High-dose methotrexate (HD-MTX) is the cornerstone of the chemotherapy treatment of the primary central nervous system non-Hodgkin lymphoma (PCNSL).1 Methotrexate is an antimetabolite interfering with the metabolism of folic acid, thereby blocking purine synthesis. HD-MTX defined by doses ≥500mg/m2, most often from 1 to 4g/m2, are required to cross the blood–brain barrier and achieved therapeutic level in the central nervous system.

MTX is mainly excreted by the kidneys, and delayed drug clearance may lead to toxicity.2 Toxicity is dependent on both duration of complete elimination from the body and serum MTX concentration (MTXc). Therapy drug monitoring is mandatory to guide folinic acid rescue and prevent severe toxicities.

Because renal dysfunction conduces to delayed MTX complete elimination and critical MTXc, end-stage renal disease (ESRD) is considered as a contra-indication for HD-MTX.

Nevertheless the drug is effectively cleared through hemodialysis,3 and drug monitoring is easily available. However, data is missing in these particular patients.

We report a case of a hemodialysis patient with PCNSL successfully treated by 100mg/m2 adjusted HD-MTX-based chemoimmunotherapy regimen.

A 64-year-old woman ongoing chronic hemodialysis for 7 years for an unspecified nephropathy, presented a brutal right facial paralysis, right hemicorpus dysesthesia and balance disorders. The magnetic resonance imaging (MRI) identified a lesion affecting the brain bridge, the right middle cerebellar peduncle and cerebellar hemisphere (Supplementary Fig. 1a, b). A stereotactic biopsy confirmed the diagnosis of diffuse large B-cell lymphoma with no other location assessed by positron emission tomography (PET) scan, establishing the diagnosis of PCNSL. EBV serology was negative. After multidisciplinary discussion, accordingly to the previous published data,4 the patient received 28 cycles of chemotherapy regimen R-MPV (Protocol described in Supplementary Methods). We used an adjusted the dose of MTX at 100mg/m2, based on the experience of one of the authors (unpublished).

Dialysis procedures was started 24h after MTX administration and conducted daily for four hours by predilution hemodiafiltration with high-flux dialyser, dialysate flow of 500mL/min, blood flow of 250mL/min, and high dialysate bicarbonate concentration (40mmol/L). Daily dialysis was discontinued when MTXc was <0.1μmol/L.

MTXc were measured before and after each dialysis session.

Median MTXc 24h after infusion was 14 [9.6–15.0]μmol/L (Fig. 1). No rebound phenomenon was observed. MTX was completely cleared on average at 5±0.6 days post-infusion.

Fig. 1.

Median [interquartile range] of plasma MTX concentration (μmol/L) following administration. Cycle 5 Days 15 was excluded. Small arrows represent dialysis sessions. The dashed line demarcates concentration at which folinic acid rescue was stopped. MTX: Methotrexate. MTXc: Methotrexate concentration.

(0.18MB).

Dose intensity was respected, and no course was delayed. Patient exhibited 2 episodes of undocumented sepsis with rapid favorable recovery, anemia requiring 2 red blood cells transfusion and mucositis.

Intermediary evaluation after 3 cycles with MRI assessment revealed a complete response.

The fifth cycle was marked by an unexplained MTX overdose at 180μmol/L 24h after administration, without clinical nor biological toxicity. The patient had an extended hemodialysis session of 16h in intensive care unit, achieving MTXc<0.5μmol/L and <0.1μmol/L after 1 more dialysis.

We thus decided to stop the chemotherapy treatment after 5 cycles, given the persistent complete response on MRI (Supplementary Fig. 1c, d) and brain PET-scan.

The patient is actually still in complete remission at 1 year.

We report here the feasibility of HD-MTX-like therapy in hemodialysis patients, and the first use of a dose divided by more than 10 from the standard dose. Herein, with an adjusted dose at 100mg/m2, with first hemodialysis session, our patient reached the expected MTXc at H24 and treatment was well tolerated with no significant toxicity and efficient with total recovery.

PCNSL is an aggressive type of lymphoma with a rapidly fatal course in the absence of treatment. HD-MTX-based chemoimmunotherapy have been shown to improve survival, even in elderly patients, and is a central part of the standard approach to treatment.2,4 Avoiding HD-MTX in hemodialysis patients leads to a loss of chance.

Although its important protein-binding and low distribution volume, 63% of MTX infused can be removed after a 6h high-flux hemodialysis session, four-fold faster than renal excretion.3

The strict monitoring of residual MTXc represents the major point for limiting its toxicity while keeping its effectiveness.

Five cases about HD-MTX use in hemodialysis patients have been reported (Table 1).3,5–8 The doses used were the same as in the general population (1–4g/m2). Some authors performed daily high-flux hemodialysis 24h after MTX infusion: cMTX were then very high (>20μmol/L) after the first dialysis session,6–8 above the threshold of toxicity.2 In any case, MTX was completely eliminated within 5–7 days after infusion.

Importantly, we used a dose of 100mg/m2 every 2 weeks, and cMTX were close to those described in non-ESRD patients with PCNSL treated by HD-MTX.4,9 Our patient had moderate and reversible MTX-induced toxicity, and favorable outcome. ESRD patients may also have an increased efficacy of MTX at lower doses, due to a potentially increased blood-brain barrier permeability.10

We argue that ESRD is not an absolute pitfall to the use of HD-MTX for hematological malignancies. Experts should consider the use of adjusted dose at 100mg/m2 as a viable therapeutic modality in ESRD patients.