Background
IELSG-32 Part 2 was the consolidation randomization of the two-part IELSG-32 phase II trial. After response to MATRix (or MAT/MA) induction, patients aged 18–65 with newly diagnosed primary CNS lymphoma (PCNSL) were randomized to consolidation with autologous stem cell transplantation (ASCT, thiotepa + carmustine/busulfan conditioning) or whole-brain radiotherapy (WBRT, 36 Gy + 9 Gy boost). WBRT had been the historical consolidation for PCNSL but carries significant risk of delayed neurotoxicity (leukoencephalopathy, cognitive decline). ASCT was hypothesized to achieve equivalent or superior disease control with less neurotoxicity.
Interventions and follow up
Arm A (Control): Whole-brain radiotherapy 36 Gy in 18 fractions + 9 Gy boost (45 Gy total) to residual disease
Arm B (Experimental): Autologous stem cell transplantation with thiotepa + busulfan (TBC) or thiotepa + BCNU conditioning
Population: n=118 randomized (59 ASCT, 59 WBRT); 1:1; age 18–65; in CR/CRu/PR after induction
Primary endpoint: 2-year progression-free survival; secondary: OS, neurocognitive function, safety
mFollow up: 33 months
Arm B (Experimental): Autologous stem cell transplantation with thiotepa + busulfan (TBC) or thiotepa + BCNU conditioning
Population: n=118 randomized (59 ASCT, 59 WBRT); 1:1; age 18–65; in CR/CRu/PR after induction
Primary endpoint: 2-year progression-free survival; secondary: OS, neurocognitive function, safety
mFollow up: 33 months
Results
2-yr PFS: ASCT 80% vs WBRT 69% (no significant difference)
2-yr OS: ASCT 83% vs WBRT 71% (no significant difference)
Neurocognitive function: preserved/improved with ASCT; WBRT arm showed attentional/executive impairment on objective testing
Disease control: both consolidations highly effective at maintaining response after MATRix induction
2-yr OS: ASCT 83% vs WBRT 71% (no significant difference)
Neurocognitive function: preserved/improved with ASCT; WBRT arm showed attentional/executive impairment on objective testing
Disease control: both consolidations highly effective at maintaining response after MATRix induction
Adverse events
Hematologic (ASCT): expected grade ≥3 cytopenias with TBC/thiotepa-BCNU conditioning; febrile neutropenia common
Infectious/mucosal (ASCT): grade ≥3 mucositis and infections frequent; treatment-related mortality reported in the ASCT arm
Neurologic (WBRT): objective neurocognitive decline (attention, executive function) on serial testing; delayed leukoencephalopathy of concern
Relapse: CNS relapses occurred in both arms during follow-up
Infectious/mucosal (ASCT): grade ≥3 mucositis and infections frequent; treatment-related mortality reported in the ASCT arm
Neurologic (WBRT): objective neurocognitive decline (attention, executive function) on serial testing; delayed leukoencephalopathy of concern
Relapse: CNS relapses occurred in both arms during follow-up
Conclusions
In PCNSL patients responding to MATRix induction, ASCT and WBRT consolidation both produced high 2-year PFS and OS with no significant survival difference, but ASCT preserved neurocognitive function whereas WBRT was associated with objective cognitive impairment. ASCT is therefore the preferred consolidation strategy for fit patients aged ≤65 years.
Key Limitations
Phase II randomization not powered to formally establish OS superiority. ASCT treatment-related mortality is non-trivial and requires careful patient selection. Age ≤65 limits generalizability to elderly PCNSL, who comprise the majority of cases. ASCT eligibility requires adequate organ function and stem cell mobilization. Patients in PR (not CR) at consolidation had inferior outcomes in both arms. Neurocognitive testing was not feasible in all patients, limiting that analysis.
Clinical Context
IELSG-32 Part 2, together with the PRECIS trial (Houillier, JCO 2019), established ASCT as a preferred consolidation for fit newly diagnosed PCNSL patients in remission after HD-MTX-based induction, given equivalent disease control and superior neurocognitive preservation versus WBRT. WBRT remains an option for patients who cannot undergo ASCT or in selected older fit patients, with careful neurocognitive counseling. The standard pathway for fit patients is MATRix induction (IELSG-32 Part 1) followed by ASCT consolidation. For elderly patients, non-ASCT consolidation and maintenance regimens (lenalidomide, ibrutinib) are being explored.