Phase II BRISMA/IELSG36 results on bendamustine and rituximab in splenic MZL

On 8 November 2018, Emilio Iannitto from University Hospital Paolo Giaccone Polyclinic, Palermo, IT, and colleagues, published in the British Journal of Haematology results from the phase II BRISMA/IELSG36 trial (NCT02853370) on the efficacy and safety of bendamustine and rituximab in splenic marginal zone lymphoma (MZL).

Splenic MZL is a rare type of indolent B-cell lymphoma. Because of its low incidence, no randomized trials for splenic MZL are available and treatment options are usually evaluated based on retrospective analyses. The aim of this study was to prospectively evaluate the efficacy and safety of first-line bendamustine and rituximab (B-R) combination treatment in patients with splenic MZL. The primary endpoint was complete response rate (CRR). Secondary endpoints included overall response rate (ORR), progression-free survival (PFS), duration of response (DoR), event-free survival (EFS), overall survival (OS), and safety.

Study design

• N = 56 eligible patients:
  • Non-splenectomized patients with CD20⁺ active symptomatic splenic MZL diagnosis and measurable disease (n = 54)
  • Splenectomized patients were also eligible if they had disease progression (PD; n = 2)
• Study duration: December 2013–October 2014
• B-R dosing (28-day cycles):
  • B: 90 mg/m² (Day 1–2)
  • R: 375 mg/m² (Day 1)
  • B administration was delayed for seven days if Grade 4 hematological or Grade ≥ 2 non-hematological toxicity occurred
• Twice a week prophylaxis with valaciclovir (500 mg, once a day) and trimethoprim/cotrimoxazole (800 mg, twice a day) was recommended for all patients during all B-R cycles
• Patients achieving complete response (CR) after three cycles received only one additional B-R cycle. Those achieving partial response (PR) received three additional B-R cycles. Patients not achieving at least PR after three courses were withdrawn from the study

Results

• Forty-five out of N = 56 patients completed treatment (80%):
  • Received four B-R cycles: n = 7 (12%)
  • Received six B-R cycles: n = 38 (68%)
  • B-R discontinuation: n = 11 (20%)
  • B dose reduction: n = 4
• Final analysis after 3 B-R cycles (by local clinicians):
  • CR, n = 7: 13% (95% CI, 5–24)
  • PR, n = 39: 70% (95% CI, 56–81)
  • ORR (CR + PR): 82% (95% CI, 72–92)
• Final analysis (centralized review based on the intention-to-treat principle):
  • CR, n = 41 (34 CR and 7 unconfirmed CR [CRu]): 73% ( 95% CI, 60–84)
  • PR, n = 10: 18% (95% CI, 9–30)
  • ORR, n = 51: 91% (95% CI, 80–97)
  • Stable disease (SD), n = 4: 7% (95% CI, 2–17)
• Median observation time (range) = 32 months (2–52)
  • Three relapses observed
  • Three-year DoR: 93% (95% CI, 81–98)
  • Three-year PFS estimate: 90% (95% CI, 77–96)
  • Three-year EFS estimate: 80% (95% CI, 65–89)
  • Three-year OS estimate: 96% (95% CI, 84–98)

Safety

• Any grade adverse events (AEs): n = 50 patients (89%)
• Treatment-related Grade ≥ 3 AEs: n = 38 patients (68%)
• Five patients discontinued treatment due to toxicity
• Most common hematological Grade ≥ 3 AEs:
  • Neutropenia: n = 24 (42.8%)
  • Thrombocytopenia: n = 9 (16.1%)
  • Anemia: n = 5 (8.9%)
• Non-hematological AEs were almost all Grade 1–2 (only three cases of Grade ≥ 3), most common:
  • Nausea/vomiting (Grade 1–2) (n = 22, 39.3%)
  • Maculo-papular rash (Grade 1–2) (n = 8, 14.3%)
  • Infusion-related reactions (Grade 1–2) (n = 12, 21.4%)
  • Infections (Grade ≥ 3, n = 2; 3.6%)
  • Febrile neutropenia (Grade ≥ 3, n = 3; 5.3%)
• Serious AEs: n = 14 (25%)
• Lethal toxicity: n = 1 (1.8%) due to lung infection

The results of this phase II trial indicate that B-R as first-line treatment for splenic MZL is safe. According to the authors, B-R led to fast and durable disease control with a high response rate and with 13% of patients achieving CR after only three B-R cycles. The investigators are urging for further randomized prospective trials comparing B-R to R treatment for the ultimate validation of these results.