Lenalidomide plus rituximab versus rituximab monotherapy in previously-untreated FL: Results from a phase II trial

On 17 May, Emanuele Zucca from 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.² The 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/m²) 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 vs 3A)
    • Bulky disease (< 6 cm vs ≥ 6 cm)
    • FL International Prognostic Index (FLIPI) score (1−2 vs ≥ 3)
• 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%

Table 1. Key baseline characteristics

Baseline characteristic

R arm
(n = 77)

RL arm
(n = 77)

Total cohort
(N = 154)

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

Table 2. Responses at Week 23 (ITT population) based on Independent Response Review (IRR) * 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% vs 42% (P = 0.001)
  • At a median follow-up of 4 years (R vs RL):
    • Median PFS rate was 2.3 vs0 years, (P = 0.035)
    • Median CR/CRu response was 3.0 years vs not reached (P = 0.055)
    • TTNT was 2.1 years vs not reached (P = 003)
    • OS was not significant: 91% (95% CI, 81−96) vs 90% (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.