ASH 2018 | Eight-year follow up of GALGB 50403 (Alliance) phase II trial: Post-transplant bortezomib in MCL

On Saturday 1 December 2018, Oral Session 623 took place at the 60^th American Society of Hematology (ASH) Annual Meeting, San Diego, CA. During that session, Abstract #146 with the results from the 8-year follow-up of the GALGB 50403 (Alliance) trial were presented by Lawrence Kaplan from the Helen Diller Family  Comprehensive Cancer Center, San Francisco, CA, USA.

GALGB 50403 (Alliance) was a phase II trial that investigated the efficacy and safety of adding post-transplant bortezomib consolidation (BC) or bortezomib maintenance (BM) in mantle cell lymphoma (MCL) patients. The primary analysis of the trial has previously reported a five-year progression-free survival (PFS) of 70% and 69% for BM and BC, respectively. Here the results from the 8-year follow-up of this trial were presented.

Study design & baseline characteristics

• N = 147 histologically-confirmed MCL patients with CD20⁺, CD5⁺, CD23^-, aged < 70, with evidence of cyclin D1 or bcl-1, t(11;14) were included in this analysis
• Median patient age (range): 59 (29−69) years
• Disease stage prior randomization:
  • Stage II/III: 14%
  • Stage IV: 86%
• Mantle Cell Lymphoma International Prognostic Index (MIPI):
  • Low: 52%
  • Intermediate: 31%
  • High: 17%
• Dosing:
  • Induction therapy: augmented R-CHOP for 2 or 3 cycles with 2000 mg/m² cyclophosphamide and methotrexate 300 mg/m² followed by high-dose cytarabine, etoposide, rituximab, filgrastim (EAR) stem cell mobilization and cyclophosphamide, carmustine, etoposide (CBV) autograft
  • After two doses of post-transplant rituximab (375 mg/m²), patients were randomized ~Day 90 to either:
    • BC:3 mg/m² intravenously (IV) on Day 1, 4, 8, and 11 of a three-week cycle, for four cycles in total
    • BM:6 mg/m² IV four times weekly every eight weeks for 18 months
  • Follow-up CT scans were performed every six months for two years from randomization
  • Minimal residual disease (MRD) was assessed every four months during BM or BC until two years after enrollment
  • Patients that were randomized: n = 102 (68%) [BC, n = 50; BM, n = 52]
  • Patients completing randomization treatment:
    • BC: n = 33 patients (66%)
    • BM: n = 34 patients (65%)

Results

• With a median follow-up of 7.8 years, median PFS was:
  • BC: 8.9 years (95% CI, 7.2−not reached)
  • BM: not reached (95% CI, not reached−not reached)
• With a median follow-up of 7.8 years, median overall survival (OS) was:
  • BC: 8.2 years (95% CI, 6.6−not reached)
  • BM: not reached (95% CI, 8.5−not reached)
• With a median follow-up of 7.8 years, MRD status (n = 42 evaluable samples):
  • MRD negative: n = 17
  • MRD positive: n = 25
• Eight-year PFS estimates:
  • BC: 58% (95% CI, 44−76%)
  • BM: 77% (95% CI, 66−90%)
• There were more withdrawals due to adverse events with BC than BM
• Patients completing randomization treatment:
  • BC: n = 33 patients (66%)
  • BM: n = 34 patients (65%)
• Patient withdrawal due to adverse events (AEs):
  • BC: 28% of patients
  • BM: 13% of patients
  • Comparison: P = 0.09
• Most common Grade ≥ 2 AEs observed (BC versus BM):
  • Neutropenia: 68% versus 50%
  • Thrombocytopenia: 50% versus 35%
  • Sensory neuropathy: 48% versus 29%
  • Fatigue: 40% versus 25%

Conclusions

• Post-transplant therapy with bortezomib is feasible but associated with significant toxicity
• MRD-negative post-induction was associated with better PFS and OS
• There was an apparent patient benefit after transplant, which should encourage the development and study of more active, less toxic agents
• The role of ASCT in post-induction MRD-negative patients is under investigation in a randomized clinical trial (EA4151)