Consolidative HDC-ASCT versus non-myeloablative immunochemotherapy for patients with primary CNS lymphoma

Currently, high-dose methotrexate (HD-MTX) based induction immunochemotherapy is prescribed to treat patients with primary central nervous system lymphoma (PCNSL) who qualify for intensive treatment approaches. This is followed by consolidative high-dose chemotherapy and autologous stem cell transplantation (HDC-ASCT). However, it is unclear whether consolidation with conventional-dose non-myeloablative immunochemotherapy, using cytotoxic agents that can cross the blood-brain barrier, can also defeat chemoresistance and subsequently eradicate minimal residual disease.¹

Here, we report primary results from the phase III MATRix/IELSG43 (NCT02531841) trial comparing HDC-ASCT with non-myeloablative consolidation therapy in patients with PCNSL, presented by Gerald Illerhaus at the 64th American Society of Hematology (ASH) Annual Meeting and Exposition in December 2022 as part of the late-breaking abstracts session.¹

Study design

This was an open-label, randomized phase III trial conducted in 79 centers across five European countries (Germany, Italy, Denmark, Norway, and Switzerland). Included patients were newly diagnosed with PCNSL, HIV-negative, aged 18–65 years irrespective of Eastern Cooperative Oncology Group (ECOG) Performance Status or 66–70 years with ECOG Performance Status ≤2, and had adequate organ function.

• induction consisted of four cycles of the MATRix regimen (rituximab: 375 mg/m²/d on Days 0 and 4; methotrexate: 3.5 g/m² on Day 1; cytarabine: 2 × 2 g/m²/d on Days 2 and 3; thiotepa: 30 mg/m² on Day 4; every 21 days)
• stem cell harvest was conducted after the 2nd cycle
• patients achieving at least partial response after completion of induction were randomly allocated to
  • Arm A: two cycles of R-DeVIC regimen (rituximab: 375 mg/m² on Day 0; dexamethasone: 40 mg/d on Days 1–3; etoposide: 100 mg/m²/d on Days 1–3; ifosfamide: 1,500 mg/m²/d on Days 1–3; carboplatin: 300 mg/m² on Day 1); or
  • Arm B: HDC (BCNU 400 mg/m² on Day 6 and thiotepa 2 × 5 mg/kg/d on Days 5 and 4) followed by ASCT on Day 0.

The primary endpoint was progression-free survival (PFS) and key secondary efficacy endpoints included complete response, overall survival, quality of life, and safety (toxicity and neurotoxicity)

Results

• Between July 2014 and August 2019, 368 patients were registered of which 346 started treatment, 260 (75%) completed the induction therapy, and 115 and 114 patients were randomly assigned to arm A and arm B, respectively
• Toxicities (25%) and disease progression (10%) were the primary reasons for not reaching randomization
• The baseline characteristics were well balanced between arms
• The median age of the randomized patients was 59 years, with 22.3% of patients aged ≥65 years

Efficacy

• At a median follow-up of 44 months, 69% of patients responded to induction treatment, 27% achieved complete remission, and 52% achieved partial remission.
• Both consolidation strategies were well tolerated, with 87% and 97% of the patients completing treatments in arm A and arm B, respectively.
• Overall, 13 patients died of treatment-related complications during induction treatment, 11 of them due to neutropenic infectious complications.
• Consolidation treatment with R-DEVIC or HDC-ASCT resulted in a substantial increase of patients with complete response (65% and 68% in arm A and arm B, respectively; p = 0.71).
• Six patients died of toxicity during consolidation treatment (two patents in arm A and four patients in arm B) and six patients died of unrelated causes while relapse-free (five patents in arm A and one patient in arm B).
• The 3-year PFS and 3-year overall survival differed significantly between both the arms (p = 0.0003 and p = 0.01, respectively; Figure 1).

Results of the subgroup analysis for PFS favored arm B compared with arm A.

HDC/ASCT, high-dose chemotherapy and autologous stem cell transplantation; OS, overall survival; PFS, progression-free survival; R-DeVIC, rituximab-dexamethasone + etoposide + ifosfamide + carboplatin.
*Adapted from Illerhaus, et al.¹

Toxicity

• safety was comparable across both arms
• no difference in toxicity was observed between both arms (Table 1)
• four treatment-related deaths were reported in arm B versus no deaths in arm A

Table 1. Grade 3 and 4 toxicities in arm A and arm B*

HDC/ASCT, high-dose chemotherapy and autologous stem cell transplantation; R-DeVIC, rituximab-dexamethasone + etoposide + ifosfamide + carboplatin. *Adapted from Illerhaus, et al.1
Toxicity, %	R-DeVIC (arm A)	HDC/ASCT (arm B)
Neutropenia	56	75
Thrombocytopenia	83	95
Anemia	69	75
Febrile neutropenia/Infections	15	63
Infections	14	53
Oral mucositis	0	55
Vascular disorder	3	9
Nervous system disorders	5	5
Psychiatric disorders	0	5
Cardiac disorders	0	3
Renal toxicity	0	5

Conclusion

In this study, consolidation with HDC-ASCT resulted in improved outcomes with a very good risk-to-benefit ratio vs non-myeloablative chemoimmunotherapy in patients with PCNSL. Additionally, there were no detectable adverse effects on neurocognitive function. These results support the standard use of consolidation HDC-ASCT therapy over non-myeloablative chemoimmunotherapy for fit patients with PCNSL.