Consolidation high-dose chemotherapy plus HSCT extends survival in primary CNS lymphoma
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NEW ORLEANS — Consolidation therapy with high-dose chemotherapy followed by hematopoietic stem cell transplant significantly prolonged PFS among adults with primary central nervous system lymphoma, according to study results.
Data from the randomized phase 3 MATRix/IELSG43 trial — presented at ASH Annual Meeting and Exposition — showed the combination also significantly extended OS when compared with a standard regimen of nonmyeloablative immunochemotherapy, researchers noted.
Background
Treatment of primary CNS lymphoma is particularly challenging due to its aggressive nature and uniquely sensitive location, according to Gerald Illerhaus, MD, medical director of the Stuttgart Cancer Center and Clinic for Haematology, Oncology, Stem Cell Transplantation and Palliative Medicine at Klinikum Stuttgart in Germany.
“Delivering the drug to the CNS is challenging due to the blood-brain barrier,” he said during a presentation. “The surrounding tissue is very sensitive to therapy, regardless of whether it is chemotherapy or radiation.”
Previous studies have demonstrated efficacy and safety of thiotepa-based high-dose chemotherapy followed by autologous HSCT (HDC-ASCT) in younger patients with primary CNS lymphoma, Illerhaus added.
However, the most effective consolidation therapy for younger adults with primary CNS lymphoma remains unclear, which required further study, Illerhaus said.
Methodology
MATRix/IELSG43 compared the effectiveness of HDC-ASCT vs. nonmyeloablative chemotherapy after induction therapy for newly diagnosed primary CNS lymphoma.
The investigators enrolled 346 immunocompetent adults who began therapy with induction treatment at one of 56 centers across Europe.
Study participants received induction therapy, including four cycles of the MATRix regimen (rituximab dosed at 375 mg/m2/day on days 0 and 5; methotrexate dosed at 3.5 g/m2 on day 1; cytarabine dosed at 2 × 2 g/m2/day on days 2 and 3; and thiotepa dosed at 30 mg/m2 on day 4, every 21 days) with a stem cell harvest after the second cycle of induction therapy.
Researchers randomly assigned patients who had a least a partial response to induction therapy to either two courses of the nonmyeloablative R-DeVIC chemoimmunotherapy regimen (rituximab dosed at 375 mg/m2 on day 0; dexamethasone dosed at 40 mg/day on days 1 to 3; etoposide dosed at 100 mg/m2/day on days 1 to 3; ifosfamide dosed at 1,500 mg/m2/day on days 1 to 3; and carboplatin dosed at 300 mg/m2 day 1) or HDC-ASCT.
One-third of patients who started induction (n = 116) discontinued treatment, most due to adverse events (n = 53) or stable/progressive disease (n = 40).
Patients randomized to the R-DeVIC (n = 115) and HDC-ASCT (n = 114) consolidation therapy groups had similar characteristics, including median age (59.9 years vs. 58.5 years) and percentage of women (46% vs. 43%).
PFS served as the study’s primary endpoint. Secondary endpoints included complete response rate, OS, quality of life and safety.
Median follow-up was 45.3 months (range, 0.2-86).
Key findings
Investigators reported a significantly higher 3-year PFS rate after consolidation therapy with HDC-ASCT compared with R-DeVIC (79% vs. 53%; HR = 0.4; 95% CI, 0.25-0.65).
They also noted significantly higher 3-year OS in the HDC-ASCT group (86% vs. 71%; HR = 0.45; 95% CI, 0.25-0.81).
Overall, the results demonstrate a 54% reduction in the risk for death with HDC-ASCT consolidation therapy.
Investigators observed unexpectedly higher rates of grade 3/grade 4 neutropenia (75% vs. 56%), thrombocytopenia (95% vs. 83%), anemia (75% vs. 69%), febrile neutropenia (63% vs. 15%) and infection (53% vs. 14%) in the HDC-ASCT group compared with the R-DeVIC group.
Thirteen deaths (3.8%) attributable to the induction treatment regimen occurred during the study, including 11 from infections complications and two from gastrointestinal bleeding. Four (3.4%) treatment related deaths attributable to HDC-ASCT occurred during the study compared with no treatment-related deaths in the R-DeVIC group.
An ongoing analysis of neurocognitive function has thus far revealed no differences in neurotoxicity rates between the two treatment groups, Illerhaus said.
Sixty-nine percent of patients had an objective response to induction therapy, with a 27% complete response rate among the entire study cohort.
The addition of consolidation therapy increased the complete response rate in both treatment groups, from 40% to 65.2% after R-DeVIC and from 39.5% to 67.5% after HDC-ASCT.
Clinical implications
The MATRix/IELSG43 trial represented the largest randomized phase 3 study investigating the impact of consolidative HDC-ASCT among adults aged younger than 70 years with newly diagnosed primary CNS lymphoma, according to Illerhaus.
“PFS and OS were significantly higher after HDC-ASCT compared with conventional immunochemotherapy with R-DeVIC, despite similar remission rates after consolidation,” he said.
Further study is ongoing via the randomized phase 3 OptiMATe trial, which is attempting to reduce overall toxicity during induction therapy using less methotrexate pretreatment followed by two cycles of MATRix.
Perspective
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Allison Winter, MD
In this phase 3 study, younger patients who achieved a partial response to induction MATRix chemotherapy were randomly assigned to non-myeloablative DeViC chemotherapy or HDC-ASCT.Notably, the MATRix regimen is an intensive protocol. This limits its use in routine clinical practice, where patients tend to be less fit with more comorbidities. This is evidenced by the 3.8% treatment related mortality.
In terms of the randomized therapy in this study, there are two important points to recognize. First, DeVIC is a standard — not the standard — for nonmyeloablative chemotherapy consolidation. As this was largely done in Europe, practice patterns may vary. In the US, less intense regimens — such as cytarabine monotherapy or cytarabine with etoposide — often are used for consolidation as opposed to this multidrug regimen.
Second, the essential component of the ASCT is the HDC or conditioning chemotherapy. This study used carmustine plus thiotepa. Again, there is no standard conditioning regimen and this is one of the options. I would clarify the note about adverse events in the HDC-ASCT arm. Cytopenias and neutropenic fever are expected consequences of HDC, which is why we need to “rescue” marrow recovery by infusing previously collected autologous stem cells.
This study certainly provides evidence supporting the use of HDC-ASCT as a successful consolidative strategy for primary central nervous system lymphoma among younger patients. However, in clinical practice, we are transplanting older patients and do not use a strict age cutoff. Therefore, further prospective studies of older patients — and subsequent to other common induction regimens — are needed. Finally, although we have retrospective data comparing conditioning (HDC) chemotherapy, randomized studies are lacking.
Collapse
Illerhaus G, et al. Abstract LBA-3. Presented at: ASH Annual Meeting and Exposition; Dec. 10-13, 2022; New Orleans.
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