Lenalidomide and rituximab combination for R/R PCNSL-DLBCL patients

Herve Ghesquieres from Hospices Civil de Lyon and University Claude Bernard Lyon 1, along with colleagues, recently published in Annals of Oncology the results of a phase II trial investigating the efficacy of lenalidomide in combination with rituximab in relapsed or refractory (R/R) primary central nervous system lymphoma (PCNSL) patients.

In this open-label, multicenter, singe-arm, prospective, phase II trial the efficacy of intravenous rituximab together with lenalidomide (R²) was assessed in diffuse large B-cell lymphoma (DLBCL)-PCNSL patients and in primary intraocular lymphoma patients. The primary endpoint of this study was overall response rate (ORR). Secondary endpoints included, progression-free survival (PFS), overall survival (OS), and safety. 

Study design & baseline characteristics

• N = 45 R/R DLBCL patients with either:
  • Brain involvement: n = 34; and/or
  • cerebrospinal fluid (CSF) involvement: n = 11
• Dosing:
  • Induction phase: eight 28-day cycles of R²
    • Lenalidomide: 20 mg orally daily during cycle 1 (Day 1−21) and thereafter 25 mg daily
    • Rituximab: 375 mg/m² intravenously (IV) on Day 1
  • Maintenance phase: initiated only in patients responding to induction phase
    • Lenalidomide: 10 mg daily from Day 1−21 for a maximum of twelve 28-day cycles
  • Corticosteroids were allowed during induction cycle 1 for patients with symptomatic brain edema:
    • Twenty-nine patients required corticosteroids during cycle 1
  • Intrathecal methotrexate (MTX) was allowed for patients with CSF lymphoma involvement:
    • Seven patients with CNS involvement received MTX
  • Median patients age (range): 69 (48−86) years
  • All patients had DLBCL diagnosis with CNS involvement

Key findings

• Median number of R² cycles (range): 7 (1−8)
• Treatment discontinuation during the induction phase occurred in 60% (n = 27) of patients, due to:
  • Progressive disease (PD): n = 23 patients
  • Treatment-related toxicity: n= 2 patients
  • Consent withdrawal: n = 2 patients
• ORR at the end of the induction phase (n = 45): 35.6% (95% CI, 21.9−51.2%)
• ORR at the end of the induction phase in the intention-to-treat (ITT) population (n = 50): 32.0% (95% CI, 21.9-51.2)
• Patients completing induction phase (eight R² cycles): 51% of patients (n = 23)
• Patients maintaining an objective response over six months: n = 8 patients
• Patients maintaining an objective response over 12 months: n = 3 patients
• Patients maintaining an objective response over 18 months: n = 1 patient
• Among the patients with brain localization (n = 34):
  • ORR: 64.7% (95% CI, 46.5−3%)
  • Complete response (CR): 35% (n = 12)
  • Partial response (PR): 29% (n = 10)
• Patients starting maintenance treatment: n = 18 (12 CR, 3 PR, and 3 PD/stable disease [SD])
• Median cycles of maintenance treatment (range): 5 (1−12)
• Patients completing 12 cycles of maintenance treatment: n = 5, of those:
  • PD: n = 1
  • Remained in CR: n = 4
• At the last follow-up:
  • Two patients remain in CR and two relapsed at 3.8 and 6.5 months after the end of the maintenance phase
• At a median follow-up of 19.2 months (range, 1.5−31):
  • Median PFS: 7.8 months (95% CI, 3.9−11.3)
  • Median OS: 17.7 months (95% CI, 12.9−not reached)
  • Median time to best response (range): 1.2 months (0.3−7.6)
• For responding patients:
  • Median PFS: 9.2 months
• For patients with brain localization (n = 34):
  • Median PFS: 3.9 months
• Patients who responded to treatment showed a higher CD4/CD8 ratio at baseline and a continuous increase in this ratio during treatment
• A CD4/CD8 ratio of 1.6 was able to discriminate between prolonged and short PFS patient populations (P = 0.03)

Safety

• Twenty patients (44%) had Grade 3−4 neutropenia
• Three patients presented with Grade 3 pneumonitis and one patient with Grade 3 Clostridium difficile colitis after cycle 1 and orchiepididymitis after cycle 2
• During the induction phase the most common adverse events (AEs) reported were:
  • Grade 3 asthenia: 13% (n = 6 patients)
  • Paresthesia: 4% (n = 2 patients)
  • Grade 3 rash: 2% (n = 1 patient)
  • Melanoma: n = 1 patient
• Serious AEs (n = 19) were reported in 33% of patients (n = 15)
• Lenalidomide dose reduction occurred in n = 19 patients, mainly due to haematological toxicity 

Conclusions

R² in R/R DLBCL-PCNSL patients showed promising activity. Nevertheless, further studies are needed to validate these results as the possibility that R² together with MTX-based chemotherapy might present a good first-line regimen for PCNSL.