Folinic Acid Administration Following MTX As Prophylaxis for GVHD in Allogeneic HSCT Centres in Australia and New Zealand

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ORIGINAL ARTICLE Folinic acid administration following MTX as prophylaxis for GVHD in allogeneic HSCT centres in Australia and New Zealand

D Bhurani1, M Schifter2,3 and I Kerridge2,3

1Department of Haemato-Oncology, Rajiv Gandhi Cancer Institute and Research Center, New Delhi, India; 2Department of Haematology, Westmead Hospital, Westmead, New South Wales, Australia and 3Blood and Marrow Transplant Service, Westmead Hospital, Westmead, New South Wales, Australia

The use of MTX for GVHD prophylaxis may be tions. Severe mucositis is also associated with prolonged associated with significant toxicity, including hepato- hospitalization, and increased costs of care.1–6 Although toxicity, graft failure and mucositis. Folinic acid may be OM is caused largely by the toxicity associated with the involved in the amelioration of MTX toxicity. There is, chemoradiotherapy conditioning regimen, it is also asso- however, no consensus regarding its use. A survey was ciated with the use of MTX prophylaxis for GVHD.7 conducted in Australian and New Zealand transplant MTX, in high doses, has an established role as an anti- centres (n ¼ 22) regarding the use of folinic acid following metabolite chemotherapeutic agent in the treatment of a MTX in the transplant setting. Of 18 participating range of haematological malignancies, including ALL and transplant centres, 12 (66%) used folinic acid following high-grade lymphomas.8,9 In lower doses, the immunosup- MTX—8 (44%) routinely and 4 (22%) only in the pressive and anti-inflammatory properties of MTX provide presence of significant mucositis. Those centres that did the rationale for its use, most commonly in combination with not use routine dosing of folinic acid post transplant chose CYA, as GVHD prophylaxis following allo-HSCT.10,11 not to do so on the grounds that they believed that it was Unfortunately, although MTX has been shown to be a not efficacious or may increase the risk of GVHD. highly effective agent for the prevention of GVHD, its use Grading of mucositis was inconsistently done. There is may be associated with considerable toxicity, including wide variation in the use of folinic acid following HSCT. delayed engraftment, hepatotoxicity and, particularly, Folinic acid is infrequently used in the adult transplant mucositis. Given the potential mortality and morbidity setting or is used after mucositis is already apparent, associated with these toxicities, and the difficulty and practices that appear to run counter to available clinical expense associated with the use of 5,10-methylenetetrahy- evidence and to pharmacological data. Further research is drofolate reductase genotyping to predict which patients required to conclusively determine whether folinic acid has carry the TT genotype and so may be more susceptible to any benefit in the post-BMT setting. MTX toxicity, it has become common practice to schedule Bone Marrow Transplantation (2008) 42, 547–550; MTX prophylaxis post transplant and omit one or, rarely, doi:10.1038/bmt.2008.197; published online 14 July 2008 two scheduled doses of MTX if unacceptable toxicity Keywords: folinic acid; MTX; GVHD; mucositis occurs or is anticipated.12 The alternative approach to preventing mucosal toxicity due to the intracellular depletion of folates by MTX is to supplement the MTX therapy with folic/folinic acid. This approach appears logical as folic/folinic acid has been Introduction shown to reduce the toxicities of MTX when it is used in autoimmune disorders, including improved compliance Oral mucositis (OM) is one of the most problematic with MTX therapy in patients with rheumatoid arthritis complications associated with allogeneic haematopoietic and by reducing the adverse effects associated with the use SCT (allo-HSCT). OM is associated with increased of MTX in high–intermediate dose chemotherapy protocols mortality and morbidity, principally from infection, as well for various neoplastic disorders.13–17 At the same time, as significant pain, dysgeusia, difficulty speaking and folic/folinic acid supplementation does not appear to difficulty receiving nutrition, hydration and oral medica- significantly reduce the effectiveness of MTX in rheumatoid arthritis and other autoimmune conditions, interfere with killing of leukaemia cells or increase the risk of leukaemic Correspondence: Dr D Bhurani, Department of Haemato-Oncology, relapse.13–17 Rajiv Gandhi Cancer Institute and Research Center, Sector 5, Rohini, Although folic/folinic acid might therefore be expected to New Delhi 110085, India. E-mail: [email protected] improve the tolerability of MTX after HSCT, the major Received 21 February 2008; revised 27 May 2008; accepted 27 May 2008; concern regarding its use in this setting has been the published online 14 July 2008 theoretical risk that it may abrogate the anti-GVHD Folinic acid following MTX as prophylaxis for GVHD D Bhurani et al 548 activity of MTX. Those studies that have been conducted and New Zealand (n ¼ 22). Participants were asked to provide reassurance. A recent retrospective analysis of 311 answer 16 questions about transplant activity in the patients who underwent HSCT for chronic myeloid previous 12 months (2004–2005), the incidence and severity leukaemia found that folic acid supplementation was not of mucositis, grading of mucositis, use of MTX for GVHD associated with an increased risk of GVHD or relapse post- prophylaxis, use of folinic acid in the transplant setting and HSCT.18 Folic acid supplementation during MTX immu- the rationale for their policy regarding folinic acid use. The nosuppression is not associated with early toxicity, risk of study was approved by the institutional ethics committee acute GVHD or relapse following haematopoietic trans- and the executive of the Australian Bone Marrow plantation. Torres et al.19 reported 57 patients undergoing Transplant Registry (ABMTR). BMT who were randomly assigned to receive either CsA or MTX followed by folinic acid rescue. They found that the MTX/folinic acid group showed similar efficacy in the Results prevention of GVHD with the additional advantage of reduced renal and hepatic toxicities. Another study looked Respondents attheinfluenceofpost-MTXfolinicacidrescueonregimen- Surveys were sent toall 22 (15 adult and 7 paediatric) related toxicity and GVHD after allo-HSCT.20 A total of transplant centres performing allogeneic transplants in 32 consecutive patients received CsA and MTX with folinic Australia and New Zealand. Questionnaires were returned acid rescue as GVHD prophylaxis. Total 50 consecutive by 18 transplant centres, including 12 (80%) adult and 6 transplant patients given the CsA/MTX combination (86%) paediatric transplant units. Together, these units without folinic acid were utilized as historical controls. performed some 436 transplants in the previous 12 months, Folinic acid rescue showed reduced regimen-related toxicity including 365 in adults and 71 in children. All units in patients receiving CsA/MTX GVHD prophylaxis with- performed sibling donor transplants, 16 performed un- out significantly influencing the incidence of GVHD or related donor transplants and 8 (3 adult and 5 paediatric) event-free survival. Similarly, Russell et al.21 showed that units performed umbilical cord blood transplants. All units addition of folinic acid post-MTX after allogeneic trans- used myeloablative conditioning and 11 adult units and 1 plantation could improve tolerance to the regimen without paediatric unit alsoperformedtransplants with reduced- inhibiting its ability toprevent GVHD and soensured that intensity conditioning (RIC) regimens. the full and complete scheduled MTX dose was given. As with many other aspects of transplantation, there Mucositis and grading of oral toxicity appears tobe considerablevariance between transplant Eleven (61%) units graded mucositis following allogeneic centres with regards to the use of folinic acid following transplant with all but one of these units assessed mucositis MTX. A 1995 survey of 87 EBMT participating centres, for on a daily basis. A number of different grading systems were example, found that 37 were using folinic acid rescue after used including the World Health Organization,24 National 22 MTX in the transplant setting. In an effort to address Cancer Institute (NCI),25 Bearman,26 oral mucositis index practice variability and provide a sound evidence base for (OMI)27 and University of Nebraska28 systems. Assessment transplant practices, the EBMT Working Party for Paediatric of OM was performed by a range of staff including; Diseases and International BFM Study Group–Subcommit- transplant physicians (four), transplant registrars (four), tee Bone Marrow Transplantation, proposed a uniform oral physicians/dentists (three) and nursing staff (four). policy for GVHD prophylaxis and therapy for their members based on the results of a large survey carried out within the European paediatric transplant centres. This policy recom- MTX administration mended that folinic acid (15 mg/m2 per day) should be All units used MTX for GVHD prophylaxis in myelo- administered 24 h after MTX toreduce the incidence and ablative transplants whereas 11 (61%) units alsoused MTX severity of adverse effects of MTX, including myelosuppres- as part of GVHD prophylaxis in RIC transplants. The sion and mucosal toxicity.23 There is nosuch uniform most common regimen used for myeloablative transplants 2 consensus policy in adult transplant groups regarding GVHD was the ‘Seattle protocol’, which uses 15 mg/m of MTX on 2 29 prophylaxis or for the use of folic/folinic acid following MTX. day þ 1 and 10 mg/m on days þ 3, þ 6 and þ 11. Given the potential, albeit contested, benefits of folinic acid Thirteen (72%) respondents indicated that over 75% of in the transplant setting and the limited data regarding its use patients were administered the complete scheduled MTX in transplantation in adults, this study’s aims were twofold: doses, whereas three (17%) units reported that 51–75% of one to describe the usage of folinic acid in the paediatric and patients received all scheduled doses and two (11%) units adult transplant centres in Australia and New Zealand and reported that greater than 50% received all the scheduled two, to elucidate the reasons why transplant centres make doses of MTX. The most common reasons given for decisions to use, or not to use, folinic acid following the omitting scheduled doses of MTX were mucositis (n ¼ 15, administration of MTX as prophylaxis for GVHD. 83%) and renal dysfunction (n ¼ 1, 5%).

Folinic acid administration Methods Of the 18, 12 (66%) transplant units (that responded to this survey) used folinic acid following MTX for GVHD Surveys were sent by post and email to all transplant prophylaxis. Eight (44%) administered folinic acid routi- centres performing allogenic transplantation in Australia nely following each dose of MTX whereas four (22%)

Bone Marrow Transplantation Folinic acid following MTX as prophylaxis for GVHD D Bhurani et al 549 administered folinic acid only if there was evidence of there was no evidence to support its use, or, because of significant mucositis. Of the adult transplant units four concerns that it may increase the likelihood of acute (33%) used folinic acid as part of standard therapy whereas GVHD. We also found that not all transplant units graded a greater proportion (that is four of the seven, 67%) of the mucositis and that a number of different grading systems paediatric transplant units routinely administered folinic were used. acid. Those units that routinely used folinic acid following These results are noteworthy for three reasons. First, MTX all used the same dose calculation of 10–15 mg/m2 for they provide a further reminder of the differences that exist the MTX, with folinic acid being administered 24 h after between transplant centres and even between paediatric each dose of MTX. and adult transplant units and of the need for ongoing Of those units that used folinic acid, 11 (61%) did so on debate about the desirability of standardizing transplant the grounds that it would reduce the risk/severity of practices. Although one may postulate that paediatric mucositis, whereas 4 (33%) indicated that they did so to transplant centres more often use folinic acid post-BMT limit the myelotoxic effects of MTX. Of those units that because they have more (relative) experience with high-dose did not routinely administer folinic acid following MTX MTX-containing regimens and have always been concerned (n ¼ 6), all indicated that they did sobecause they with minimizing the long-term toxicities of chemo- considered that there was no evidence of efficacy in this radiotherapy and transplantation, we are unable to explain setting, whereas three (50%) indicated that they did not these differences on the basis of this survey. Second, this administer folinic acid because of the possibility that it may study raises questions both about the practice of using increase the risk of acute GVHD. folinic acid in situations when mucositis is already established or is becoming apparent (wherein the administration of folinic acid is too late) and about decisions not Discussion to use folinic acid because it is ineffective and/or may increase the risk of acute GVHD. The effectiveness of Oral mucosal toxicity presents one of the most difficult MTX is largely attributable to its role as an inhibitor of challenges in transplantation as it is associated with dihydrofolate reductase and the reduction of the inter- substantial morbidity, contributes to transplant-related cellular folate substrate pool. And while the quality of mortality and has been largely resistant to most of the evidence in support of folinic acid following MTX in the interventions designed to reduce its incidence and severity. transplant setting is weak, there are data tosuggest that it Although a Cochrane Systematic review of 71 studies may reduce MTX toxicity in the transplant (and non- involving 5217 patients receiving chemotherapy found a transplant) setting and there is nodata that supportthe number of agents had some benefit in preventing or claim that its use diminishes the effectiveness of MTX as reducing the severity of mucositis, including amifostine, prophylaxis for GVHD.18–20 Finally, the finding that antibiotic pastes or pastilles, hydrolytic enzymes and ice outside of clinical trials not all transplant units grade chips, in all instances the benefit was modest and/or of mucositis and, when/where they do, they use a range of limited clinical significance, and in some instances, the different grading systems, is troubling because uniform therapy was onerous or unpleasant (as with ice chips) or grading is necessary for consistent assessments and for itself was associated with considerable toxicity (as with providing the basis for meaningful comparisons between amifostine).30 More promisingly, recent studies of Palifer- patient populations, conditioning regimens and interven- min, a recombinant humanized keratinocyte growth factor tions to prevent or treat mucositis. has demonstrated that it may reduce the incidence, severity Mucositis remains a significant problem and, whereas and duration of mucositis following allo-HSCT.31,32 there are now promising biological therapies in trial and in Most reviews and original research has, however, practice (most notably Palifermin) these are expensive and addressed the problems of mucositis following chemother- even if effective, do not remove the need to consider apy, rather than specifically post-HSCT, and where such therapies that specifically counter the toxicity of MTX, research has been conducted in the transplant setting, the particularly where mucositis may lead to some patients not concern (appropriately) has been with the impact of receiving the full scheduled dose of post transplant MTX chemoradiotherapy conditioning regimens on the muco- and therefore potentially be at greater risk of acute GVHD. sitis, rather than specifically on the potential harms Ongoing research to establish more effective and less toxic associated with the post transplant administration of regimens for reducing GVHD is essential. At the same time, MTX, an agent well known to cause stomatitis and however, in the absence of adverse data regarding the use of mucositis. The place of folinic acid in preventing or folinic acid in the transplant setting, it is worthwhile asking ameliorating MTX toxicity, particularly mucositis, has in again what role folinic acid can, or should, have in contrast, received little attention and its use in transplant preventing and/or limiting the severity and duration of centres appears to be more a matter of medical culture and oral mucosal toxicity. precedent than evidence-based prescribing. This survey found that 33% of adult and 67% of paediatric of the transplant centres (that responded to the survey) in Australia and New Zealand routinely use Acknowledgements folinic acid to reduce mucositis following post transplant MTX. The majority of centres that did not use folinic We acknowledge the assistance of all those transplant centres acid chose not to do so either because of the belief that that participated in this research.

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