The chemoimmunotherapy combination of fludarabine, cyclophosphamide and rituximab (FCR or R-FC) is recommended for young or fit elderly patients with previously untreated chronic lymphocytic leukemia (CLL).
The German CLL study group CLL8 study, a phase 3 randomized controlled trial comparing the combination of rituximab, fludarabine and cyclophosphamide (R-FC, n=408 patients) to FC alone (n=409), demonstrated superior response rates (Table 1), progression-free survival and overall survival for patients who received R-FC versus FC alone.r The overall response rate (ORR) were 90% (FCR) compared to 80% (FC, p<0.0001) including a complete response rate (CR) of 44% (FCR) versus 22% (FC, p<0.0001). The hazard ratios for PFS and OS were 0.56 [95%CI: 0.46 – 0.69] and 0·67 [0·48–0·92] respectively.
The MD Anderson group updated their outcomes with the FCR regimen.r The 6-year median overall survival of 77% and failure-free survival of 51% suggest that a significant proportion of patients may achieve long-lasting remissions with this chemoimmunotherapy regimen. Both studies demonstrated that patients with 17p deletions were less likely to achieve long-lasting responses following either FC or FCR.
Table 1r
| |
FC |
|
FCR |
|
| |
CR |
ORR |
CR |
ORR |
| All Patients |
22 |
80 |
44 |
90 |
| Less than 65 years |
20 |
79 |
45 |
89 |
| Greater than or equal to 65 years |
24 |
83 |
43 |
93 |
| FISH Result |
|
|
|
|
| 13q deletion |
23 |
80 |
48 |
96 |
| 11q deletion |
15 |
87 |
51 |
93 |
| Trisomy 12 |
19 |
84 |
71 |
100 |
| 17p deletion |
0 |
34 |
5 |
68 |
| No abnormality |
28 |
91 |
35 |
89 |
FCR may also be used in the relapsed CLL. The REACH studyr demonstrated superior responses and progression-free survival of FCR over FC in patients with CLL in first relapse who had received prior fludarabine or alkylator-based therapy. Patients who had received prior FC or rituximab were excluded. There was no statistical difference in overall survival between the two groups at a median follow-up time of 25 months.r
The MD Anderson group updated their experience with FCR in a phase II single arm study of FCR for patients with relapsed CLL. This study demonstrated good responses (ORR 74% and CR 30% for all patients) and progression-free survival (21 months) following administration of FCR in this population. CLL patients who had received more than 3 prior treatments, were fludarabine-refractory, or patients with chromosome 17 abnormalities experienced suboptimal responses and short progression-free survival.
r
Efficacy
Progression free survival (A) and overall survival (B) in all patients with Previously Untreated Chronic leukaemia receiving chemoimmunotherapy (FCR) compared to chemotherapy (FC)r(GCLLSG CLL8 study)
© Lancet 2010
In a more recent meta-analysis conducted by Nunes et al. comparing FC and FCR in patients with CLL, the PFS was 32.8 months in the FC group and 51.8 months in the FCR group. The difference between the two groups was statistically significant (p<0.05).r
Toxicity
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 if 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).
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% v. 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 with relapsed CLL and adjustment in dosing of fludarabine should be considered according to estimated glomerular filtration rate (eGFR).
Table 2: Grade 3 or 4 toxicity of FCR as initial therapy for chronic lymphocytic leukemiar
© 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 leukemia/ myelodysplastic syndrome (t-AML/MDS) (5.1%) and Richter transformation (RT) (9%) were high while solid tumors were not increased. The survival of affected patients is shorter.r