Long-term outcomes of the MURANO phase III trial: Venetoclax plus rituximab leads to prolonged outcomes in R/R CLL

On 1 December 2018, during the 60^th Annual Meeting of the American Society of Hematology (ASH), San Diego, CA, John Seymour, from the Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, AU presented a long-term outcome analysis of the MURANO phase III trial (Abstract #184).

This abstract was presented during Oral Session 642 ‘CLL: Therapy, excluding Transplantation: Measurable Residual Disease in CLL: Moving Towards a Cure’. The MURANO trial demonstrated that fixed-duration venetoclax and rituximab (VenR) provide a significantly longer progression-free survival (PFS), compared to bendamustine and rituximab (BR) in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) patients. Here, with all patients having completed therapy the investigators analyzed long-term outcomes with a median follow-up of 36.0 months.

Study design

• MURANO phase III trial: N = 389 R/R CLL patients were randomized to VenR (n = 194) or BR (n = 195)
• Dosing:
  • VenR: 5 weeks with gradual dose increase from 20 mg to 400 mg daily; then, for up to two years, 400 mg Ven daily and 375 mg/m² R
  • BR: 70 mg/m² B and 375 mg/m² R for six months
• Median follow-up: 36 months (May 2018). By then, 18% of patients progressed, died or withdrew from study in the VenR arm, compared to 66% in the BR group
• Median treatment exposure (range):
  • VenR: 24.4 (0.1−9) months
  • BR: 5.5 (0.9−5) months
• Patient baseline characteristics were not significantly different between the two arms (median age, high lymphocyte count patients, TP53 mutation incidence, unmutated IGHV patients, number of prior lines, type of prior therapies)

Results

• At a median follow-up of 23.8 months (range, 0.0−4):
  • VenR:
    • median progression-free survival [PFS]: not reached; n = 194
    • 2-year PFS: 84.9% (95% CI, 79.1−6); n = 194
  • BR:
    • median PFS: 17.0 months; n = 195
    • 2-year PFS: 36.3% (95% CI, 28.5−0); n = 195; When compared to VenR: HR = 0.17 (95% CI, 0.11−0.25); P < 0.001)
  • At a median follow-up of 36.0 months (range, 0.0−6):
    • VenR (36.1 months):
      • median PFS: not reached; n = 194
      • 3-year PFS: 71.4% (95% CI, 64.8−1); n = 194
      • 3-year overall survival (OS): 87.9% (95% CI, 83.1−7); n = 194
    • BR (35.9 months):
      • median PFS: 17.0 months; n = 195
      • 3-year PFS: 15.2% (95% CI, 9.1−4); n = 195; When compared to VenR: HR = 0.16 (95% CI, 0.12−0.23)
      • 3-year OS: 79.5% (95% CI, 73.3−6); n = 195; When compared to VenR, HR = 0.50 (95% CI, 0.30−0.85)
      •  
    • Most patients did not progress after cessation of Ven monotherapy at end of treatment
    • Richter’s transformation occurred in similar numbers of patients in each arm:
      • VenR: 3.6 % (n = 7/194)
      • BR: 3.2% (n = 6/188)
    • After the end of treatment, for patients who continued Ven monotherapy (n = 130), median follow-up off-treatment was 9.9 months:
      • 6-month PFS: 92.0% (95% CI, 87.1−8)
      • 1-year PFS: 87.4% (95% CI, 81.1−8)
      • Patients with events: 12.3%

Safety

• The most common Grade 3−4 adverse events (AEs) in each arm were:
  • VenR (n = 194):
    • Neutropenia: 58.8%
    • Anemia: 10.8%
    • Thrombocytopenia: 5.7%
    • Febrile neutropenia: 3.6%
    • Pneumonia: 5.2%
    • Infusion-related reaction: 2.1%
    • Tumor lysis syndrome (TLS): 3.1%
    • Hyperglycemia: 2.1%
    • Hypogammaglobulinemia: 2.1%
  • BR (n = 188):
    • Neutropenia: 39.9%
    • Anemia: 13.8%
    • Thrombocytopenia: 10.1%
    • Febrile neutropenia: 9.6%
    • Pneumonia: 8.0%
    • Infusion-related reaction: 5.3%
    • TLS: 1.1%
    • Hypertension: 2.7%
  • During Ven monotherapy period (n = 171):
    • Neutropenia: 11.7%
    • Anemia: 2.9%
    • Thrombocytopenia: 1.8%
    • Pneumonia: 1.2%
    • Hypogammaglobulinemia: 0.6%

Conclusions

• After a median follow-up of 36 months and with all patients having completed therapy, PFS was still significantly prolonged with VenR versus BR treatment
• With this longer follow-up, clinically longer OS was observed with VenR versus BR treatment
• VenR was well tolerated by R/R CLL patients and no new safety signal were observed
• Overall, the data indicate the feasibility of using fixed-duration VenR as treatment for R/R CLL patients