy and toxicity when modifying dose due to renal dysfunction.
Table 2: Grade 3 or 4 toxicity of FCR as initial therapy for chronic lymphocytic leukaemiar
© Lancet 2010
Table 3: Toxicity of FCR as first salvage therapy of relapsed chronic lymphocytic leukaemiar
© American Society of Clinical Oncology 2010
In a more recent trial conducted by Benjamini et al., the risk of second cancers was found to be 2.38 times higher than the expected risk in the general population (40% had other cancers before and 28% after FCR). Second cancer risk after frontline FCR is mainly due to high rates of acute myeloid leukaemia / myelodysplastic syndrome (t-AML/MDS) (5.1%) and Richter transformation (RT) (9%) while solid tumors were not increased. The survival of affected patients is shorter.r
Early studies incorporating single agent fludarabine confirmed similar pharmokinetic data for IV fludarabine 25mg and oral fludarabine 40mg. Retrospective reviews of studies in fludarabine and cyclophosphamide demonstrate comparable efficacy, however increased gastrointestinal toxicity when substituting oral fludarabine.r With these data oral FCR has been incorporated into clinical trials, though there are no head-to-head trials of IV and oral FCR. The ARCTIC and ADMIRE studies used the regimen of fludarabine 24 mg/m2 daily and cyclophosphamide 150 mg/m2 daily for 5 days with similar outcomes to historical IV FCR.rr The CLL2007 SA studyr used oral fludarabine 40 mg/m2 and cyclophosphamide 250 mg/m2 for 3 days and ICORG 07-01 studyr allowed IV or oral formulations, however cycle numbers were limited to 4, and direct comparisons can not be made. Oral fludarabine and cyclophosphamide utilising modified dosing may be considered.