Background
IELSG-32 was a two-part phase II randomized trial for newly diagnosed PCNSL in immunocompetent patients aged 18–70 (n=227; 1:1:1 randomization, stratified by ECOG PS and MSKCC risk score). Part 1 (induction) compared three MTX-based induction regimens of increasing intensity: MTX + cytarabine (MA), MTX + cytarabine + thiotepa (MAT), and MTX + cytarabine + thiotepa + rituximab (MATRix). The rationale for intensification was that MTX + cytarabine (from IELSG-20) provided a CR rate of only ~33%, and adding thiotepa (CNS-penetrant alkylating agent) and rituximab might deepen responses and improve outcomes.
Interventions and follow up
Arm A (MA): MTX 3.5 g/m² IV day 1 + cytarabine 2 g/m² q12h × 4 doses days 2–3, every 21 days × 4 cycles (n=75)
Arm B (MAT): MA + thiotepa 30 mg/m² IV day 4 every 21 days × 4 cycles (n=73)
Arm C (MATRix): MAT + rituximab 375 mg/m² IV days −5 and 0 of cycles 1–2, every 21 days × 4 cycles (n=79)
Primary endpoint: Complete response (CR) rate after induction; secondary: OS, EFS, toxicity; Part 2 randomized responders to WBRT vs ASCT consolidation
mFollow-up: 30 months
Arm B (MAT): MA + thiotepa 30 mg/m² IV day 4 every 21 days × 4 cycles (n=73)
Arm C (MATRix): MAT + rituximab 375 mg/m² IV days −5 and 0 of cycles 1–2, every 21 days × 4 cycles (n=79)
Primary endpoint: Complete response (CR) rate after induction; secondary: OS, EFS, toxicity; Part 2 randomized responders to WBRT vs ASCT consolidation
mFollow-up: 30 months
Results
CR rate: MATRix 49% vs MAT 31% vs MA 23% (P=.006, MATRix vs MA)
ORR: MATRix 87%, MAT 79%, MA 73%
2-yr OS: MATRix 69%, MAT 64%, MA 42% (MATRix vs MA: HR 0.56, P=.025)
2-yr EFS: MATRix 52%, MAT 41%, MA 29%
2-yr PFS: per ASCT or WBRT arm results among responders proceeding to Part 2 consolidation
ORR: MATRix 87%, MAT 79%, MA 73%
2-yr OS: MATRix 69%, MAT 64%, MA 42% (MATRix vs MA: HR 0.56, P=.025)
2-yr EFS: MATRix 52%, MAT 41%, MA 29%
2-yr PFS: per ASCT or WBRT arm results among responders proceeding to Part 2 consolidation
Adverse events
Overall: Grade ≥3 AEs MATRix 91% vs MAT 89% vs MA 70% — intensification increases hematologic toxicity; treatment-related deaths MATRix 1 (1.3%), MAT 0, MA 1 (1.3%)
Hematologic: Grade 4 neutropenia MATRix 64%, MAT 59%, MA 38%; Grade ≥3 thrombocytopenia MATRix 61%
Infectious: febrile neutropenia MATRix 37%, MAT 36%, MA 22%
Renal/infusion: MTX-related Grade ≥3 renal toxicity 5–8% across arms; rituximab infusion reactions Grade ≥3 <2%
Hematologic: Grade 4 neutropenia MATRix 64%, MAT 59%, MA 38%; Grade ≥3 thrombocytopenia MATRix 61%
Infectious: febrile neutropenia MATRix 37%, MAT 36%, MA 22%
Renal/infusion: MTX-related Grade ≥3 renal toxicity 5–8% across arms; rituximab infusion reactions Grade ≥3 <2%
Conclusions
MATRix (MTX + cytarabine + thiotepa + rituximab) achieved the highest CR rate (49%) and best 2-year OS among the three induction regimens in newly diagnosed PCNSL, establishing MATRix as the most effective standard induction backbone for fit patients aged 18–70, at the cost of substantially higher but manageable hematologic toxicity.
Key Limitations
Phase II, 3-arm — exploratory; not powered for OS comparison; MATRix vs MAT comparison not pre-specified as a primary comparison; thiotepa's independent contribution uncertain — MAT also superior to MA; rituximab has limited CNS penetration (may act systemically, not intracranially); CR rate of 49% with MATRix still leaves majority of patients without CR after induction — consolidation is essential; small n per arm (~79 MATRix); elderly patients (>70) not eligible; no comparison to regimens with ibrutinib, lenalidomide, or other novel agents; HD-MTX dose (3.5 g/m²) lower than some protocols (8 g/m² in CALGB 50202); cranial RT deferred to Part 2 consolidation randomization.
Clinical Context
IELSG-32 Part 1 established MATRix as the standard induction for fit newly diagnosed PCNSL patients aged 18–70, and it is incorporated into ESMO and EANO guidelines as a preferred induction regimen. MATRix is the standard backbone for subsequent ASCT consolidation (Part 2 of IELSG-32; PRECIS trial). For elderly or unfit patients (>70 or frailer), regimens such as MT-R (CALGB 50202), R-MPV (DeAngelis), or MTX monotherapy are used. Ongoing trials (PRECIS-2, IELSG-43) are exploring the addition of ibrutinib or other BTK inhibitors to MATRix induction and ASCT consolidation in PCNSL.