On 17 May, Emanuele Zuccafrom the Oncology Institute of Southern Switzerland, Bellinzona, CH, and colleagues, published results from a phase II trial in follicular lymphoma (FL) ( NCT01307605), in Blood . 1 This trial compared the efficacy and safety of rituximab monotherapy to rituximab plus lenalidomide in patients with previously untreated FL.
Rituximab in combination with chemotherapy is a standard of care treatment for patients with symptomatic advanced stage FL. 2The investigators sought to examine whether in previously untreated patients with FL, rituximab alone or with chemotherapy, is an effective treatment plan.
The primary endpoint of this open-label, randomized, multicentre trial was complete response (CR) rate at around six months following treatment. Secondary endpoints included overall response rate (ORR), CR rate at 30 months post treatment, progression-free survival (PFS), duration of response (DoR), time-to-next treatment (TTNT), overall survival (OS), and safety.
Study design & baseline characteristics
- N = 154 patients with previously untreated Grade 1−3A FL with CD20 immunohistochemistry, stage II−IV not eligible for radiotherapy
- Dosing:
-
Rituximab monotherapy (R arm; n= 77):eight cycles of intravenous R administration (375 mg/m
2) at Day 1 of Week 1−4
- In responding patients, R was repeated at Day 1 of Week 12−15
- Rituximab + lenalidomide (RL arm; n = 77):eight cycles of R (as above) plus 15 mg of oral L daily, starting 14 days prior to R administration and daily until 14 days after the last R administration (18 weeks in total)
- Randomization was stratified according to:
- Histological grade (Grade 1−2 vs3A)
- Bulky disease (< 6 cm vs≥ 6 cm)
- FL International Prognostic Index (FLIPI) score (1−2 vs≥ 3)
-
Rituximab monotherapy (R arm; n= 77):eight cycles of intravenous R administration (375 mg/m
2) at Day 1 of Week 1−4
- No R dose adjustments were allowed but L could be adjusted according to renal function and toxicity
- Median patient age (range) in total cohort: 62 (26−85)
- Male patients in total cohort: 47%
|
Baseline characteristic |
R arm
|
RL arm
|
Total cohort
|
|---|---|---|---|
|
Ann Arbor stage II III IV |
10% 38% 52% |
14% 38% 48% |
12% 38% 50% |
|
FLIPI score Low risk Intermediate risk High risk |
19% 34% 47% |
27% 26% 47% |
23% 30% 47% |
|
FL histological grade 1 2 3a |
23% 60% 17% |
26% 58% 16% |
25% 59% 16% |
|
Bulky disease < 6 cm ≥ 6 cm |
60% 40% |
58% 42% |
59% 41% |
Key findings
- All R cycles (eight) were completed by:
- R arm: 71% of patients
- RL arm: 91% of patients
- Number of patients completing treatment with the planned L dose (RL arm): ≥ 90% of patients
- 29% patients in RL arm had at least one L dose reduction:
- Treatment discontinuation due to insufficient response at week 10 occurred in:
- R arm: 21% of patients
- RL arm: 4% of patients
- Median follow-up of the intention-to-treat (ITT) population (range): 4 (3.3−7) years
| * P= 0.001 | ||
|
|
R arm (n = 77) |
RL arm (n = 77) |
|---|---|---|
|
CR & unconfirmed CR (CRu)* |
36% (95% CI, 26−48) |
61% (95% CI, 49−72) |
|
Partial response (PR) |
21% |
17% |
|
Stable disease (SD) |
9% |
3% |
|
Progressive disease (PD) |
4% |
1% |
|
Not evaluable |
30% |
18% |
- The CR/CRu improvement seen with the addition of L was sustained over time
- At a follow-up of 30 months the CR/CRu rate was 19% vs42% ( P= 0.001)
- At a median follow-up of 4 years (R
vsRL):
- Median PFS rate was 2.3 vs0 years, ( P= 0.035)
- Median CR/CRu response was 3.0 years vsnot reached ( P= 0.055)
- TTNT was 2.1 years vsnot reached ( P= 003)
- OS was not significant: 91% (95% CI, 81−96) vs90% (95% CI, 79−95)
- However, multiple regression analysis revealed that CR/CRu rate at Week 23 was not associated with treatment regimen ( P= 0.1094), FLIPI score ( P= 0.9979), tumor bulk ( P= 0.2672) or FL grade ( P= 0.5797)
- Cox proportional hazard modelling revealed that FLIPI score was associated with longer PFS (HR = 1.845; [95% CI, 1.148−962]; P= 0.0113)
- Number of patients who started a second-line immunochemotherapy at the time of analysis:
- R arm: 60% of patients
- RL arm: 39% of patients
Safety
- Treatment discontinuation due to toxicity occurred in:
- R arm: n = 1 patient
- RL arm: n = 13 patients (11 patients stopped L only)
- Grade ≥ 3 adverse events (AEs) occurred in:
- R arm: 22% of patients
- RL arm: 56% of patients
- Grade 3 and 4 neutropenia occurred in:
- R arm: 7% of patients
- RL arm: 23% of patients
- No treatment-related deaths occurred during the trial in either arm
- AEs more commonly observed in the RL arm:
- Fatigue
- Diarrhea
- Skin rash
Conclusions
Lenalidomide in combination with rituximab led to a significantly better CR/CRu rate, longer PFS and TTNT, when compared to rituximab monotherapy in patients with previously untreated FL. However, there was no significant effect on OS.