MATRix/IELSG43
(2026)Objective
In newly diagnosed primary CNS lymphoma (PCNSL) responding to MATRix induction, does thiotepa-based high-dose chemotherapy with autologous stem-cell transplantation (HCT-ASCT) improve progression-free survival compared with non-myeloablative R-DeVIC consolidation?
Study Summary
• 3-year progression-free survival 78% (HCT-ASCT) vs 51% (R-DeVIC); 3-year overall survival 86% vs 71% (HR 0.46, p=0.0075)
• Higher toxicity with HCT-ASCT (mean 14.6 vs 9.3 AEs/patient; febrile neutropenia 61% vs 14%; 5 vs 2 treatment-related deaths in consolidation)
Intervention
Thiotepa/carmustine high-dose chemotherapy with autologous stem-cell transplantation (HCT-ASCT) vs two cycles of R-DeVIC (rituximab, dexamethasone, etoposide, ifosfamide, carboplatin) after four cycles of MATRix induction (rituximab, methotrexate, cytarabine, thiotepa)
Inclusion Criteria
Untreated, immunocompetent patients with B-cell primary CNS lymphoma, aged 18-65 (any ECOG) or 66-70 (ECOG 0-2), who achieved at least partial response after 4 cycles of MATRix induction with adequate stem-cell harvest
Study Design
Arms: HCT-ASCT (carmustine 400 mg/m2 + thiotepa 5 mg/kg BID x 2 days, then autologous stem-cell reinfusion) vs R-DeVIC (rituximab 375 mg/m2, dexamethasone 40 mg, etoposide 100 mg/m2, ifosfamide 1500 mg/m2, carboplatin 300 mg/m2; 2 cycles q21d) — both preceded by 4 cycles of MATRix induction
Patients per Arm: R-DeVIC n=115; HCT-ASCT n=114 (229 randomised of 346 who started induction)
Outcome
• Overall survival: 3-yr 86% vs 71% (HR 0.46, 95% CI 0.26-0.81; p=0.0075)
• 3-yr cumulative relapse: 19% vs 45% (SHR 0.40, 95% CI 0.24-0.66); complete response day 60: 69% vs 65% (OR 1.22, 95% CI 0.68-2.18)
• Safety: fatal SAEs during consolidation 5 (HCT-ASCT; 4 infections, 1 pulmonary embolism) vs 2 (R-DeVIC; both AML); febrile neutropenia 61% vs 14%; stomatitis 79% vs 9%
Clinical Question
In patients up to 70 years old with newly diagnosed primary CNS lymphoma who respond to MATRix induction, does thiotepa-based HCT-ASCT improve progression-free survival compared with non-myeloablative R-DeVIC chemoimmunotherapy consolidation?
Bottom Line
In fit patients with newly diagnosed PCNSL who respond to MATRix induction, thiotepa-based HCT-ASCT consolidation nearly halved the risk of progression or death and yielded superior 3-year PFS (78% vs 51%) and OS (86% vs 71%) compared with non-myeloablative R-DeVIC, at the cost of substantially higher toxicity — establishing HCT-ASCT as the preferred consolidation strategy.
Major Points
- Largest randomised phase 3 trial ever conducted in untreated PCNSL (229 randomised of 346 who started induction, from 368 enrolled) across 56 European centres.
- Uniform MATRix induction (rituximab, methotrexate 3.5 g/m2, cytarabine 2 g/m2 BID, thiotepa 30 mg/m2 x 4 cycles) was used in all patients, allowing isolation of the consolidation effect.
- Primary endpoint met: 3-year PFS 78% (HCT-ASCT) vs 51% (R-DeVIC); HR 0.43 (95% CI 0.27-0.68), p=0.0003.
- Overall survival was also significantly prolonged with HCT-ASCT (3-year OS 86% vs 71%; HR 0.46, 95% CI 0.26-0.81, p=0.0075).
- 3-year cumulative relapse incidence was more than halved: 19% (HCT-ASCT) vs 45% (R-DeVIC); SHR 0.40 (95% CI 0.24-0.66).
- Toxicity of HCT-ASCT was substantially greater (mean 14.6 vs 9.3 AEs/patient; febrile neutropenia 61% vs 14%; stomatitis 79% vs 9%; diarrhoea 59% vs 7%).
- Treatment-related mortality during consolidation: 5 deaths in the HCT-ASCT arm (4 infections, 1 pulmonary embolism) vs 2 in the R-DeVIC arm (both secondary AML).
- One-third of enrolled patients (116/346) did not reach randomisation, mainly due to induction toxicity or progression — underscoring the need to optimise induction.
- Quality-of-life (EORTC QLQ-C30) trends favoured HCT-ASCT over time; detailed neurocognitive analysis will be reported separately.
Study Design
- Study Type
- Randomized Controlled Trial (Phase 3)
- Randomization
- Yes
- Blinding
- Open-label (central neuroradiological response review was blinded to treatment allocation)
- Sample Size
- 229
- Follow-up
- Median 45.3 months (IQR 31.7-58.3)
- Centers
- 56
- Countries
- Germany, Italy, Denmark, Norway, Switzerland
Primary Outcome
Definition: Progression-free survival (time from randomisation to progression, relapse, or death from any cause), full analysis set
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 3-year PFS 51% (95% CI 41-60); median 39 months (95% CI 26-not reached); 56 events | 3-year PFS 78% (95% CI 69-85); median not reached; 27 events | 0.43 (0.27-0.68) | 0.0003 |
Limitations & Criticisms
- Only 229/346 patients (66%) who started induction reached randomisation - one-third dropped out due to induction toxicity or early progression, so the survival benefit does not apply to the full enrolled cohort.
- Open-label design: treatment allocation was not masked to patients, investigators, or local outcome assessors (central neuroradiological review was blinded).
- Investigator discretion in judging fitness for HCT-ASCT (cardiac, pulmonary, hepatic) introduces potential selection bias.
- Population restricted to Western European centres with established transplantation expertise; race/ethnicity data were not collected; generalisability to other populations and to less resourced settings is uncertain.
- R-DeVIC arm delivered only 2 consolidation cycles - some argue longer or more intensive non-myeloablative regimens (e.g., CALGB50202 EA) might narrow the gap.
- Detailed neurocognitive and quality-of-life outcomes reported only in abbreviated form; full analysis pending in a separate publication.
- 26/115 (23%) patients in the R-DeVIC arm went on to receive off-protocol HCT-ASCT after progression, which may have attenuated the OS difference.
Citation
Lancet 2026;408(10554):532-544