High-dose methotrexate plus temozolomide with or without rituximab for naïve PCNSL

On 1 March 2019, Cui Chen from Sun Yat-Sen University Cancer Center, Guangzhou, CN and colleagues, published in Cancer Medicine a Chinese retrospective study comparing the efficacy and safety of high-dose methotrexate plus temozolomide (MT) versus MT plus rituximab (RMT) in previously-untreated primary central nervous system lymphoma (PCNSL) patients.

The aim of this retrospective study was to investigate whether rituximab can enhance the response rates to chemotherapy and even the survival outcomes of naïve PCNSL patients in Southern China. The primary endpoint of this report was objective response rate to RMT versus MT treatment in PCNSL. Secondary endpoints included, progression-free survival (PFS), overall survival (OS), and safety.

Study design

• N = 62 previously-untreated PCNSL patients with no other involvement other than the CNS and pathologically diagnosed as diffuse large B-cell lymphoma (DLBCL)
• Median patient age (range): 53.5 (29–77) years
• Male patients: 51.6%
• Dosing (regimen was repeated every three weeks; up to 6–8 cycles):
  • MT (n = 30):
    • Methotrexate: 3.5 g/m² intravenously (IV) administered on Day 1
      • Every methotrexate dose, after 12 hours was followed by 30 mg leucovorin every six hours until methotrexate levels were < 1x10^-7 mol/l
    • Temozolomide: 150 mg/m² orally administered on Day 1–5
  • RMT (n = 32):
    • Methotrexate: 3.5 g/m² intravenously (IV) administered on Day 1
      • Every methotrexate dose, after 12 hours was followed by 30 mg leucovorin every six hours until methotrexate levels were < 1x10^-7 mol/l
    • Temozolomide: 150 mg/m² orally administered on Day 1–5
    • Rituximab: 375 mg/m² IV on Day 0
  • Treatment responses were assessed by contrast-enhanced magnetic resonance imaging (MRI), which was performed at baseline and after cycle 2, 4, and 6 of chemotherapy
  • Except for gender, the rest of the baseline characteristics were well balanced between the RMT and MT patient groups (RMT males: 65.6%; MT males: 36.7%; P = 0.041)

Key results

• Response rates per treatment group (n = 61 evaluable patients):
  • RMT group (n = 32):
    • Overall response rate (ORR): 93.7% (n =30)
    • Complete response (CR): 53.2% (n = 17)
    • Partial response (PR): 40.6% (n = 13)
    • Progressive disease (PD): 3.1% (n = 1)
    • Stable disease (SD): 3.1% (n = 1)
  • MT group (n = 29):
    • ORR: 69.0% (n = 20)
    • CR: 27.6% (n = 8)
    • PR: 4% (n = 12)
    • PD: 24.1% (n = 7)
    • SD: 6.9% (n = 2)
  • The percentage of patients achieving CR with RMT was significantly higher than that with MT treatment (P < 0.001)
  • The percentage of patients achieving PR with RMT was not significantly different than that with MT treatment (P = 0.572)
  • The RMT regimen led to a significant higher ORR than MT treatment (P = 0.018)
• Median follow-ups per group:
  • RMT: 13.7 months
    • During this time, six patients relapsed but with no extra CNS involvement
  • MT: 15.5 months
    • During this time, ten patients relapsed but with no extra CNS involvement
  • Two-year PFS rate:
    • RMT: 81.3%
    • MT: 46.5%
  • Five-year PFS rate:
    • RMT: 53.3%
    • MT: 29.1%
    • Comparison: P = 0.019
  • Two-year OS rate:
    • RMT: 82.3%
    • MT: 65.7%
  • Five-year OS rate:
    • RMT: 82.3%
    • MT: 50.0%
    • Comparison: P = 0.015
  • Median PFS:
    • RMT: not reached
    • MT: 25.3 months
  • Median OS:
    • RMT: not reached
    • MT: not reached
  • Multivariate analysis revealed that only treatment approach was an independent prognostic factor for OS (after age and gender adjustment)
  • Compared to MT, the RMT regimen reduced the risk of progression by 75% and then risk of mortality by 81.9%

Safety

• No deaths due to drug toxicity were observed
• Febrile neutropenia occurred in:
  • RMT: 9.4% (n = 3) of patients
  • MT: 6.7% (n = 2) of patients
  • Comparison: P = 1.00
• Grade 1–2 hepatotoxicity was observed in:
  • RMT: 40.6% (n = 13) of patients
  • MT: 40% (n = 12) of patients
  • Comparison: P = 1.00
• Grade 1–2 nausea vomiting was observed in:
  • RMT: 46.6% (n = 14) of patients
  • MT: 62.5% (n = 18) of patients
  • Comparison: P = 0.049
• Grade 3–4 hematological adverse events (AEs) like anemia, neutropenia, and thrombocytopenia were not frequently observed in either group (P > 0.05)
• Grade 3–4 non-hematological AEs were generally uncommon in both groups
• Consolidation therapy in the form of whole-brain radiation was given to 32.3% of patients and as autologous stem cell transplantation to 3.2% of patients
• After a median follow-up of 14.2 months (range, 3.57–60.8):
  • Deaths: n = 15 (RMT, n = 3; MT. n = 12) all due to tumor progression or relapse

Conclusions

In this retrospective analysis, RMT showed great efficacy, survival outcomes and tolerable toxicity when compared to MT. Thus, the authors suggest that RMT might be a feasible and safe therapeutic approach as a first‐line treatment for PCNSL. The results of this retrospective study although promising, they need to be further validated by large prospective studies to ensure the efficacy and safety of RMT in PCNSL.