MZL

IELSG-19 Final Results: Is Combination Chlorambucil And Rituximab More Effective Than Monotherapy In The Treatment Of MALT Lymphoma?

On March 29th, 2017, Emanuel Zucca, from the Oncology Institute of Southern Switzerland, Ospedale San Giovanni, Bellinzona, Switzerland, and colleagues published in the Journal of Clinical Oncology the final results of the International Extranodal Lymphoma Study Group 19 (IELSG-19) study. This open-label, multicenter, randomized, phase III study which aimed to assess the efficacy of either chlorambucil alone (CL) or a combination of chlorambucil and rituximab (CL+R) in the treatment of extranodal marginal zone lymphoma of Mucosa-Associated Lymphoid Tissue (MALT) in the first-line setting. Patients were randomized 1:1. The initial study had two arms but a third arm, assessing the efficacy of rituximab only therapy (R), was later added, which resulted in a 1:1:6 ratio. The primary endpoint was Event Free Survival (EFS).

Key Highlights:

  • Total 452 pts randomized:
    • CL = 151 pts, 131 pts in final analysis
    • CL+R = 151 pts, 132 pts in final analysis
    • R = 151 pts, 138 pts in final analysis
  • Treatment:
    • CL = induction: 6 mg/m2 daily for 42 days
      • After restaging, pts with SD or OR received 6mg/m2 daily for up to four cycles of 14 days on, 14 days off
    • CL+R = Induction as CL plus rituximab: 375mg/ m2 on D1, 8, 15, and 22 of induction
      • After restaging: 375mg/m2 rituximab given on D1 of each CL cycle
    • R = rituximab 375mg/ m2 on D1, 8, 15, and 22 of induction
      • After restaging: 375mg/m2 rituximab given on D1 of week 9, 13, 17, and 21
    • Efficacy:
      • Total: ORR = 86%, CR = 65.8%, PR = 20.2%, SD = 7%, PD = 5.7%
      • CL alone = ORR = 85.5%, CR = 63.4%, PR = 22.1%, SD = 8.4%, PD = 5.3%
      • CL + R = ORR = 94.7%, CR = 78.8%, PR = 15.9%%, SD = 0.8%, PD = 3%
      • R alone = ORR = 78.3%, CR = 55.8%, PR = 22.5%, SD = 11.6%, PD = 8.7%
    • Median follow-up: CL and CL+R arms = 9.3 years vs7 years for R alone
      • Median EFS (mEFS): CL = 5.1 years, R = 5.6 years, CL+R = not reached - mEFS significantly longer in CL+R arm (P = 0.0009)
      • Five-year EFS: CL = 51% vs R = 50% vs CL+R = 68% (95% CI, 60–76)
    • mPFS: CL = 8.3 years, R = 6.9 years, CL+R = median not reached - significantly longer mPFS in CL+R (P = 0.0119)
      • Five-year PFS was longer in CL+R (72%) than with CL or R alone (59% and 57%)
    • No significant difference in OS observed (P = 0.464)
      • Five-year OS: CL = 89%, R = 92%, CL+R = 90%
    • Haematological toxicities were higher in combination arm
    • No febrile neutropenia of any grade was reported in CL or R arms, but three patients had grade 3 febrile neutropenia in the CL+R arm

In conclusion, the authors stated that chlorambucil in combination with rituximab was more effective in treating MALT patients than monotherapy with either drug. The improved EFS and PFS reported did not result in a significantly higher OS, but given that combination therapy resulted in few added toxicities this combination therapy is justified as first-line treatment. The authors concluded by stating that the results of this study may help to define a standard regimen for MALT lymphoma patients.

Reference:
  1. Zucca E. et al. Final Results of the IELSG-19 Randomized Trial of Mucosa-Associated Lymphoid Tissue Lymphoma: Improved Event-Free and Progression-Free Survival With Rituximab Plus Chlorambucil Versus Either Chlorambucil or Rituximab Monotherapy. Journal of Clinical Oncology. 2017 Mar 30. DOI: 1200/JCO.2016.70.6994. [Epub ahead of print: 2017 Mar 30].

Abstract:

Purpose. There is no consensus on the optimal systemic treatment of patients with extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue. The IELSG-19 phase III study, to our knowledge, was the first such study to address the question of first-line treatment in a randomized trial. Patients and Methods. Eligible patients were initially randomly assigned (1:1 ratio) to receive either chlorambucil monotherapy (6 mg/m2/d orally on weeks 1 to 6, 9 to 10, 13 to 14, 17 to 18, and 21 to 22) or a combination of chlorambucil (same schedule as above) and rituximab (375 mg/m2 intravenously on day 1 of weeks 1, 2, 3, 4, 9, 13, 17, and 21). After the planned enrollment of 252 patients, the protocol was amended to continue with a three-arm design (1:1:6 ratio), with a new arm that included rituximab alone (same schedule as the combination arm) and with a final sample size of 454 patients. The main end point was event-free survival (EFS). Analysis of chlorambucil versus the combination arm was performed and reported separately before any analysis of the third arm. Results. At a median follow-up of 7.4 years, addition of rituximab to chlorambucil led to significantly better EFS (hazard ratio, 0.54; 95% CI, 0.38 to 0.77). EFS at 5 years was 51% (95% CI, 42 to 60) with chlorambucil alone, 50% (95% CI, 42 to 59) with rituximab alone, and 68% (95% CI, 60 to 76) with the combination (P = .0009). Progression-free survival was also significantly better with the combination (P = .0119). Five-year overall survival was approximately 90% in each arm. All treatments were well tolerated. No unexpected toxicities were recorded. Conclusion.Rituximab in combination with chlorambucil demonstrated superior efficacy in mucosa-associated lymphoid tissue lymphoma; however, improvements in EFS and progression-free survival did not translate into longer overall survival.