BRIEF RESEARCH REPORT published: 19 August 2021 doi: 10.3389/fped.2021.635152 Charcoal Hemoperfusion for Methotrexate Toxicity: A Safe and Effective Life-Rescue Alternative When Glucarpidase Is Not Available Alejandra Rosales 1*, Alvaro Madrid 2 , Marina Muñoz 3 , Jose Luis Dapena 4,5 and Gema Ariceta 3 1 Department of Pediatrics, Medical University Innsbruck, Innsbruck, Austria, 2 Pediatric Nephrology, University Hospital Sant Joan de Deu, University of Barcelona, Barcelona, Spain, 3 Pediatric Nephrology, Vall d’Hebron Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain, 4 Pediatric Oncology and Hematology Department, Vall d’Hebron Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain, 5 Pediatric Oncology and Hematology Department, University Hospital Sant Joan de Deu, University of Barcelona, Barcelona, Spain Background: High dose methotrexate (HDMTX) is used for the treatment of pediatric hemato-oncological diseases. HDMTX can induce acute kidney injury in cases of delayed elimination. The use of leucovorin remains the most effective rescue action. Further Edited by: treatment options are of difficult access in the rare cases where leucovorin fails to Jakub Zieg, prevent renal failure from occurring. Glucarpidase is an effective treatment in cases University Hospital in Motol, Czechia of methotrexate (MTX) delayed elimination, but cost is high and availability is limited. Reviewed by: Charcoal hemoperfusion (CHP) is a very efficient procedure to remove protein-bound Dominique Leveque, Hôpital d’Hautepierre, France drugs, promoting fast MTX elimination, but is rarely considered as a treatment option. Alka Khadwal, Post Graduate Institute of Medical Methods: We present three pediatric cases with prolonged exposure to MTX after Education & Research, India HDMTX and delayed elimination in which hemoperfusion was performed as rescue *Correspondence: treatment for methotrexate intoxication. Alejandra Rosales alejandra.rosales@i-med.ac.at Results: Charcoal hemoperfusion was performed with positive results and no orcid.org/0000-0002-8819-5302 complications as bridging until glucarpidase was available in two cases and in one case where two doses of glucarpidase led to insufficient reduction of MTX levels. Specialty section: This article was submitted to Conclusions: CHP can be considered as a rescue treatment option in MTX intoxication, Pediatric Nephrology, since it is an effective and safe extracorporeal method for removing MTX, in cases where a section of the journal Frontiers in Pediatrics rescue with leucovorin is insufficient and glucarpidase is not available or while waiting Received: 29 November 2020 for delivery. Accepted: 25 May 2021 Keywords: charcoal, hemoperfusion, methotrexate, high dose methotrexate, glucarpidase, methotrexate toxicity Published: 19 August 2021 Citation: Rosales A, Madrid A, Muñoz M, Dapena JL and Ariceta G (2021) INTRODUCTION Charcoal Hemoperfusion for Methotrexate Toxicity: A Safe and Methotrexate (MTX) is administered in high doses (HDMTX, dose > 500 mg/m2 ) for the treatment Effective Life-Rescue Alternative When of several hemato-oncological diseases in the pediatric age (including lymphoblastic leukemia, Glucarpidase Is Not Available. lymphoma and osteosarcoma). MTX is a folate analog antimetabolite that interferes with folate Front. Pediatr. 9:635152. metabolism impeding purine and thymidine synthesis and DNA production promoting cell death. doi: 10.3389/fped.2021.635152 MTX action is cell-cycle dependent, acting specifically during DNA-synthesis and making tissues Frontiers in Pediatrics | www.frontiersin.org 1 August 2021 | Volume 9 | Article 635152 Rosales et al. Charcoal Hemoperfusion for Methotrexate Toxicity with high turnover more susceptible to cytotoxicity. Fifty percent method for toxins with high molecular weight, a low volume of circulating MTX is bound to proteins, mostly albumin, of distribution and high protein binding, where hemodialysis regardless of its concentration in serum. MTX molecules are is less effective. Table 1 shows previous reports on the use 454 Da, and MTX has a distribution volume of 0.4/0.8 L/kg of CHP in cases of MTX toxicity alone or combined with (1, 2). Elimination occurs through glomerular filtration and other extracorporeal treatments and they results (Table 1). We tubular secretion. At a urinary pH <7, MTX and its metabolites present three pediatric cases in which CHP was used successfully precipitate in renal tubules leading to delayed elimination and for the treatment of MTX intoxication when glucarpidase was prolonged exposure times, causing further MTX precipitation not available. and perpetuating renal damage (3). HDMTX regimens include intensive hydration and urine MATERIALS AND METHODS alkalinization to prevent acute kidney injury (4, 5). Monitoring of plasma MTX levels, monitoring diuresis and urinary pH are Three pediatric cases which presented delayed MTX elimination mandatory to prevent toxicity. Nevertheless, inadequately high after HDMTX during the treatment of different oncological MTX levels are observed in 0.5–1.8% patients, increasing the risk diseases are presented in this report. The clinical and laboratory of MTX toxicity (4, 6, 7). Factors such as impaired renal function, data were analyzed retrospectively. Details on treatment protocol, presence of ascites, pleural effusion or bowel obstruction, or definition of toxic range and leucovorin rescue are presented in concomitant administration of certain drugs (such as antibiotics, Table 2. aspirin, probenecid, and proton pump inhibitors), increase the MTX levels were measured using the Architect Methotrexate risk of MTX toxicity (4). Prolonged exposure to MTX results chemiluminescent assay (Abbott Diagnostics, IL, USA) on the not only in renal impairment but also in gastrointestinal distress, Architect i2000SR (Abbott Diagnostics). Plasma MTX levels may hepatic insufficiency, and bone marrow suppression (8). be overestimated in this report, since the method measures Leucovorin (folinic acid) competes with MTX and prevents not only MTX but also its metabolites due to antibody this drug toxicity in normal cells: it provides reduced folates to cross reactivity. bypass the metabolic blockage produced by MTX (9). Leucovorin Hemoperfusion was performed using the Prismaflex R system remains one of the cornerstones of preventing MTX toxicity, CHP with Adsorba R C 300 kit (cellulose-coated activated since it is the only available approach that acts intracellularly. charcoal). The procedure required a central venous access Treatment protocols with HDMTX include a 2–3 days period of using a dual-lumen hemodialysis catheter. Anticoagulation was multiple leucovorin doses. Safety of HDMTX regimens requires performed with heparin. Sessions lasted 2.5–3 h. careful monitoring of blood MTX levels for the adjustment All the procedures being performed were part of the routine of leucovorin doses. Hydration and alkalinization should be care and were performed in accordance to relevant guidelines continued and adjusted, since successful rescue with leucovorin and regulations. In view of the retrospective nature of the depends on patient renal elimination of MTX (10). study, the need for informed consent was waived by the local Glucarpidase (VoraxazeTM , a recombinant bacterial ethics committee. carboxypeptidase G2) is a very effective treatment option for MTX poisoning. Glucarpidase provides an enzymatic RESULTS method for MTX cleavage into non-toxic metabolites, 2, 4- diamino-N(10)-methylpteroic acid (DAMPA) and glutamate. Patient 1 A single dose of glucarpidase can reduce MTX level by >95% An 11-year-old male (41.1 kg, 151 cm, BSA 1.32 m2 ) treated in 15 min, but it has no influence in intracellular MTX levels. for second malignant disease (an osteoblastic osteosarcoma Cost is elevated and availability limited (in the European Union involving the facial bones), and previous history of radiotherapy only on compassionate use) often causing delays in the start of and chemotherapy due to bilateral retinoblastoma during the treatment (10). 1st year of life. He received his first course of HDMTX Diverse reports exist on the use of extracorporeal treatments according to protocol EURAMOS 1 in an external center for MTX intoxication. The choice of a treatment method for (EURAMOS 1) (23). Before receiving HDMTX, he showed drug removal depends on molecular weight of the drug, protein correct renal and liver function and normal serum albumin. binding, volume of distribution, treatment availability, and Prehydration (3 L/m2 ) and urine alkalinization were performed expertise in the center. Hemodialysis is a suitable method for low as recommended (EURAMOS 1). HDMTX (12 g/m2 e.v. over molecular weight, water soluble molecules. Larger size molecules, 4 h) was administered with a short interruption due to exanthema such as MTX, are insufficiently removed by standard HD and during infusion, which improved with antihistaminics and require high flux filters (11). High-flux hemodialysis is the most cortisone (MTX at 4 h 1,081 µmol/L, creatinine 0.81). The frequently implemented extracorporeal therapy in cases of MTX serum MTX level 24 h after infusion was with 491 µmol/L toxicity but efficacy is limited (12). MTX redistribution from the clearly in toxic range (toxic >8.5 µmol/L, serum creatinine 1.73 cellular compartment or third space may result in a rebound of mg/dl). An intensification of hyperhydration (5 L/m2 ), forced MTX levels after treatment discontinuation, requiring repeated diuresis (furosemide), urine alkalinization and intensification dialysis or CHP sessions (10). of treatment with leucovorin (250 mg/m2 /3 h) were performed. Charcoal hemoperfusion (CHP) is a successful extracorporeal Forty-eight hours after infusion and despite of intensified method for the removal of a variety of toxins. It is a suitable treatment, MTX levels remained persistently high (202 µmol/L, Frontiers in Pediatrics | www.frontiersin.org 2 August 2021 | Volume 9 | Article 635152 Rosales et al. Charcoal Hemoperfusion for Methotrexate Toxicity TABLE 1 | Existing reports on the use of hemoperfusion in MTX toxicity cases. References Case number Indication (treatment MTX dose Supportive treatment Extracorporeal Results (age, gender) protocol) method Djerassi et al. (13) 4 (?) Osteosarcoma 300 mg/kg Citrovorum Factor CHP and/or iHD CHP more effective than IHD at low MTX levels Gibson et al. (14) 1 (56 y, f) Breast carcinoma 600 mg Leucovorin HP (Amberlite Amberlite XAD-4 hemoperfusion XAD-4 Column) effective Charcoal more effective than XAD-4 in vitro Rebound after treatment observed, no sustained effect Bouffet et al. (15) 3 (71, 7, 52 y) ? 1.5 and 3 g/m² ? CHP, iHD, PE CHP efficient, no complications observed Plasma exchange less effective HD did not decrease MTX levels but corrected renal failure. Molina et al. (16) 1 (60 y, m) Lymphocytic 130 mg/m² Allopurinol, urine iHD + CHP Sustained reduction of MTX levels lymphoma alkalinization, citrovorum using sequential HD and CHP. Relling et al. (17) 1 (15 y, f) Osteosarcoma (OS-86) (12 g/m²) Hydration, urine iHD + CHP Combined HD-CHP more effective alkalinization, Leucovorin, Thymidine than HP only. Thymidine Grimes et al. (18) 1 (18 y, f) Osteosarcoma 8 g/m² Urine alkalinization, CHP, iHD Rebound of MTX levels after CHP and leucovorin, oral activated HD. Authors attribute more success charcoal to supportive treatment than extracorporeal therapies. McIvor (19) 1 (39 y, m) Burkitt Lymphoma 3 g/m² Allopurinol, urine CHP Rapid reduction of MTX level after alkalinization, leucovorin CHP. No complications. Nowicki et al. (20) 1 (10 y, m) Osteosarcoma 12 g/m² Hydration, urine iHD and CHP, HD due to hyperkalemia, followed by alkalinization, leucovorin glucarpidase CHP. Significant reduction of MTX levels using HD, HP and glucarpidase. Nemoto et al. (21) 1 (12 y, f) Osteosarcoma 10 g/m² Hydration, urine HP, iHD and PE Effective removal of MTX using CHP. alkalinization, leucovorin HDF due to renal failure. PE due to liver failure. Significant reduction in MTX level after CHP, no significant reduction after PE Grafft et al. (22) 1 (64 y, f) B-cell lymphoma 8 g/m² Hydration, urine CHP and high CVVH combined with CHP not more alkalinization, leucovorin dose CVVH effective than CVVH alone. Chan and Hui (11) 1 (11 y, f) Osteosarcoma 12 g/m² Hydration, urine SPAD + CHP Faster drop in MTX level after (HKPSOSG) alkalinization, leucovorin sequential use of SPAD and CHP than using only leucovorin toxic >1 µmol/L) and the patient developed leukocytosis (34.5 96 h after MTX infusion (5.29 µmol/L, toxic >1 µmol/L) the × 109 /l), progressive acute renal failure (increase of serum patient received a second glucarpidase dose leading to a sufficient creatinine to 2.94 mg/dL, eGFR 21 ml/min/1.73 m²), liver reduction of MTX level. Later on, treatment with leucovorin failure with elevated liver enzymes (AST 125 UI/L, ALT 193 was maintained until day 31 (MTX <1 µmol/L). Diuresis UI/L) and coagulopathy (Quick 47%) treated with vitamin was preserved and a progressive recovery of renal (creatinine K and plasma. Nevertheless, the patient was clinically stable, 0.86 mg/dL, eGFR 72 ml/min/1.73 m²), normalization of liver showed no hypertension, no mucositis and besides erythema and function and blood count were observed during the follow-up emesis no further symptoms. Due to temporary unavailability (Figure 1A). of glucarpidase, the patient was referred to our center where one session of CHP was performed at his arrival, as bridge until Patient 2 glucarpidase became available. The first CHP session started 52 h A 12 years old male (34.5 kg, 139 cm, BSA 1.15 m2 ) with pre-B after start of MTX infusion. A significant reduction of MTX lymphoblastic lymphoma, previously healthy and with normal level from 202 to 124 µmol/L was achieved using CHP, and renal function and serum albumin at the start of treatment the procedure was performed without complications. Further, (creatinine 0,48 mg/dl at 0 h). The patient received the second glucarpidase (50 U/kg) was administered as soon as available HDMTX course (5 g/m2 e.v., in 24 h), 14 days after first course (54 h after MTX infusion), which led to a reduction of MTX (which had been well-tolerated), according to Protocol Euro LB level to 8.09 µmol/L. Due to persistent elevated MTX levels 02 (24) after adequate prehydration and urine alkalinization. Frontiers in Pediatrics | www.frontiersin.org 3 August 2021 | Volume 9 | Article 635152 Rosales et al. Charcoal Hemoperfusion for Methotrexate Toxicity TABLE 2 | Detailed information on treatment protocols. Study, References MTX dose Duration of Hyperhydration Leucovorin Time to first leucovorin MTX at 24 h infusion EURAMOS (23) 12 g/m² 4h 3,000 ml/m² 15 mg/m², 24 h <8.5 µmol/L adjusted to nomogram Euro LB 02 (24) 5 g/m² 24 h 3,000 ml/m² 15 mg/m2 42 h <150 µmol/L ALL SEHOP/PETHEMA 5 g/m² 24 h 3,000 ml/m² 15 mg/m² 42 h <150 µmol/L 2013 HR (25) During the first 24 h after the initiation of MTX infusion the diarrhea, mucositis, or other symptoms such as hypertension. patient developed non-oliguric acute renal failure (creatinine Persistent renal failure (with maintained diuresis) and increasing 3.13 mg/dL, eGFR 18 ml/min/1.73 m²). An elevated MTX creatinine (max. creatinine 3.45 mg/dL at day 9 after MTX) was level was observed with 180 µmol/L after 24 h (toxic >150 observed at admission. Leukopenia (1.4 × 109 /l) was observed µmol/L) that was managed by intensification of hydration (4,000 too. Rescue treatment with hemoperfusion was indicated. CHP mL/m²/day) and leucovorin rescue (100 mg/m²/3 h). At 36 h was performed without complications on days 9, 10, 11, and MTX level remained persistently high with 85 µmol/L (toxic 12 after MTX infusion with no complications other than slight > 3 µmol/L) and the patient was referred to our center to anemia (hemoglobin 8 g/dl) and thrombocytopenia (100 × start treatment with CHP due the unavailability of glucarpidase. 109 /l). Progressive improvement was achieved under treatment The patient presented clinically stable with abdominal pain with CHP, with reduction in MTX levels, recovery of renal and vomiting, epistaxis, no cutaneous lesions, no neurological function and normalization of blood count (Figure 1C). symptoms, no hypertension. After the first session of CHP (48 h after start of MTX infusion) a decrease of MTX level to DISCUSSION 43 µmol/L (toxic > 0.4 µmol/L) was observed, and after the second session an MTX level of 20 µmol/L achieved. Anemia High-dose methotrexate-induced toxicity is an oncologic (hemoglobin 6.4 g/dL) and thrombocytopenia (37 × 109 /l) emergency that can potentially result in serious organ damage were observed at this point, needing blood cell and platelet and life threat. The introduction of standardized supportive transfusions. Glucarpidase was administered as soon as available care measures such as hyperhydration, urine alkalinization, and (82 h after start of MTX infusion), decreasing MTX to 0.96 leucovorin rescue has dramatically reduced the risk of MTX µmol/L. Subsequently, we observed a recovery of renal function toxicity (6). In the rare cases where pharmacokinetically guided (creatinine 0.55 mg/dL, eGFR 104 ml/min/1.73 m²) remission of leucovorine rescue is insufficient, glucarpidase has become the gastrointestinal symptoms and normal blood count (Figure 1B). treatment of choice (10). However, delays in drug availability may happen. Extracorporeal treatments can be used as a bridge Patient 3 in cases where glucarpidase is not available or insufficiently An 11 years old male (46.2 kg, 142 cm, BSA 1.36 m2 ) with T- effective. Studies assessing the efficacy of different extracorporeal cell acute lymphoblastic leukemia, under treatment according treatment approaches for MTX poisoning show mixed results, to protocol ALL SEHOP/PETHEMA 2013 HR (25). The patient reporting mostly of isolated cases, presenting no control patients had no history of previous diseases, with normal renal and and using differing concomitant interventions. liver function and serum albumin at the start of treatment. The election of an extracorporeal treatment method for drug During the first course of HDMTX (5 g/m2 e.v., in 24 h) intoxication should rely on the pharmacological characteristics with adequate previous hydration and urine alkalinization an of the toxin, the antagonist availability, and the expertise of the elevated MTX level was detected 24 h after starting infusion center. Charcoal hemoperfusion (CHP) is based in the adsorption (190 µmol/L, toxic > 150 µmol/L). Despite adequate treatment of toxins to charcoal particles, which makes it a suitable method with hydration (3,000 ml/m²/24 h) and leucovorin rescue (30 for protein bound toxins, liposoluble toxins and toxins which mg/m²/6 h), the patient presented persistently elevated MTX have high molecular weight, such as MTX. Common side effects levels after 36 and 48 h (620 and 510 µmol/L). In addition, are thrombocytopenia, hypocalcemia and hypoglycemia. In the non-oliguric renal failure with creatinine increase to 2.36 mg/dL three presented cases CHP was a safe and well-tolerated method (eGFR 34.5 ml/min/1.73 m2 ) was observed. The patient received leading to a significant reduction in MTX levels. the first dose of glucarpidase (50 U/kg) 48 h and second dose 96 h Despite fast efficacy and improved tolerance with less after starting MTX infusion, nevertheless an insufficient decrease hypersensitivity reactions and charcoal embolization nowadays, in MTX levels was observed (Figure 1). MTX levels continued since cellulose coated charcoal filters were introduced, and persistently high (MTX at 100 h 3.8 µmol/L, toxic >0.4) despite in parallel with the advance of hemodialysis techniques and two doses of glucarpidase, hydration, urine alkalinization and availability of high efficacy filters, CHP has lost popularity leucovorin rescue. Glucarpidase was no further available. The (11). Decline in the use of CHP relies on the high cost of patient presented in reduced general status, in the absence of the columns, which become saturated and loose effectiveness Frontiers in Pediatrics | www.frontiersin.org 4 August 2021 | Volume 9 | Article 635152 Rosales et al. Charcoal Hemoperfusion for Methotrexate Toxicity FIGURE 1 | This figure shows the progression of MTX and creatinine levels after HDMTX in the three presented cases [(A) patient 1, (B) patient 2, and (C) patient 3]. Furthermore, the applied supportive treatments are depicted. The dotted line represents the toxic MTX level according to each treatment protocol. Frontiers in Pediatrics | www.frontiersin.org 5 August 2021 | Volume 9 | Article 635152 Rosales et al. Charcoal Hemoperfusion for Methotrexate Toxicity during the treatment, and short expiration time. In contrast to after glucarpidase administration since it could interfere with the intermittent hemodialysis (iHD), CHP does not contribute to cleavage of MTX (28). normalize electrolyte or fluid disbalances, and therefore cannot Glucarpidase should remain the first line treatment in replace acute dialysis if needed (26). Reversely, CHP will cause cases of MTX delayed elimination, even if only insufficient less electrolyte imbalance in those intoxicated patients with quantity of glucarpidase available, since its efficacy is not preserved renal function. dose dependent (29). Recommendations in cases of insufficient Currently, iHD is often used for extracorporeal toxic removal, decrease in MTX levels after use of glucarpidase are missing. since it is an effective procedure for a broad range of toxins with Existing reports refer of no further reduction in MTX low molecular weight and which are water-soluble. However, levels after extra doses of glucarpidase within 48 h of MTX iHD is less suitable for protein bound toxins depuration, infusion. The benefit of administering glucarpidase after such as MTX. iHD also serves as treatment for fluid and >60 h can be discussed, since lasting toxicities may not be electrolyte disbalances in those patients, who often present acute undone beyond this point (28). In our patients the use of renal failure. Furthermore, iHD is more frequently available glucarpidase led to further decrease of MTX levels, despite and lower-priced than CHP (26). Reports on the use of the time of administration. One should consider the possible iHD in HDMTX toxicity show variable results. Many patients overestimation of MTX levels after glucarpidase infusion, since experience a rebound in MTX levels after iHD, probably most laboratories measure MTX with immunoassay, which due to multicompartmental distribution of MTX and slow shows a cross reactivity with its metabolite DAMPA (30). MTX redistribution from tissues to blood stream (14, 18). Avoiding levels after use of glucarpidase may be overestimated in this delays in the initiation of treatment could prevent distribution report. We could have probably avoid the second dose of of MTX in intracellular compartment and maximize removal glucarpidase and the use of CHP in case 3 if a more specific through extracorporeal treatment (27). High-dose continuous method for measuring MTX levels, as HPLC, would have venovenous hemofiltration (CVVHDF) may prevent rebound been available. of plasma drug levels as well (22). Lack of trials comparing These three cases show that CHP is an eligible bridging CHP vs. iHD efficacy and adverse events in MTX removal rescue treatment approach for life-threatening MTX does not support an evidenced-based decision process between intoxications in the absence of glucarpidase or after lack those procedures. of response. Despite limitations such as small sample size, We report our experience with CHP in MTX toxicity after or lack of comparison with iHD, our experience shows a a regional transient lack of availability of glucarpidase, and fast and positive response to few CHP sessions in severe as a life-saving treatment in a patient with limited response cases with MTX toxicity, in the absence of significant to the drug. In cases 1 and 2 successful stabilization and adverse events or technical issues, but venous central reduction of MTX levels were achieved after 1 or 2 sessions access requirement. Acute renal failure was successfully of CHP. Glucarpidase was administered as soon as available, managed by conservative treatment in all cases, and renal leading to a significant reduction of MTX levels. That fast and function recovered spontaneously in parallel to MTX good outcome indicates that possibly both patients would had level reduction. responded to glucarpidase if available, but CHP facilitated a Therefore, and based on MTX body distribution, we favor fast MTX removal and the achievement of low-risk levels. In the use of CHP instead of iHD as recue treatment of refractory comparison, case 3 presented with persistent elevated MTX levels MTX toxicity. CHP does not replace supportive measures or despite 2 doses of glucarpidase, although we have to mention rescue with leucovorin but should be considered in centers that MTX levels after glucarpidase may be overestimated with expertise in the method and available cartridges since it due to the cross reactivity with its metabolites using an leads to a significant reduction of MTX levels with concomitant immunoassay for measurement. We could have probably avoided improvement of renal function. to repeat glucarpidase doses at high cost if a more specific Up-to-date treatment recommendations for MTX toxicity measurement method for MTX would have been available. are urgently needed. The international EXTRIP (extracorporeal Treatment with CHP was considered since glucarpidase was treatments in poisoning workgroup) reviewed the use of no longer available for few days, and the patient remained extracorporeal treatments for MTX toxicity recently, a report in a critical situation. Fortunately, under treatment with daily on the results should be available soon. Furthermore, we CHP sessions we observed a decrease in MTX levels and retrospectively evaluated the course of MTX levels in our patients normalization of renal function. Unfortunately, leucovorin levels using the MTXPK.org tool, which is very practical and easy to use were not measured before and after CHP sessions and could be resource for clinical decision making (31). reduced through CHP leading to insufficient protection during CHP sessions. Leucovorin rescue was continued in all patients, in parallel DATA AVAILABILITY STATEMENT to glucarpidase treatment and CHP, since it is the most effective resource to protect cells from MTX toxicity. Leucovorin rescue The data analyzed in this study is subject to the following should be maintained until negative MTX levels are reached as licenses/restrictions: Data out of patients’ clinical records. described and replaced after dialysis may be removed through Requests to access these datasets should be directed HD and CHP (17). Leucovorin should not be given until 2 h to alejandra.rosales@i-med.ac.at. Frontiers in Pediatrics | www.frontiersin.org 6 August 2021 | Volume 9 | Article 635152 Rosales et al. Charcoal Hemoperfusion for Methotrexate Toxicity ETHICS STATEMENT AUTHOR CONTRIBUTIONS Ethical review and approval was not required for the AR analyzed and interpreted the data, drafted the article, and study on human participants in accordance with the approved the final version. AM, MM, and JD provided content local legislation and institutional requirements. Written of critical importance, revised the article, and approved the final informed consent from the participants’ legal guardian/next version. GA conceived the study, drafted and revised the article, of kin was not required to participate in this study provided content of critical importance, and approved the final in accordance with the national legislation and the version. All authors contributed to the article and approved the institutional requirements. submitted version. REFERENCES 17. Relling MV, Stapleton FB, Ochs J, Jones DP, Meyer W, Wainer IW, et al. Removal of methotrexate, leucovorin, and their metabolites by combined 1. Bleyer WA. Methotrexate: clinical pharmacology, current hemodialysis and hemoperfusion. Cancer. (1988) 62:884–8. doi: 10.1002/ status and therapeutic guidelines. Cancer Treat Rev. (1977) 1097-0142(19880901)62:5<884::AID-CNCR2820620506>3.0.CO;2-A 4:87–101. doi: 10.1016/S0305-7372(77)80007-8 18. 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Reply to: glucarpidase for the treatment of hemodialysis to reduce serum methotrexate levels in a patient with acute methotrexate-induced renal dysfunction and delayed methotrexate renal insufficiency. Am J Med. (1987) 82:350–2. doi: 10.1016/0002-9343(87) excretion. Pediatr Blood Cancer. (2016) 63:365. doi: 10.1002/pb 90085-4 c.25800 Frontiers in Pediatrics | www.frontiersin.org 7 August 2021 | Volume 9 | Article 635152 Rosales et al. Charcoal Hemoperfusion for Methotrexate Toxicity 30. Christensen AM, Pauley JL, Molinelli AR, Panetta JC, Ward DA, Stewart CF, Publisher’s Note: All claims expressed in this article are solely those of the authors et al. Resumption of high-dose methotrexate after acute kidney injury and and do not necessarily represent those of their affiliated organizations, or those of glucarpidase use in pediatric oncology patients. Cancer. (2012) 118:4321– the publisher, the editors and the reviewers. Any product that may be evaluated in 30. doi: 10.1002/cncr.27378 this article, or claim that may be made by its manufacturer, is not guaranteed or 31. Taylor ZL, Mizuno T, Punt NC, Baskaran B, Navarro Sainz A, Shuman endorsed by the publisher. W, et al. MTXPKorg: a clinical decision support tool evaluating high- dose methotrexate pharmacokinetics to inform post-infusion care and use Copyright © 2021 Rosales, Madrid, Muñoz, Dapena and Ariceta. This is an open- of glucarpidase. Clin Pharmacol Ther. (2020) 108:635–43. doi: 10.1002/ access article distributed under the terms of the Creative Commons Attribution cpt.1957 License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the Conflict of Interest: The authors declare that the research was conducted in the original publication in this journal is cited, in accordance with accepted academic absence of any commercial or financial relationships that could be construed as a practice. No use, distribution or reproduction is permitted which does not comply potential conflict of interest. with these terms. Frontiers in Pediatrics | www.frontiersin.org 8 August 2021 | Volume 9 | Article 635152