Durable Survival Benefit Observed Following HD-ASCT Vs Non-Myeloablative CRT for Primary CNS Lymphoma

Patients with with primary central nervous system lymphoma experienced prolonged progression-free survival and a reduction in risk of death following treatment with high-dose chemotherapy and autologous stem cell transplant compared with non-myeloablative chemoimmunotherapy.

Treatment with consolidation high-dose chemotherapy (HDC) plus autologous stem cell transplantation (ASCT) resulted in improved survival outcomes vs non-myeloablative chemoimmunotherapy in those diagnosed with primary central nervous system lymphoma (PCNSL), according to data from the phase 3 MATRix/IELSG43 trial (NCT02531841) that were presented at the 2022 American Society of Hematology (ASH) Annual Meeting.

“This is the largest randomized, multicenter, phase 3 trial investigating the impact of high-dose chemotherapy in untreated patients with primary CNS lymphoma not older than 70 years. Progression-free survival and overall survival is significantly higher after high-dose chemotherapy compared to conventional immune-chemotherapy, despite similar remission rates after consolidation,” explained Gerald Illerhaus, MD, during his presentation.

High-dose methotrexate (HD-MTX)-based induction immuno-chemotherapy followed by consolidation HD-ASCT is the current standard of care for PCNSL, however, there was no research showing that conventional-dose non-myeloablative immuno-chemotherapy can overcome chemotherapy resistance, eliminate minimal residual disease, and cross the brain-blood-barrier. Determining the full ability of this treatment strategy was the main purpose of MATRix/IELSG43 trial, according to the presenter, Illerhaus of the department of Hematology, Oncology and Palliative Care, at Klinikum Stuttgart.

The open-label, randomized, phase 3 study included 230 patients who were evaluated at 79 centers across 5 European countries (Germany, Italy, Denmark, Norway, and Switzerland). The primary end points was progression-free survival (PFS), and the secondary end points included complete response rate, overall survival, quality of life, and safety.

Patients in the study were randomized to receive 2 cycles of the R-DeVIC regimen consisting of rituximab (Rituxan) 375 mg/m2/d on day 0 (d0), dexamethasone 40 mg/d (d1-3), etoposide 100 mg/m2/d (d1-3), ifosfamide 1500 mg/m2/d (d1-3), carboplatin 300 mg/m2 (d1) in the consolidation arm or carmustine (BCNU) 400 mg/m2 or busulfan 2 × 2 mg/kg plus thiotepa (Tepadina) 2 × 5 mg/kg (d5-(-4) and ASCT.

At baseline, characteristics were balanced between the 2 arms, according to Illerhaus. The median age was 58.9 years in the HD-ASCT arm vs 58.5 years in the non-myeloablative chemoimmunotherapy arm. In the R-DeVIC arm, 46.1% were women and in the HD-ASCT arm, 43.0% were women. Most patients had an ECOG performance status of greater than 1, increased lactate dehydrogenase level, increased cerebrospinal fluid protein, and multiple lesions determined by MRI. Few patients in both arms had meningeal involvement per MRI.

In the HD-ASCT arm, the complete response (CR) and unconfirmed CR rate was 40.0% before consolidation and 65.2% after consolidation compared with 39.5% and 67.5%, respectively, in the control arm. The partial response (PR) rate was 60.0% before consolidation in the HD-ASCT arm and 15.7% after consolidation vs 60.5% and 21.1%, respectively in the R-DeVIC arm. After consolidation in the HD-ASCT arm, 8.7% of patients has stable disease (SD) and 8.7% has progressive disease (PD). In comparison, the control arm had a 5.3% rate of SD and a 6.2% rate of PD.

Results for the primary end points favored the HD-ASCT arm. The PFS rate was 79% (95% CI, 71%-86%) vs 53% (95% CI, 44%-62%) with the control (HR, 0.404; 95% CI, 0.252-0.650; P =.0002). The PFS benefit was also seen across most subgroups.

Regarding the key secondary end point of OS, HD-ASCT led to a 54% reduction in the risk of death. The OS rate was 86% (95% CI, 78%-91%) with HD-ASCT vs 71% (95% CI, 61%-78%) with R-DeVIC (HR, 0.456; 95% CI, 0.256-0.812; P =.0077).

The most common grade 3 and 4 toxicities observed HD-ASCT vs R-DeVIC arms were neutropenia 75% vs 56%, thrombocytopenia (95% vs 83%), anemia (75% vs 69%, and febrile neutropenia/infections (63% vs 15%). Treatment-related deaths occurred in 3.4% of the HD-ASCT arm compared with 0% of the control arm. Illerhaus noted that there has been no difference in neurotoxicity between the treatment arms.

Further research around the safety and efficacy of HDC with methotrexate will be investigated in the OptiMATe trial (NCT04931368).

Reference

Illerhaus G, Ferreri A, Binder M, et al. Effects on survival of non-myeloablative chemoimmunotherapy compared to high-dose chemotherapy followed by autologous stem cell transplantation (HDC-ASCT) as consolidation therapy in patients with primary cns lymphoma - results of an international randomized phase III trial (MATRix/IELSG43). Blood. 2022;140(suppl 2):LBA-3. doi:10.1182/blood-2022-171733