Efficacy and safety of first-line high-dose cytarabine in patients with primary CNS lymphoma ineligible for high-dose methotrexate: A case series

Abstract

In recent years, significant progress has been made in the treatment of primary central nervous system lymphoma (PCNSL).^1,2 However, this is not the case for elderly and frail patients.³ Treatment of these patients is challenged by relevant comorbidities, poor baseline performance status (PS), and drug toxicities. Approximately 13%-30% of patients are deemed ineligible for high-dose methotrexate (HD-MTX)-based therapies, leaving them with limited treatment options, such as whole-brain radiotherapy (WBRT) and best supportive care.⁴ There have been proposals to use single agent high-dose cytarabine (HD-araC) in these patients.⁵ This approach has previously demonstrated limited efficacy and high toxicity in relapsed/refractory setting.⁶ Chamberlain et al. reported that over two-thirds of patients receiving HD-araC experienced severe hematological toxicity (grade 3-4, based on Common Toxicity Criteria [CTCAE]), with approximately one-third developing neutropenic fever. There is a lack of data on the use of HD-araC in patients with newly diagnosed PCNSL. Our study aimed to assess the efficacy and toxicity of HD-araC as an upfront treatment for patients with PCNSL who are ineligible for HD-MTX.

Methods

We conducted a retrospective analysis of our institution’s database (in the sense of a key word/phrase search) from January 2010 to January 2023 to identify immunocompetent patients with PCNSL, as defined by the 2022 WHO classification,⁷ who received first-line treatment with HD-araC, with or without rituximab. Only newly diagnosed patients with PCNSL who were either initially considered ineligible for HD-MTX or who experienced significant HD-MTX-related toxicity were included. The treatment protocol consisted of HD-araC (3 g/m², administered twice daily on days 1 and 2, every 3 weeks) with or without rituximab (375 mg/m² on day 1, every 3 weeks), for a total of six cycles. Patients with relapsed/refractory PCNSL and those with secondary central nervous system lymphoma were excluded. Data regarding baseline patients’ characteristics (from the time point on starting the induction), frontline therapy, and outcomes were extracted by retrospective chart review. To obtain a comparable measure of comorbidities, charlson comorbidity index (CCI) at the time of PCNSL diagnosis was determined.⁸

Due to the retrospective chart review and using routine clinical data, written informed consent was not required within our study. The study protocol was approved by the institutional review board of the Medical Faculty of the Otto von Guericke University Magdeburg, Magdeburg, Germany (no. 18/22).

Treatment response was evaluated according to international workshop criteria for PCNSL.⁹ Overall survival (OS) was defined as the time from the date of diagnosis to death from any cause or last follow-up. Progression-free survival (PFS) was calculated from the date of diagnosis to the occurrence of disease progression, relapse, death or last follow-up. For the patients in group 2, we also analyzed the post-MTX-OS and post-MTX-PFS, de-fined as the time from HD-MTX-discontinuation to death from any cause or last follow-up and from HD-MTX-discontinuation to the occurrence of disease progression, relapse, death or last follow-up, respectively.

Results

We identified 12 consecutive patients with PCNSL (out of a total of 68) who received first-line treatment with HD-araC, with or without rituximab. Six patients (50%) received this treatment upfront (group 1), while the other six (50%) received it after discontinuing HD-MTX-(based) therapy (group 2) (Table 1). The median age of the patients was 73 years (range 62-84 years). Five patients were female and seven were male. Most of them had poor PS (i.e., an Eastern Cooperative Oncology Group [ECOG] PS of 2-4 in 10 out of 12 patients [83.3%]) and relevant comorbidities (i.e., CCI ≥ 1 [excluding lymphoma] in 8 out of 12 patients [66.7%]). Seven patients had a high-risk disease according to the so-called three-factor (3F) prognostic model.¹⁰ All patients had histologically confirmed diffuse large B-cell lymphoma.

In group 1 (HD-MTX-naive patients), three of the six patients had severe comorbidities (CCI ≥ 4). HD-MTX was primarily omitted due to chronic kidney disease (CKD) stage 3 or higher. One patient had heart failure, and another had a combination of advanced age and poor PS. The outcome in these patients was very poor (Figure 1.), with a PFS and OS of 1-6 months each (median 1.5 months and 2 months for PFS and OS, respectively). Only one of the six patients showed an objective response, achieving partial remission. Four patients proceeded to WBRT due to disease progression or treatment-related toxicity. One patient died as a result of the treatment. All of these patients experienced severe (grade 3-4 according to CTCAE) hematological and infectious complications after HD-araC treatment.

Figure 1.

Graphical overview about overall survival (OS) and progression-free survival (PFS). All patients considered in this retrospective analysis were presented, arranged by group in ascending order of PFS: HD-MTX-naïve patients (Group 1) and patients after MTX discontinuation (Group 2). An OS or PFS over the 12-month period shown was marked with an arrow. Cartoon created with Biorender.com (BioRender.com/k37r166).

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In group 2, none of the patients had severe comorbidities (CCI ≥ 4) at the time of their PCNSL diagnosis. They received 1-2 cycles of HD-MTX before discontinuing treatment, primarily due to stage 1-3 acute kidney injury (AKI). Patient outcomes varied, with PFS ranging from 4 to 29 months (median 8.5 months) and OS ranging from 4 to 54 months (median OS 14 months) (Figure 1.). Three patients achieved complete remission, two of whom had received 2 prior cycles of HD-MTX. The post-MTX-PFS and post-MTX-OS was ranging from 2-27 months and 2-52 months, respectively. Currently, two patients in this group remain alive and in complete remission, at 19 and 29 months. In contrast to group 1, significant treatment-related toxicity was observed only in two patients over 70 years old.

Discussion

Treatment with HD-araC resulted in poor outcomes in our patients with newly diagnosed PCNSL, especially in those initially considered ineligible for HD-MTX (with OS ranging from 1 to 6 months). Survival rates appear to be comparable to those achieved with WBRT,^11,12 but at the cost of high treatment-related toxicity. Patients who had previously received at least one cycle of HD-MTX appeared to have slightly better outcomes (with OS ranging from 4 to 54 months), possibly suggesting the importance of HD-MTX in the treatment of PCNSL. On the other hand, these patients appear to be fitter than those who are primarily ineligible for HD-MTX, as some of them had an ECOG PS < 2 and a CCI of 0. It is possible that some of these patients would have benefited from an additional cycle of HD-MTX at a reduced dose. However, the number of patients is too small to draw any further conclusions.

In particular, treatment with HD-MTX requires adequate renal (i.e., creatinine-clearance [CrCl] > 50 mL/min) and cardiac function (LVEF > 50%). Of note, almost 50% of patients >70 years of age are reported to have CKD (defined as CrCl < 60 mL/min).¹³ In patients with impaired renal function (CrCl 30-50 mL/min), HD-MTX can be administered at a reduced dose,¹⁴ although there are no clear recommendations on dosage/HD-MTX administration. On the other hand, older patients (>70 years) are much more prone to AKI and subsequent dose reduction or treatment discontinuation of HD-MTX (i.e., MTX dose reduction in 18% patients ≤ 60 years vs. 70% > 70 years).¹⁵ Another critical issue in this population is the impaired PS, often resulting from a combination of organ dysfunction, frailty, and the PCNSL itself. Despite its high efficacy, HD-MTX is therefore often not applicable in elderly patients with PCNSL.

WBRT is the preferred treatment approach in patients ineligible for HD-MTX,¹⁶ with an OS ranging from 5-8 months.^5,11,12 In contrast to the relevant treatment-related toxicity caused by HD-araC demonstrated here, WBRT is generally well tolerated and rarely causes severe toxicity.^11,12 Recently, a small retrospective analysis (n = 15) in newly diagnosed and relapsed PCNSL showed that the combination of WBRT with lenalidomide may improve outcomes, resulting in a 2-year PFS of 70%.¹⁷ This could be a potential option for this vulnerable PCNSL population. The effectiveness of dose-attenuated WBRT is currently under investigation in arm B of the FIORELLA trial (NCT03495960).¹⁸ This trial focuses on patients who are ineligible for HD-MTX and are receiving a treatment regimen of WBRT, temozolomide, and rituximab, followed by TMZ maintenance therapy. TMZ-monotherapy has also been retrospectively studied in elderly patients with PCNSL (n = 19).¹⁹ A proportion of the patients, especially those with a methylated O⁶-methylguanine-DNA methyltransferase promoter, showed durable responses lasting longer than 12 months. Additionally, in the relapsed/refractory setting, treatment with ibrutinib (with or without rituximab) resulted in a PFS of 3-5 months, making it an attractive candidate for maintenance therapy in the first-line setting, such as after WBRT.^20–22 In the rarer cases involving younger and fitter patients with impaired renal function, the administration of HD-MTX should be pursued because of its crucial role in the treatment of PCNSL. In fact, there are cases where MTX has been used successfully in patients undergoing hemodialysis.²³

It is important to note that our analysis has certain limitations, primarily due to its retrospective design, which may introduce bias and confounding factors. Additionally, the small sample size restricted our ability to conduct comprehensive statistical analyses.

Our case series showed limited efficacy and substantial toxicity of (R)-HD-araC in patients with PCNSL ineligible for HD-MTX. This treatment should be omitted in elderly/frail patients to avoid further compromising their quality of life. Until new and urgently needed treatments become available, WBRT and/or oral treatments should be preferred.

Conflict of interest statement

VZ, TRH none declared. DM reported following disclosures: consulting fees: Abbvie, AvenCell, Beigene, Galapagos, Gilead, Janssen, Miltenyi, Novartis, and Roche; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: AstraZeneca, BMS, Gilead, and Roche; support for attending meetings and/or travel Abbvie, Beigene, Gilead, Janssen, Miltenyi, and Roche.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Author Contributions

VZ collected, analyzed and interpreted the data and wrote the paper. TRH reviewed and revised the paper. DM interpreted the data and revised the paper. All authors approved the final version.

Data Availability

The data supporting the results of this study are available on request from the corresponding author.

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