RETRACTED ARTICLE: New recommendations for reversal of high-dose methotrexate cytotoxicity with folinic acid

Abstract

Purpose

Folinic acid (FA) rescue protocols to counter the adverse effects of high-dose methotrexate (HDMTX) vary widely, and the risk of over-rescue and potential adverse effects of excessive FA (e.g., hypercalcemia) are under-recognized issues when providing augmented rescue in cases of delayed methotrexate elimination (DME). This opinion summary defines over-rescue, describes its potential adverse impacts, highlights the risk of hypercalcemia associated with excessive FA dosing in patients with acute kidney injury (AKI) from HDMTX, and provides recommendations to improve safety and efficacy of FA rescue in patients receiving HDMTX.

Methods

A multidisciplinary panel of experts with clinical experience in HDMTX treatment convened in three roundtable meetings to coalesce expert opinion and best published evidence on the pharmacology and clinical effects and interactions of FA and HDMTX.

Results

The type of FA (calcium folinate, calcium levofolinate, sodium levofolinate), dose, and frequency of FA administration may be factors for over-rescue and the development of hypercalcemia due to their respective pharmacokinetic characteristics, especially in cases of DME requiring augmented FA rescue.

Conclusion

Clinicians are reminded of the possibility of over-rescue with FA and its impact on subsequent HDMTX courses, types of FA available and their durations of action, and avoid providing too frequent doses. In the setting of AKI and DME requiring high doses of FA, use of sodium levofolinate or calcium levofolinate may be considered to reduce the risk of hypercalcemia associated with calcium folinate.

Supplementary Information

The online version contains supplementary material available at 10.1007/s00280-025-04749-w.

Introduction

High-dose methotrexate (HDMTX; ≥ 500 mg/m²) is used to treat various cancers including acute lymphoblastic leukemia (ALL), systemic and central nervous system (CNS) lymphomas, and osteosarcoma. Methotrexate (MTX) enters cells by active transport through the reduced folate carrier but at higher serum concentrations it can cross the cell membrane by passive diffusion into the intracellular space [1–3]. MTX and its intracellularly formed polyglutamylated derivatives inhibit the enzyme dihydrofolate reductase (DHFR) to interrupt the folate cycle and deplete intracellular stores of reduced folates, thus inhibiting the downstream synthesis of tetrahydrofolate-dependent nucleic acids and proteins. High doses of MTX, however, can lead to potentially irreversible toxicities, especially in cases of delayed MTX elimination (DME) [4]. Folinic acid (FA; calcium folinate or leucovorin calcium) has been used to counteract the effects of MTX for decades [5]; it competes with MTX for cell entry through the reduced folate carrier and the subsequent polyglutamylation which enhances its intracellular retention [6, 7], and functions as an intracellular storage vitamin (in the form of reduced folates) following consecutive courses of HDMTX [8, 9]. The competitive processes occurring between MTX and FA at the reduced folate carrier, DHFR, and polyglutamylation, warrants judicious FA administration following HDMTX infusion to minimize toxicities while simultaneously ensuring the full therapeutic effect of MTX.

Although FA over-rescue has been a topic of ongoing discussion for decades, a consensus to identify and prevent it has yet to be established [3, 10–12]. While FA rescue is essential for preventing serious adverse effects due to MTX toxicity, the therapeutic efficacy of HDMTX may be compromised by excessive, too frequent, or too early administration of FA, or by a subsequent MTX dose administered too soon after FA rescue when residual FA could diminish the antineoplastic benefit of MTX [10]. These FA applications can in turn lead to disease relapse, prolonged duration of treatment, other toxicities, and higher treatment costs. The issue may be more problematic in patients who require glucarpidase for DME. As FA and its active metabolite, 5-methyltetrahydrofolate (5-MTHF) are substrates for glucarpidase, additional FA rescue is required after glucarpidase is administered. Also, because glucarpidase does not inactivate intracellular MTX, intensified FA rescue is needed until MTX effluxes sufficiently from normal cells, which may lead to hypercalcemia in patients who have acute kidney injury (AKI) and decreased ability to excrete calcium [7].

This report summarizes discussions from three online roundtable meetings convened by a multidisciplinary panel of hematologists, oncologists, pharmacologists, and pharmacists with extensive clinical experience in HDMTX treatment to coalesce expert opinion and best published evidence on factors leading to FA over-rescue and toxicity and their impact on patient outcomes. This summary also discusses the potential consequences of excessive FA delivery and presents new recommendations for the improved FA rescue in HDMTX therapy.

Methods

An invitation to participate in first virtual roundtable meeting was sent to 15 clinicians providing care to adult and pediatric patients with ALL, osteosarcoma, and lymphoma who were identified through recent publications/presentations and participants of the international High-Dose Methotrexate Research and Care Network meetings hosted by Resonance. Nine clinicians agreed to participate and included 4 hematologists, 1 oncologist, 1 neuro-oncologist, 2 pharmacologists, and 1 pharmacist; 3 were based in Europe and 6 in the United States. Four weeks prior to the first roundtable meeting, a list of 7 questions in 4 domains of pharmacology/pharmacokinetics, dosing and administration, disease-specific guidelines, and potential risks of FA rescue in HDMTX treatment was sent to the participants (Supplementary Document). Participants were asked to provide their responses with relevant literature which were later compiled for the roundtable discussion. A total of 3 virtual meetings took place over the course of 9 months.

Folinic acid pharmacology

Calcium folinate is a racemic mixture of the diastereoisomers of folinic acid (D,L−5-formyltetrahydrofolate [D,L-FA]), is widely available, and has been listed as a World Health Organization essential medicine since 1979 [13]. Calcium levofolinate and sodium levofolinate are commercially available forms of FA that contain only the naturally occurring active levo-isomer (L-FA) and have equivalent potency at one-half the dose of D,L-FA [14]. Once D,L-FA is administered, L-FA is rapidly reduced to its active metabolite 5-MTHF which becomes the predominant circulating form that enters the cell through the reduced folate carrier [15]. Because 5-MTHF is already in its reduced form, it bypasses the MTX-induced blockage of DHFR and restarts the folic acid cycle by repleting the reduced folates distal to the block. The reduced folates are subsequently polyglutamated with three to six glutamates added in series, conferring a larger molecule that retains the folate intracellularly [5]. The dextro-isomer (D-FA) is a chemically synthesized compound that is not metabolized and competes poorly with MTX for cellular uptake through the reduced folate carrier [14, 16, 17]. While only L-FA gains cell entry by active transport through the reduced folate carrier, both L- and D-isomers cross the cell membrane through passive diffusion if the transmembrane concentration gradient is sufficiently high [5]. Although D-FA is considered to be inactive, when present in higher concentration than L-FA and 5-MTHF, it gains increased cell entry, and at higher intracellular concentrations the D-FA can indirectly cause expulsion of 5-MTHF out of the cell to impair rescue [16, 18]. This is due to the ATP-binding cassette transporter having a higher affinity to 5-MTHF (than D-FA) which leads to its transport out of the cell, leaving the intracellular space with lower reduced folates to restart the folic acid cycle. The impact of D-FA on the pharmacokinetics of L-FA remains to be better elucidated. The calcium component of FA in relation to the D-isomer, however, may have significant clinical implications that will be discussed later in this paper.

Pharmacokinetics

Intravenous administration of FA leads to an initial rise of serum folates in the parent form of L-FA which reaches its peak concentration at 10 min, then rapidly decreases (t_½ = 31.6 ± 1.1 min) as its active metabolite 5-MTHF emerges as the main circulating form. 5-methyltetrahydrofolate reaches a peak serum concentration at 1.3 h and has a t_½ of 227 ± 20 min (4 h). The D-isomer has a much longer t_½ of 451 ± 24 min (8 h) due to its substantial renal reabsorption and minimal metabolism (Table 1) [5, 16]. Further, the D-isomer has a lower volume of distribution (7.9 ± 0.4 L) than that of 5-MTHF (22.9 ± 2.7 L) and thus a higher free drug concentration especially as only 15% is bound to albumin [16, 19].

Table 1.

Summary of folinic acid terminology

Name	Synonyms	Components following intravenous administration	Plasma half-life (min)a	Abbreviations
Calcium folinate	Leucovorin calcium Leucovorin d,l-Folinic acid 5-formyltetrahydrofolate D,L-N5-formyltetrahydrofolic acid	l-folinic acid (L-FA)	32.0 ± 1.8	FA; D,L-FA
		5-methyltetrahydrofolate (5-MTHF)	224 ± 28
		d-folinic acid (D-FA)	485 ± 35
Calcium levofolinate	Levoleucovorin calcium			Ca-L-FA
Sodium levofolinate	Levoleucovorin disodium			Na-L-FA

^aMean half-life following intravenous administration of 50 mg of calcium folinate in 12 (6 male, 6 female) healthy adults[16]

The majority (80–90%) of L-FA is eliminated in the urine mainly as 10-formyltetrahydrofolate and 5,10-methenyltetrahydrofolate; fecal elimination accounts for 5–8% [20, 21]. D-FA is excreted in the urine unchanged.

Folinic acid dose and administration

Treatment protocols for various cancers using different HDMTX doses, infusion durations, and intervals between courses led to the wide variation of empiric dosing regimens currently in use for FA rescue [22, 23]. Treatment protocols for ALL often incorporate 2–4 courses of HDMTX at 14-day intervals [24–26]. The courses usually provide 3–5 g/m² of MTX infused over 24 h, followed by FA rescue beginning at 36–42 h after the start of HDMTX infusion at a dose of 15 mg/m², and continuing every 6 h until plasma MTX concentration (MTXc) is ≤ 0.2 µM (Supplementary Table 1). Osteosarcoma regimens usually involve 2 cycles of neoadjuvant therapy and 6–10 cycles of postoperative therapy, with each cycle consisting of 2 consecutive courses of HDMTX at 1-week intervals (Supplementary Table 3) [27–31]. MTX doses of 12 g/m² are infused over 3–4 h with FA rescue initiated 24 h after the start of HDMTX infusion at a dose of 8 or 15 mg/m² and repeated every 6 h for a total of 11 doses or until the MTXc < 0.1 or < 0.2 µM depending on the protocol. Rescue protocols for non-Hodgkin lymphomas, including primary CNS lymphoma, are more varied depending on the treating institution. Treatment regimens incorporate 4 to 8 courses of HDMTX provided at 2-to-4-week intervals [32, 33]. MTX doses range between 3–8 g/m² with infusion duration of 2–4 h; FA rescue is initiated 24 h after the start of HDMTX infusion at a dose of 15 mg or 25 mg and is repeated every 6 h for 11–12 total doses or until serum MTXc < 0.1 to 0.2 µM depending on the protocol [25, 34].

For all of the aforementioned conditions, augmented FA rescue is indicated in patients with renal dysfunction and DME, usually with the serum creatinine level increasing > 50% of baseline or MTXc remaining elevated at set time points following the start of infusion, and involves increasing the dose and frequency of FA delivery (Supplementary Tables 2, 4, 5) [31, 35–37].

Folinic acid over-rescue

While preventing HDMTX-related toxicities is the main objective of FA administration, the possibility of over-rescue should be considered especially when more frequent and higher doses are given in the setting of DME [10, 38, 39]. Potential over-rescue may occur if 1) FA is given in excess; 2) FA is given too early following HDMTX infusion; or 3) the subsequent course of HDMTX is administered before the FA from the previous course has cleared from the system [5].

Excessive FA dose with HDMTX

Clinical trials that used different doses of FA for rescue have shown trends of increased relapse in pediatric ALL patients who received higher doses compared to those receiving lower doses [38, 39]. A case of osteosarcoma with worsening tumor symptoms was reported following an excessive dose of FA (a total 1275 mg was given instead of the prescribed 760 mg) after the third course of HDMTX of 12.5 g/m²; the symptoms and tumor progression itself were subsequently managed with 8 additional doses of HDMTX [40]. Also, a recent study on adults with CNS lymphoma revealed that higher pretreatment cumulative doses of FA was associated with inferior progression free survival [41]. These reports reflect the competitive relationship between FA (as 5-MTHF) and MTX for cell entry and the intracellular competition of 5-MTHF to displace free MTX from DHFR before it undergoes polyglutamylation [42].

Early FA administration following HDMTX infusion

With regard to timing, FA delivery is usually started 36 to 42 h following the start of a 24-h infusion (e.g., ALL), or 24 h following the start of a 4-h infusion (e.g., lymphoma, osteosarcoma) of HDMTX. While FA administration should not be delayed beyond current practice guidelines, it is strongly recommended that at least 24 h pass after the start of HDMTX infusion before FA delivery to allow MTX time to exert its anti-tumor effect [43]. However, in cases of severe DME leading to dangerous levels of MTX, FA should be administered regardless of time since HDMTX infusion, especially if glucarpidase is not readily available. In such cases, the benefits of preventing life-threatening toxicities outweigh the risks of neutralizing the anti-cancer effects of that cycle of HDMTX, which can be repeated once the patient has recovered.

Timing of subsequent course of HDMTX following FA rescue from previous course

The intracellular storage and accumulation of FA in the form of polyglutamated reduced folates may protect cancer cells from a subsequent course of HDMTX, potentially leading to over-rescue [5, 41]. Sterba and colleagues demonstrated that following the first course of HDMTX, subsequent HDMTX courses had lower MTXc and higher pre-course concentrations of folates, which remained in the circulation for 14 days [10]. Further, the pre-course folate concentration was the principal determinant of peak MTXc and following a number of parallel investigations it was concluded that there was no cause for the increased pre-course folate levels other than that originating from the FA provided during the previous course. The reduced folates in this increased folate pool likely displaces MTX from the DHFR, leading to decreased intracellular MTX and thus less anticancer effect [3]. These findings likely explain the observation of the first course of HDMTX being associated with more frequent toxicities than subsequent courses as the subsequent courses have been pre-rescued by the FA administered after the first course. The increased pre-course folate pool and associated intracellular retention of folates underscore the importance of allowing a sufficient time interval between the last FA dose and subsequent HDMTX course to avoid potential over-rescue (pre-rescue, in this case). This is of particular concern in regimens using shorter intervals between treatment courses such as osteosarcoma regimens which usually involve two successive courses at 1-week intervals. The fact that osteosarcoma patients receive 2 doses of 12 g/m² of HDMTX one week apart, yet experience toxicities no greater than patients receiving 3–5 g/m² every 2 weeks suggests that pre-rescue might potentially play a role in reducing toxicity, which implies that the second dose (at day 8) may have been pre-rescued to the point of having little activity. When the first course (at day 1) requires additional FA rescue due to DME and AKI, FA may be administered for 5–6 days and stopped just prior to the day 8 HDMTX cycle, long before the tissue reduced folates have returned to normal levels. It has yet to be determined the duration of action of the stored folates or the timing of their extracellular redistribution, both of which may impact the efficacy of subsequent HDMTX courses. Further, if augmented rescue is implemented in cases of DME, the more frequent and higher doses of FA may increase the accumulation of folates, potentially leading to over-rescue in the next course of HDMTX.

Folinic acid and hypercalcemia

Systemic administration of FA is generally considered to be a safe method to counter the effects of MTX and literature on FA overdose is sparse. This may have led to overconfidence in providing generous doses of FA to minimize HDMTX-induced toxicities. An under-recognized issue following the delivery of large amounts of FA is the potential development of hypercalcemia. Calcium folinate (D,L-FA) contains 0.08 mg of calcium per 1 mg of FA [44], which if administered repeatedly, may lead to significant accumulation of calcium in the circulation. In susceptible patients, the calcium content of calcium folinate warrants a slow rate of infusion (< 160 mg/min) to avoid cardiac arrhythmias and symptomatic hypercalcemia [44, 45]. Hypercalcemia not only causes catheter obstruction from calcium carbonate crystallization if given in the same line as bicarbonates, but also reduces glomerular filtration rate (GFR) and can exacerbate the nephrotoxic effects of MTX [46, 47].The risk of hypercalcemia during augmented FA rescue in cases of DME could result in potentially lethal outcomes. This pertains to the widely available form of FA, calcium folinate, comprised of both L- and D-isomers. While L-FA is rapidly metabolized, D-FA remains in the circulation for 40 h (i.e., 5 times its t_½ of 8 h) from the last given dose [48]. With repeated administration at higher doses every 3 or 6 h per current augmented rescue protocols, an increasing accumulation of D-FA can ensue [16, 49]. A recent case was experienced by one of the authors (J.H.) in which a 34-year-old female with ALL undergoing her first course of HDMTX developed hypercalcemia (serum calcium 8.34 mg/dL at baseline increased to 15.3 mg/dL) following treatment for DME consisting of 2000 units of glucarpidase followed by multiple intravenous infusions of FA totaling 103 g (Fig. 1). Although there are no published reports regarding the risk of hypercalcemia with repeated FA administration, it is possible that such cases are not reported due to their rarity in occurrence and attribution of HDMTX-related morbidity/mortality to other causes such that hypercalcemia is overlooked. In addition to the hypercalcemia risk, the higher concentration of D-FA than 5-MTHF allows for increased cell entry of D-FA via passive diffusion and accelerates 5-MTHF release from the intracellular space, potentially preventing the active 5-MTHF from effective cell rescue [50, 51]. As both the L- and D-isomers of FA are calcium salts, repeated administration of high doses of calcium folinate leads to accumulation of both isomers and can potentially cause dangerous hypercalcemia (Table 2) [49]. Delivery of calcium levofolinate (Fusilev^®, Isovorin^®) consisting of only the L-isomer may be a safer option as it clears more rapidly and has the same efficacy of D,L-FA at one-half the dose, thus one-half the calcium content [14, 52, 53]. Sodium levofolinate (Khapzory^®) which is devoid of calcium and has a higher solubility than D,L-FA, is ideal in cases of severe DME requiring prolonged augmented rescue, as it allows for a more rapid infusion/bolus injection, faster clinical effect, and shortened treatment duration [54]. Additionally, it can be delivered via the same intravenous line as that used for hydration and bicarbonate, thus contributing to a higher sodium concentration in the IV fluids which in turn facilitates MTX clearance following HDMTX infusion [55].

Fig. 1

Table 2.

Calcium content per calcium folinate (FA calcium) and calcium levofolinate dose with augmented rescue in acute lymphoblastic leukemia [56]

MTX concentration, μM	< 1.0	1.0 to < 2.0	2.0 to < 3.0	3.0 to < 4.0	4.0 to < 5.0	5.0 to < 6.0	6.0 to < 7.0	7.0 to < 8.0	8.0 to < 9.0	9.0 to < 10.0
aFA calcium (D,L-FA) dose, mg/m2	15	30	45	60	75	90	105	120	135	150
bCa2+ content (mg) per D,L-FA dose /m2	1.2	2.4	3.6	4.8	6.0	7.2	8.4	9.6	10.8	12.0
aCalcium levofolinate (Ca-L-FA) dose, mg/m2	7.5	15	22.5	30	37.5	45	52.5	60	67.5	75
cCa2+ content (mg) per Ca-L-FA dose /m2	0.6	1.2	1.8	2.4	3.0	3.6	4.2	4.8	5.4	6.0
Na-L-FA dose, mg/m2	7.5	15	22.5	30	37.5	45	52.5	60	67.5	75

MTX concentration, μM	10 to < 20	20 to < 30	30 to < 40	40 to < 50	50 to < 60	60 to < 70	70 to < 80	80 to < 90	90 to < 100	100 to < 200
aFA calcium (D,L-FA) dose, mg/m2	225	375	525	675	825	975	1125	1275	1425	1500
bCa2+ content (mg) per D,L-FA dose/m2	18	30	42	54	66	78	90	102	114	120
aCalcium levofolinate (Ca-L-FA) dose, mg/m2	113	188	263	338	413	488	563	638	713	750
cCa2+ content (mg) per Ca-L-FA dose /m2	9	15	21	27	33	39	45	51	57	60
Na-L-FA dose, mg/m2	113	188	263	338	413	488	563	638	713	750

^aDose given every 6 h until serum MTXc ≤ 0.2 μM based on 42H MTXc

Calcium folinate (Leucovorin) dose = MTXc x D,L-FA 15mg/m² x BSA; lowest dose, 15mg/m²

Calcium or sodium levofolinate dose = MTXc x L-FA 7.5 mg/m² x BSA; lowest dose, 7.5 mg/m²

Administered as slow IV push ≤ 160 mg/min

^bCalcium content: 0.08 mg of Ca²⁺ per 1 mg of FA calcium

^cCalcium content: 0.04 mg of Ca²⁺ per 1 mg of calcium levofolinate

Values in bold italics represent dangerous levels of calcium content (mg) per FA dose

Recommendations for improved folinic acid rescue

Dose and type of FA

• Typical MTX elimination and no severe toxicity

  • o
    Rescue should be delivered according to the respective treatment protocols, usually consisting of 15 mg/m² of D,L-FA or 7.5 mg/m² of levofolinate (L-FA) and repeated every 6 h until MTXc ≤ 0.2 μM. Standard and augmented rescue should not be delivered more frequently than every 6 h as L-FA (in the form of 5-MTHF) remains in the circulation for 20 h; more frequent delivery would increase the circulating folates which can potentially cause over-rescue in the subsequent HDMTX course. In fact, pharmacokinetic studies have shown significant accumulative 5-MTHF concentrations (20% increase per 24 h) even when rescue is delivered at 8-h intervals [16].
• DME but no evidence of AKI or other toxicities

  • o
    Augmented rescue with sodium levofolinate (Na-L-FA) in lieu of D,L-FA may help to reduce the risk of hypercalcemia and maintain adequate GFR [56]. If MTXc > 40 μM and requires greater than 675 mg/m² of D,L-FA (at 42H post-HDMTX infusion for ALL and 24H post-infusion for osteosarcoma or lymphoma), the panel recommends the use of Na-L-FA. If Na-L-FA is unavailable, calcium levofolinate (Ca-L-FA) can be used to rescue MTXc up to 80 μM (Ca-L-FA dose up to 638 mg/m²) (Table 1). If D,L-FA is the only available form of FA that is available when MTXc > 40 μM, a reduced dose of D,L-FA (675 mg/m² maximum) may be delivered while preparing for glucarpidase administration.
• Severe DME and AKI or other toxicities

  • o
    Intravenous glucarpidase should be administered to rapidly remove MTX. As glucarpidase enzymatically removes both MTX and FA, FA should be replaced after its administration [57]. However, early FA replacement after glucarpidase is not helpful as it will be enzymatically removed. Thus, post-glucarpidase dosing with FA should begin no sooner than 2 h after administration of glucarpidase [7].
  • o
    FA rescue should be continued for at least 48 h following glucarpidase administration as unbound MTX will re-enter the circulation from tissues following the concentration gradient. The dose of FA should be sufficient to restart the intracellular folic acid cycle but not so high as to risk hypercalcemia. In countries participating in the EU A2G Protocol [26], post-glucarpidase FA dose is determined according to the MTXc measured by immunoassay (e.g., ELISA or EMIT) which captures both MTX and DAMPA and likely approximates the intracellular MTXc [58]. This is considered preferable to using the pre-glucarpidase MTXc [57] which may lead to an excessive FA dose and risk of hypercalcemia. While high-pressure liquid chromatography (HPLC) differentiates MTX from DAMPA following glucarpidase in the circulation, it does not measure intracellular MTX; hence, this underestimates the intracellular MTX content and may result in a FA dose that is insufficient for restarting the intracellular folic acid cycle [59]. If available, however, HPLC would provide accurate monitoring of MTXc especially within 48 h of glucarpidase delivery until DAMPA is cleared [7].

Timing of subsequent HDMTX course

The type of rescue administered in the previous course (D,L-FA vs L-FA) should be verified to estimate its elimination time. Based on the pharmacokinetic principle of 5 times the t_½ of an active drug required for 97% clearance [48], courses in which D,L-FA or L-FA were used would require a delay of at least 40 h or 20 h, respectively, following its last delivery before the subsequent HDMTX course. This estimate, however, does not account for the storage capacity of FA in the form of intracellular reduced folates, which if accumulated following repeated doses, may protect the cancer cell from MTX. Nevertheless, 40 h can be used as an absolute minimum time interval from the last dose of FA before initiating the next HDMTX course, especially in patients who required augmented or extended rescue.

Research needed

Although there have been numerous past studies on the pharmacokinetics of antifolates and folates separately, investigations in the simultaneous pharmacokinetics of both HDMTX and FA are sparse [22]. Data are needed on the reciprocal influences of the pharmacokinetics between these two structural analogs, including competition for cell membrane transport, intracellular binding and intracellular polyglutamylation. Investigations are also needed to elucidate the duration of action as well as the timing and mode of redistribution of the stored intracellular folates following FA rescue to better determine the optimal timing for subsequent HDMTX courses to prevent pre-rescue. The impact of calcium accumulation following repeated doses of FA warrants critical investigation regarding its contribution to a potential electrolyte imbalance which can lead to dangerous renal and cardiac dysfunction in the setting of cancer treatment with HDMTX.

Conclusions

Folinic acid is a necessary component in HDMTX therapy. However, over-rescue in the form of pre-rescue after a prior HDMTX course may potentially reduce the efficacy of HDMTX and increase relapse risk. Further, hypercalcemia may possibly develop in cases of DME requiring augmented FA rescue, especially in patients with acute kidney injury. Clinicians should be knowledgeable of the types of FA available and their durations of action and avoid providing FA at intervals shorter than every 6 h. We recommend that, in addition to D,L-FA (calcium folinate), sodium levofolinate and calcium levofolinate be made available at institutions providing HDMTX treatment. The significantly higher cost of sodium levofolinate and calcium levofolinate compared to the conventionally available FA poses a hindrance to access in countries without universal healthcare coverage and in lower- and middle-income countries. As noted in the Recommendations section, if D,L-FA is the only available form of FA that is available when MTXc > 40 μM (at 42H post-HDMTX infusion for ALL and 24H post-infusion for osteosarcoma or lymphoma), a reduced dose of D,L-FA (675 mg/m² maximum) may be delivered while preparing for glucarpidase administration. However, prospective clinical data on this issue are lacking and dose optimization of FA should be evaluated in future clinical trials.

Supplementary Information

Below is the link to the electronic supplementary material.

Author contributions

J.H. contributed to the content and writing of the manuscript, prepared Table 2, and provided supervision. A.B. and S.H. reviewed and edited the manuscript, and provided supervision. L.R., L.S., B.B., S.S., E.C., C.T. reviewed and edited the manuscript. M.H. is the corresponding author, wrote the manuscript, prepared Figure 1, contributed to Table 2, and served as project lead administrator. M.G. organized and chaired the first roundtable meeting and reviewed the manuscript. All authors participated in 3 roundtable meeting discussions.

Funding

This project was funded by BTG Specialty Pharmaceuticals.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Conflict of interest

J.H, A.B, L.R, L.S, B.B., S.S, and E.C. received honorarium from BTG Specialty Pharmaceuticals for participation in the roundtable discussions. L.R. received research support and consulting fees from BTG Specialty Pharmaceuticals. L.S. and B.B. received research support from and was on the advisory board for BTG Specialty Pharmaceuticals. S.S. received research support from Protherics Medicine Development, Ltd; received honoraria from SERB Pharmaceuticals, Akademie für Infektionsmedizin, AMGEN, AvirPharma, CSi Hamburg, Labor28, Pfizer; received travel grants from and is/was an advisory board member of AMGEN, Gilead, Pfizer, SERB Pharmaceuticals. E.C. received consulting fees from SERB Pharmaceuticals; serves as co-Editor-in-Chief for Cancer Chemotherapy and Pharmacology. S.H. received research support and speaker honorarium from BTG Specialty Pharmaceuticals. M.H, C.T., and M.G declare no financial interests.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.