1. Two pivotal CLL trials: CLL8, FCR vs FC in CLL upfront and REACH, FCR vs FC in relapsed CLL
Summary Author: Dr. C. Tom Kouroukis, MD MSc FRCPC
Date posted: January 30, 2009

2. REACH trial in CLL
Considered to be the pivotal randomized trial of adding rituximab to fludarabine and cyclophosphamide in patients with relapsed CLL
Rituximab responses in CLL traditionally have been poor when used as a single agent
Addition of rituximab in phase II studies with purine analogues has shown encouraging response rates (Wierda et al, J Clin Oncol, 2005)
Robak et al., ASH 2008, #1

3. Fludarabine 25 mg/mg2 IV daily x 3 days
REACH trial in CLL
Open label multicentre study of rituximab with fludarabine/cyclophosphamide in relapsed/refractory CD20+ CLL patients
Rituximab was given on day 1 of treatment, 375 mg/m2 for cycle 1 and 500 mg/m2 for cycles 2-6
Fludarabine 25 mg/mg2 IV daily x 3 days
Cyclophosphamide 250 mg/m2 IV daily x 3 days
6 cycles given, interval q28 days
Primary endpoint: PFS
Robak et al., ASH 2008, #1

4. Balanced baseline features Median of one prior therapy
REACH trial in CLL
552 patients
Median age 63 years
Balanced baseline features
Median of one prior therapy
Mostly Binet stages B and C
Prior FC treatment or prior rituximab not eligible
Median observation time of 25 months
Robak et al., ASH 2008, #1

5. Subgroup analysis showed benefits across all Binet stages
REACH trial in CLL
Median PFS better by 10 months in R-FC arm (30.6 vs 20.6 months, p=0.0002)
Secondary endpoints of EFS, time to next treatment, duration of response also better for R-FC arm
Subgroup analysis showed benefits across all Binet stages
Median OS not reached for R-FC, was 53 months for FC (p=0.29)
Robak et al., ASH 2008, #1

6. Higher grade ¾ adverse events in R-FC arm
REACH trial in CLL
Higher grade ¾ adverse events in R-FC arm
No difference in serious adverse events or serious infections
Slightly higher fatal adverse events with R-FC (13% vs. 10%)
Robak et al., ASH 2008, #1

7. Some increase in toxicities with R-FC Await more mature survival data
REACH trial in CLL
Conclusions:
Benefits in progression free survival with the addition of rituximab to FC in relapse/refractory CLL patients
Some increase in toxicities with R-FC
Await more mature survival data
Robak et al., ASH 2008, #1

8. REACH trial in CLL Canadian context
Reimbursement for rituximab in CLL has been uneven across Canada, mostly due to the lack of published comparative/phase III data
This study is considered the pivotal one to show a benefit in PFS for relapsed/refractory CLL patients treated with R-FC
As some patients received rituximab upon progression, not sure if survival benefits will be demonstrable in the long term
Robak et al., ASH 2008, #1

9. REACH trial in CLL Canadian context
One may assume the benefits of R-FC may also be seen with R-F alone, this might be less toxic than R-FC
Rituximab for the most part has shown benefits across all tested low grade lymphoma histologies including CLL, suggesting that generalizing its beneficial effects is reasonable
Caution regarding selection of patients for R-FC as there may be significant toxicities and this may not be generalizable to the more elderly or frail patient with CLL

10. Background hypothesis similar to REACH trial
CLL8 Trial
Background hypothesis similar to REACH trial
Trial designed to test the benefits of adding rituximab to upfront treatment of patients with newly diagnosed CLL, in combination with fludarabine and cyclophosphamide (FC)
Multicentre, international phase III trial run by the German CLL study group
Hallek et al., ASH 2008, #325

11. 817 patients with good renal function and limited comorbidities
CLL8 Trial
817 patients with good renal function and limited comorbidities
Random assignment to either 6 cycles of FC or R-FC (same doses as REACH study)
Median age 61 years
Both arms balanced for baseline factors
Hallek et al., ASH 2008, #325

12. Median number of treatments: 5.2 for RFC and 4.8 for FC
CLL8 Trial
Median number of treatments: 5.2 for RFC and 4.8 for FC
Growth factors were not routinely recommended
Median observation time of 25.5 months
761 pts evaluable for response
Overall response better for RFC (95% vs 88%, p=0.001)
Hallek et al., ASH 2008, #325

13. PFS at 2 years better for RFC arm (77% vs. 62%, p<0.0001)
CLL8 Trial
PFS at 2 years better for RFC arm (77% vs. 62%, p<0.0001)
No detectable 2 year overall survival difference (RFC 91% vs. FC 88%, p=0.18)
More neutropenia and leukopenia in the RFC arm
Grade 3 and 4 infections similar
Treatment related mortality similar for RFC and FC (2% vs. 1.5%)
Hallek et al., ASH 2008, #325

14. CLL8 Trial
Multivariable analysis for outcome showed that age, sex, Binet stage, comorbidity score, renal function were independent prognostic factors for OS and PFS
RFC improves response rates and PFS when compared to FC chemotherapy in newly diagnosed patients with CLL who are reasonably “fit”
Hallek et al., ASH 2008, #325

15. CLL8 Trial – Canadian Context
As in the REACH study, this study provides high level evidence for the benefit of rituximab when added to FC chemotherapy as upfront therapy for CLL
Caution regarding generalizability to more elderly or frail patients with CLL as one may expect more toxicities
Similar to REACH, it may be reasonable to assume that the benefits of R with FC may extent to R with F alone as upfront therapy.
Hallek et al., ASH 2008, #325