Clinical outcomes of etoposide and cytarabine as consolidation in elderly patients with primary CNS lymphoma

Abstract Background A consolidation strategy has not been established for transplant-ineligible elderly patients with primary central nervous system lymphoma (PCNSL). In this study, we aimed to retrospectively evaluate the clinical outcomes of etoposide and cytarabine (EA) as consolidation chemotherapy for transplant-ineligible patients with PCNSL following high-dose methotrexate (MTX)-based induction chemotherapy. Materials and Methods Between 2015 and 2021, newly diagnosed transplant-ineligible patients with PCNSL with diffuse large B-cell lymphoma were consecutively enrolled. All enrolled patients were over 60 years old and received EA consolidation after achieving a complete or partial response following induction chemotherapy. Results Of the 85 patients who achieved a complete or partial response to MTX-based induction chemotherapy, 51 received EA consolidation chemotherapy. Among the 25 (49.0%, 25/51) patients in partial remission before EA consolidation, 56% (n = 14) achieved complete remission after EA consolidation. The median overall survival and progression-free survival were 43 and 13 months, respectively. Hematological toxicities were most common, and all patients experienced grade 4 neutropenia and thrombocytopenia. Forty-eight patients experienced febrile neutropenia during consolidation chemotherapy, and 4 patients died owing to treatment-related complications. Conclusion EA consolidation chemotherapy for transplant-ineligible, elderly patients with PCNSL improved response rates but showed a high relapse rate and short progression-free survival. The incidences of treatment-related mortality caused by hematologic toxicities and severe infections were very high, even after dose modification. Therefore, the use of EA consolidation should be reconsidered in elderly patients with PCNSL.


Introduction
The incidence of primary central nervous system lymphoma (PCNSL) has increased over time, with the highest incidence rate in patients ≥75 years old. 1,2Although the clinical outcomes of PCNSL have improved since the introduction of high-dose methotrexate (MTX)-based induction chemotherapy, the survival of elderly patients has not dramatically improved. 2,3MTX-based induction chemotherapy elicits a considerably high response rate; however, most patients eventually experience relapses.Therefore, intensive consolidation therapy should be administered after achieving an appropriate response following induction chemotherapy. 25][6] Because most elderly patients with PCNSL cannot tolerate ASCT, various efforts have been undertaken to develop appropriate consolidative strategies for elderly patients. 1,73][14][15] In addition to delayed neurotoxicity, WBRT has some limitations for controlling disseminated lymphoma outside the radiation field. 16ther combination chemotherapeutic agents as consolidation, with mechanisms of action different from MTX, have been studied to avoid neurotoxicity from WBRT in transplant-ineligible patients. 8Consolidation of etoposide and cytarabine (EA) is one of the recommended regimens for consolidation therapy in patients with PCNSL.However, the consolidative role of EA chemotherapy for elderly patients has been minimally explored. 15,17,18A Cancer and Leukemia Group B (CALGB) 50202 trial suggested that EA consolidation was an effective, well-tolerated regimen and that the progression-free survival (PFS) among elderly patients was comparable to that among younger patients. 15Two other real-world studies on EA consolidation have also proven its efficacy.However, many enrolled patients experienced a higher incidence of toxicities.Furthermore, significant discrepancies exist between real-world data and recommendations based on clinical trials. 17,18Because previous studies on EA consolidation have been conducted in patients of all ages, the number of enrolled elderly transplant-ineligible patients was very small.Although current treatment guidelines e798 The Oncologist, 2024, Vol. 29, No. 6   recommend cytarabine-based consolidation chemotherapy for transplant-ineligible patients, the rationale for EA consolidation chemotherapy in elderly transplant-ineligible patients with PCNSL remains insufficient. 19Herein, we evaluated the clinical outcomes of EA consolidation chemotherapy following high-dose MTX-based induction chemotherapy in transplant-ineligible patients with PCNSL >60 years old.

Patients
Between 2015 and 2021, newly diagnosed transplantineligible patients with PCNSL with diffuse large B-cell lymphoma were enrolled consecutively.The patients were registered from a prospective cohort at Severance Hospital (Yonsei University College of Medicine, Seoul, Republic of Korea; IRB 4-2014-0236, ClinicalTrials.govID: NCT02330718).Only patients > 60 years old who were immune competent were analyzed.Patients who did not receive at least one cycle of high-dose MTX-based chemotherapy or who did not respond to induction chemotherapy were also excluded.All enrolled patients received EA consolidation therapy after achieving a complete response (CR) or partial response (PR) after induction chemotherapy.Memorial Sloan-Kettering Cancer Center (MSKCC) and International Extranodal Lymphoma Study Group (IELSG) scores were calculated as previously described. 20,21This study was approved by the institutional review board of Severance Hospital.

Response and toxicity assessment
The response was assessed using magnetic resonance imaging (MRI) based on the International PCNSL Collaborative Group response criteria. 22Induction treatment response was assessed by MRI after the second and fourth cycles of induction chemotherapy.The response was evaluated after the completion of EA consolidation chemotherapy, every 3 months for 2 years, and then every 6 months for 3 years.Toxicities were graded using the National Cancer Institute Common Toxicity Criteria for Adverse Events (version 4.0).

Statistical analysis
Overall survival (OS) was defined as the duration from the date of diagnosis to the date of death from any cause.PFS was defined as the time from the date of diagnosis to progression, relapse, or death from any cause.Survival analyses were estimated using the Kaplan-Meier method.All reported P-values were 2-sided, and a P-value < .05 was considered statistically significant for all analyses.All statistical analyses were performed using SPSS Statistics for Windows, version 23.0 (IBM Corp., Armonk, NY, USA).

Patients' characteristics
During the study period, 131 patients over 60 years of age were diagnosed with PCNSL at our institution.A total of 115 patients were treated with high-dose MTX-based induction chemotherapy.Among them, treatment responses were accessible in 100 (76.3%) patients, including patients with disease progression (n = 15, 15.0%) and CR or PR (n = 85, 85.0%).Among the 85 patients who achieved CR or PR after highdose MTX-based induction chemotherapy, 19 underwent ASCT, 7 received radiotherapy, 6 did not receive further treatment, and 51 received EA consolidation.Finally, 51 patients who received EA consolidation treatment were included in this study.The study diagram is shown in Figure 1.

Response and survival
All 51 patients in this study received at least 4 cycles of highdose MTX-based combination chemotherapy, and treatment response was available.Twenty-six (51.0%) patients received EA consolidation in the CR state, and 25 in the PR state.Among the 25 (49.0%,25/51) patients with PR before EA consolidation, 56% (14/25) eventually achieved CR after EA consolidation.Response evaluation after EA consolidation was assessable in 47 patients, with 37 (78.7%)achieving CR, 8 (17.0%) achieving PR, and the remaining 2 (4.25%) experiencing disease progression.Among these 8 patients with PR, 5 achieved CR following radiotherapy after EA consolidation, 1 received additional salvage chemotherapy, and 2 did not receive any further treatment because of poor performance The Oncologist, 2024, Vol. 29, No. 6 e799 status.Among the 37 patients who achieved CR following EA consolidation, 6 (16.2%) maintained the response, whereas 31 (83.7%)patients experienced relapses.The median time to relapse was 236 (range: 47-2471) days.
The median follow-up period was 23 (range: 3-87) months for all 51 patients who received EA consolidation.Of the 51 patients, 6 (11.7%) were alive with disease-free status, 4 (7.8%)died due to treatment-related complications, and 31 (60.7%)experienced relapse after EA consolidation chemotherapy.Among the 31 relapsed patients, 4 achieved a CR again after salvage treatment, 14 patients did not achieve an appropriate response after salvage treatment or refused further treatment, and 13 patients died from relapse.The 2-year OS and PFS rates for the EA consolidation group were 71.7% and 26.1%, respectively (Figure 2).

Toxicity
Most patients experienced grade 3-4 hematologic toxicities.All patients experienced grade 4 neutropenia and thrombocytopenia.The median period of neutropenia (absolute neutrophil count < 500/μL) was 10 (range: 6-20) days, and the median duration of hospital stay was 24 (range: 17-92) days for EA consolidation.Forty-eight (94.1%) patients experienced febrile neutropenia, and 4 (7.8%)died due to grade 5 febrile neutropenia.A total of 22 patients had documented infections caused by infectious organisms, such as vancomycin-resistant enterococci (1 in urine and 3 in blood), methicillin-resistant Staphylococcus aureus (1 in blood), Klebsiella pneumoniae (3 in blood and 3 in urine), Escherichia coli (1 in urine and 4 in blood), Gram-positive cocci (5 in blood), Candida (1 in blood), and Pseudomonas (1 in blood and 1 in sputum).The toxicity grades according to the National Cancer Institute Common Toxicity Criteria for Adverse Events are presented in Table 2.

Discussion
This study analyzed the efficacy and safety of EA consolidation in transplant-ineligible patients with PCNSL who responded to high-dose MTX-based induction chemotherapy.Although CR rates can be improved from 50% to 70% after additional EA consolidation therapy, a relapse rate of approximately 76% and very high rates of treatment-related hematologic toxicities and infections warrant further improvements, as this is a formally recommended consolidation strategy in elderly patients with PCNSL.
The induction and consolidation phases are the 2 main components of the therapeutic strategy for PCNSL.Although PCNSL is sensitive to high-dose MTX-based induction chemotherapy, most patients who do not receive additional  appropriate consolidation treatment eventually cannot maintain the response due to the high rate of relapse.ASCT has been implemented as an effective consolidation strategy for younger fit patients; nonetheless, no standard consolidation strategy has been established in elderly transplant-ineligible patients. 2igh-dose cytarabine penetrates the blood-brain barrier, and cytarabine combined with MTX produces a better outcome than MTX alone. 23,24The addition of cytarabine (3 g/ m 2 /day for 2 days) after WBRT as consolidation is associated with a high response and disease control with acceptable toxicities. 13,25,26Etoposide can also cross the blood-brain barrier and lower the risk of CNS events in nodal diffuse large B-cell lymphoma. 27EA combination therapy has already shown favorable outcomes in refractory or recurrent PCNSL. 28herefore, the combination of etoposide and high-dose cytarabine may be considered an appropriate consolidation regimen after high-dose MTX-based induction chemotherapy.Although several previous studies on EA consolidation reported remarkable efficacy and tolerable safety (Table 3), 15,17,18 they could not confirm the role of EA consolidation in elderly transplant-ineligible patients because of the small number of enrolled patients older than 60.Therefore, our real-world evidence of EA consolidation chemotherapy for elderly patients with PCNSL would be useful in developing appropriate consolidation guidelines for this population.
The 2-year PFS and OS rates were only 26.1% and 71.7%, respectively, which were inferior to those of 2 previous studies for EA consolidation that reported rates of 78% and 93%, and 83% and 92%, respectively. 17,18However, caution is warranted when interpreting this difference in dose intensity.Because the first 2 patients who received the same dose of EA consolidation (etoposide 40 mg/kg total dose and cytarabine 16 g/m 2 total dose) as reported in a previous trial 15 experienced grade 4 septic shock during the neutropenic period, the dose of EA consolidation was modified (etoposide 30 mg/kg total dose, cytarabine 8 g/m 2 total dose) for further enrolled patients.Despite these dose reductions and careful supportive care such as antibacterial and antifungal prophylaxis and G-CSF support, treatment-related mortality occurred in 4 patients, and the incidences of hematologic toxicities and documented infections were very high.Because the previously proposed dose of EA consolidation was not targeted for elderly patients, this dose modification is considered appropriate, and further investigation should be conducted to identify the appropriate dose intensity of EA consolidation for elderly patients.
According to the CALGB 50202 trial, EA consolidation showed a high CR rate, favorable PFS/OS, and mild treatment-related toxicities with 16% neutropenic fever. 15he most important thing to note is that approximately 20% of patients who were unfit for EA consolidation were excluded.It is unlikely that a higher rate of toxicities related to EA consolidation was reported in the real-world data (Table 3). 15,17,18In our study, neutropenic fever and documented infections were reported in 94.1% and 43.1% of patients, respectively, comparable to the incidences of toxicities in previous real-world data.Because of the relatively high rate of hematologic toxicities and infections, hospitalization for managing these toxicities was required  for all patients.Although treatment-related mortality was observed in 2 patients, our strategy of dose-modified EA consolidation with intensive supportive care would be feasible in elderly patients with PCNSL.Nevertheless, the relatively short PFS was still a challenge in routinely applying EA consolidation in elderly patients with PCNSL.Therefore, a more effective and safe treatment strategy other than EA consolidation chemotherapy should be investigated for elderly transplant-ineligible patients with PCNSL.][31] Considering the pathophysiology of PCNSL, Bruton's tyrosine kinase inhibitors, such as ibrutinib, may also be good candidates for maintenance therapy in elderly patients with PCNSL.This study had some limitations.We retrospectively conducted this study at a single center.However, considering the low incidence of PCNSL, the number of 51 elderly patients who received EA consolidation can be considered sufficient for evaluating the efficacy and safety of EA consolidation in elderly transplant-ineligible patients with PCNSL.After induction chemotherapy, we attempted to perform ASCT whenever possible in patients who were younger than 70 years old, and patients who were not appropriate for EA consolidation such as poor performance status or serious co-morbidities were treated with radiotherapy, which may have a potential selection bias.To minimize selection bias, we analyzed all enrolled patients with PCNSL who received EA consolidation from a prospective registry (ClinicalTrials.govID: NCT02330718).

Conclusion
Although EA consolidation for transplant-ineligible elderly patients elicited a high CR rate, the incidences of hematologic toxicities and severe infections were very high, which eventually led to treatment-related mortality even after dose modification.Therefore, EA consolidation should be reconsidered for use in elderly patients with PCNSL.In addition, other therapeutic strategies such as maintenance therapy based on the pathophysiology of PCNSL are eagerly required in elderly patients with PCNSL because of the high rate of relapse and relatively short PFS even after EA consolidation chemotherapy.

Figure 2 .
Figure 2. Overall survival (A) and progression-free survival (B) among patients who received etoposide and cytarabine (EA) consolidation.

Table 3 .
Comparison of studies related to EA consolidation in newly diagnosed PCNSL patients.: EA, etoposide and cytarabine; MTX, methotrexate; NR, not reached; OS, overall survival; PCNSL, primary central nervous system lymphoma; PFS, progression-free survival; TRM, treatment-related mortality. Abbreviations