levoleucovorin and Graft-vs-Host-Disease

Methotrexate (MTX) is one of the main therapeutic agents currently used for the prophylaxis of graft-versus-host disease (GvHD) following hematopoietic stem cell transplantation. However, it is associated with significant toxicity and considerable side effects in many patients, which lead to either early withdrawal or dose reductions that may expose patients to the risk of GvHD and graft failure. Folinic acid (FA) can bypass the inhibitory effects of MTX on folate availability and control MTX toxicity. However, concerns that FA might inhibit the anti-GvHD effect of MTX and limited reports on its clinical usefulness have led to reluctance in its inclusion in standard GvHD prophylaxis regimens. Additionally, universal dosing and timing guidelines are lacking. I discuss the available literature and evaluate the evidence for the effect of FA on MTX toxicity and its safety regarding GvHD development and graft rejection in both adult and pediatric patients. Although FA administration appears to be safe, its efficacy for routine use in all types of transplants in adult patients is unproven and further research is required to confirm its MTX toxicity-lowering effect, identify the individual parameters that influence its usefulness in clinical practice, and evaluate its potential when developing a personalized prophylaxis regimen.

Topics: Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Leucovorin; Methotrexate; Vitamin B Complex

The use of methotrexate (MTX) for graft-versus-host disease (GVHD) prophylaxis is associated with increased rates of organ-specific toxicities. Despite limited data, the European Society for Blood and Marrow Transplantation-European LeukemiaNet working group recommend the use of folinic acid (FA) rescue to reduce MTX toxicity after allogeneic hematopoietic cell transplantation (allo-HCT). In a multicenter, double-blind, randomized, controlled trial, we explored whether FA rescue reduces MTX-induced toxicity. We enrolled patients undergoing allo-HCT with myeloablative conditioning with peripheral blood stem cell grafts, with GVHD prophylaxis consisting of cyclosporine and MTX. Patients were randomized to receive FA or placebo starting 24 hours after each MTX dose and continuing over 24 hours in 3 to 4 divided doses. The primary end point was the rate of grades 3 and 4 oral mucositis. After enrollment of 52 patients (FA, n = 28; placebo, n = 24), preplanned interim analysis revealed similar rates of grade 3 and 4 (46.6% vs 45.8%; P = .97) and grades 1 to 4 (83.3% vs 77.8%; P = .65) oral mucositis. With a median follow-up of 17 (range, 4.5-50) months, there was no difference in the rates of acute and chronic GVHD, disease relapse, nonrelapse mortality, and overall survival. These interim results did not support continuation of the study. We conclude that FA rescue after MTX GVHD prophylaxis does not decrease regimen-related toxicity or affect transplantation outcomes. This study was registered at clinicaltrials.gov as #NCT02506231.

Topics: Cyclosporine; Double-Blind Method; Graft vs Host Disease; Humans; Immunosuppressive Agents; Leucovorin; Methotrexate

Fifty-seven patients undergoing bone marrow transplantation were randomly assigned to receive either cyclosporin A (CsA, n = 26) or methotrexate, followed by rescue with folinic acid (MTX + FA, n = 31) as prophylaxis for graft-versus-host disease (GVHD). All patients but one receiving CsA had evidence of sustained engraftment, and there was no difference between the two groups on the day in which marrow engraftment was documented. Oropharyngeal mucositis was of similar incidence and severity in the two groups. In contrast, patients receiving CsA showed higher renal and hepatic toxicity rates than those treated with MTX + FA. Severe-to-moderate acute GVHD (grades II-IV) was documented in 12 patients receiving CsA and in 12 treated with MTX + FA. The cumulative incidence of this complication was similar in both groups (46.1% and 38.7%). Similarly, there was no difference in the incidence of chronic GVHD. The leukemic relapse rates were also comparable, as well as the estimated probability of survival, which was 55% in patients treated with MTX + FA and 41% in those who were given CsA. We conclude that MTX + FA is as effective as CsA in the prevention of GVHD, with the additional advantage of reduced renal and hepatic toxicities.

Topics: Actuarial Analysis; Acute Disease; Adolescent; Adult; Blood Transfusion; Bone Marrow Transplantation; Cyclosporins; Drug Therapy, Combination; Female; Graft vs Host Disease; Humans; Leucovorin; Leukemia; Male; Methotrexate; Middle Aged; Postoperative Complications; Prospective Studies; Random Allocation; Recurrence

The effect of folinic acid (FA) on toxicity secondary to the use of methotrexate (MTX) for the prevention of graft-versus-host disease (GVHD) has not been determined. We retrospectively analyzed data from 111 patients who received allogeneic bone marrow transplantation (allo-BMT) in our institution. Fifty patients did not receive FA (non-FA), 37 received FA four times (low dose, LD-FA), and 24 received FA 25 times (high dose, HD-FA) in BMT. No significant differences were observed in the severity of stomatitis after allo-BMT among the three groups while the median of peak value of ALT in HD-FA was significantly lower (P = 0.031). The median time to neutrophil engraftment after allo-BMT in the HD-FA group was significantly shorter than that in the non-FA group (P = 0.034). No significant difference in the median time to neutrophil engraftment was observed between the LD-FA and non-FA groups (P = 0.44). Stepwise multiple regression analysis revealed that the determinants of the shorter duration of neutropenia were transfused total nucleated cell dose (P = 0.001) and the administration of HD-FA (P = 0.036). There was no significant difference in 3-year overall survival among the three groups. Frequent administration of FA may reduce the time to neutrophil engraftment after hematopoietic stem cell transplantation.

Topics: Adolescent; Adult; Bone Marrow Transplantation; Child; Child, Preschool; Drug Administration Schedule; Female; Graft vs Host Disease; Humans; Infant; Infant, Newborn; Leucovorin; Male; Methotrexate; Patient Outcome Assessment; Premedication; Retrospective Studies; Transplantation Conditioning; Transplantation, Homologous; Young Adult

Cyclosporine (CsA) and MTX are commonly used for GVHD prophylaxis in pediatric allo-SCT. Mucositis and hepatic toxicity frequently restrict the delivery of the fourth dose of MTX. Folinic acid (FA) may ameliorate MTX toxicity. We conducted a retrospective chart review of all pediatric patients who received CsA and MTX for GVHD prophylaxis from January 2000 to July 2010. Patients treated before July 2007 (N=29) did not receive FA and those treated from July 2007 onward did receive FA (N=18). Patients who received FA were significantly more likely to receive day +11 MTX (odds ratio (OR) 10.42, 95% confidence interval (CI): 1.21-262.27) but there was no significant difference in Grade III-IV GVHD between the two groups (OR 1.15, 95% CI: 0.08-18.14). FA did not impact relapse-free survival (RFS) (P=0.82). Increased likelihood of receiving day +11 MTX suggests that FA ameliorates MTX toxicity, such as severe mucositis. FA administration for MTX GVHD prophylaxis should be studied in a prospective, randomized fashion.

Topics: Adolescent; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Cyclosporine; Drug Monitoring; Drug Therapy, Combination; Female; Folic Acid Antagonists; Graft vs Host Disease; Humans; Immunosuppressive Agents; Infant; Leucovorin; Male; Methotrexate; Mucositis; Retrospective Studies; Severity of Illness Index; Stem Cell Transplantation; Survival Analysis; Transplantation, Homologous; Vitamin B Complex

As the safety of folinic acid administration and its efficacy for reducing the toxicity of MTX remain controversial, we assessed the effect of folinic acid administration after MTX treatment for GVHD prophylaxis on the incidence of oral mucositis and acute GVHD. We retrospectively analyzed data for 118 patients who had undergone allogeneic hematopoietic SCT and had received MTX for GVHD prophylaxis. Multivariate analysis showed that systemic folinic acid administration significantly reduced the incidence of severe oral mucositis (odds ratio (OR)=0.13, 95% confidence interval (CI) 0.04-0.73, P=0.014). There was also a tendency for a lower incidence of severe oral mucositis in patients who received folinic acid mouthwash (OR=0.39, 95%CI 0.15-1.00, P=0.051). No significant difference was observed in the incidence of acute GVHD between patients who received systemic folinic acid administration and those who did not (P=0.88). Systemic folinic acid administration and mouthwash appear to be useful for reducing the incidence of severe oral mucositis in patients who have received allogeneic hematopoietic SCT using MTX as GVHD prophylaxis.

Topics: Adolescent; Adult; Aged; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Leucovorin; Male; Methotrexate; Middle Aged; Retrospective Studies; Stomatitis; Transplantation Conditioning; Transplantation, Homologous; Young Adult

This study examined the contribution single nucleotide polymorphisms (SNPs) of the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene have on clinical outcomes in hematopoietic stem cell transplant patients treated with the antiproliferative drug methotrexate. Two common SNPs, 677C>T and 1298A>C, were genotyped by polymerase chain reaction-restriction fragment-length polymorphism (PCR-RFLP) from samples obtained from patient DNA samples. Eleven clinical outcomes including survival and graft-versus-host disease (GVHD) were assessed against donor and recipient MTHFR genotypes against pretransplantation variables. Folinic acid (FA) as treatment for oral mucositis toxicity was used at investigator discretion in 72 of 140. Donor MTHFR 1298AA genotype was associated with decreased 5-year survival (P = .03) and event-free survival (EFS) (P = .02) in patients withheld FA. Donor MTHFR 677CC genotype was associated with earlier GVHD (P = .003), and more severe acute GVHD (P = 0.02). FA was significantly associated with decreased survival (P = 0.02) in patients given a donor MTHFR 677CT transplant. FA was significantly associated with decreased survival (P = .04), EFS (P = .009) in patients given a donor MTHFR 1298AC transplant MTHFR gene polymorphisms indicate a potentially useful gene for donor selection where more than one donor is available. Use of FA following transplantation should be reconsidered in the context of patient and donor MTHFR genotypes.

Topics: Antineoplastic Agents; Australia; Cohort Studies; Disease-Free Survival; DNA Mutational Analysis; Female; Genotype; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Leucovorin; Male; Methotrexate; Methylenetetrahydrofolate Reductase (NADPH2); Polymorphism, Restriction Fragment Length; Polymorphism, Single Nucleotide; Severity of Illness Index; Stomatitis; Transplantation, Homologous

Topics: Animals; Dogs; Drug Administration Schedule; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Leucovorin; Methotrexate; Vitamin B Complex

The use of MTX for GVHD prophylaxis may be associated with significant toxicity, including hepatotoxicity, graft failure and mucositis. Folinic acid may be involved in the amelioration of MTX toxicity. There is, however, no consensus regarding its use. A survey was conducted in Australian and New Zealand transplant centres (n=22) regarding the use of folinic acid following MTX in the transplant setting. Of 18 participating transplant centres, 12 (66%) used folinic acid following MTX--8 (44%) routinely and 4 (22%) only in the presence of significant mucositis. Those centres that did not use routine dosing of folinic acid post transplant chose not to do so on the grounds that they believed that it was not efficacious or may increase the risk of GVHD. Grading of mucositis was inconsistently done. There is wide variation in the use of folinic acid following HSCT. Folinic acid is infrequently used in the adult transplant setting or is used after mucositis is already apparent, practices that appear to run counter to available clinical evidence and to pharmacological data. Further research is required to conclusively determine whether folinic acid has any benefit in the post-BMT setting.

Topics: Australia; Data Collection; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Leucovorin; Male; Methotrexate; Mucositis; New Zealand; Transplantation, Homologous; Vitamin B Complex

We report our experience of CD34 positive selection as a means of graft T-cell depletion (TCD) in 14 consecutive HLA-identical Peripheral blood stem cells (PBSC) allografts as prophylaxis against graft versus host disease (GVHDp). CD34 positive selection was performed by immunomagnetic separation achieving a median CD34 and T-cell dose of 4.17 (range 1.4-8.50) x 10(6)/kg and 1.89 (range 0.92-13.18) x 10(4)/kg, respectively, in the graft. This represents 4-log depletion of T-cells. The median time to achieve a neutrophil count of 0.5 x 10(9)/l was 15 days and to achieve a platelet count of 50 x 10(9)/l was 20 days. Only four patients developed acute GVHD at a median of 41 days but this was exclusively mild grade I cutaneous disease and settled with oral steroids. Four patients, all of whom had AML, relapsed or progressed after transplant at a median of 161 (range 109-311) days. One of these had been transplanted in early relapse (9% blasts) whilst another was in second remission. The remaining 10 patients are alive and well. The median progression free survival for the whole population is 69% at 686 days. We conclude that CD34 positive selection by immunomagnetic separation in HLA-identical PBSC allografting achieves significant TCD with clinically trivial acute GVHD, prompt engraftment and an acceptable disease relapse risk.

Topics: Acute Disease; Adolescent; Adult; Antigens, CD34; Cyclophosphamide; Cyclosporine; Female; Graft Survival; Graft vs Host Disease; Hematopoietic Stem Cells; Humans; Immunomagnetic Separation; Immunophenotyping; Immunosuppressive Agents; Leucovorin; Leukemia, Myeloid; Lymphocyte Depletion; Male; Methotrexate; Middle Aged; Peripheral Blood Stem Cell Transplantation; T-Lymphocytes, Cytotoxic; Transplantation Conditioning; Transplantation, Homologous; Whole-Body Irradiation

A study was performed to determine whether the addition of folinic acid to a combination of methotrexate (MTX) and cyclosporin A (CsA) after allogeneic bone marrow transplantation (BMT) could improve tolerance to the regimen without inhibiting its ability to prevent graft-versus-host disease (GVHD). Sixty-nine adult BMT patients received CsA plus MTX 15 mg/m2 on day 1 and 10 mg/m2 on days +3, +6 and +11. Folinic acid 5 mg was started 24 h after each MTX dose and continued 6 hourly until 12 h before the next dose of MTX. The median age of the group was 37 years and 13 patients (19%) received bone marrow from mismatched and/or unrelated donors. No MTX doses were omitted or modified. Grade II-IV acute GVHD occurred in 18 patients (29%) and chronic GVHD in 35 of 56 (64%) patients at risk. There were no cases of grade > or = III stomatitis. Transplant-related mortality was 7% before 100 days and 20% overall (9% for low risk leukaemia) with a median follow-up of 41 months (range 24-88 months). This regimen of folinic acid rescue may contribute to a well tolerated GVHD prophylaxis protocol with reasonably low BMT-related mortality. Our results suggest that the ability of MTX to prevent acute GVHD is not abrogated by folinic acid given in this way.

Topics: Acute Disease; Administration, Oral; Adolescent; Adult; Bone Marrow Transplantation; Chronic Disease; Cyclosporine; Drug Therapy, Combination; Female; Follow-Up Studies; Graft Rejection; Graft vs Host Disease; Humans; Leucovorin; Leukemia; Male; Methotrexate; Middle Aged; Transplantation, Homologous

Topics: Adult; Arthritis, Rheumatoid; Bone Marrow Transplantation; Cyclosporine; Female; Graft vs Host Disease; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Leucovorin; Leukemia, Myeloid, Acute; Methotrexate; Neutropenia; Prednisolone

Fluorouracil is a common cause of acral erythema and a variety of pigmentary anomalies. These conditions are believed to be the result of a direct toxic effect or a graft-versus-host-like reaction. We describe two cases in which an erythematous eruption that evolved into hyperpigmented, hyperkeratotic lesions developed in two patients who were receiving combination chemotherapy (5-fluorouracil, folinic acid, and alpha-interferon). The histologic features included apoptotic keratinocytes with exocytosis of mononuclear cells, some showing satellitosis, and hydropic change of the basal cell layer with an interface dermatitis that was most marked within the distal eccrine duct and acrosyringium. Clinicopathologic correlation suggests that the eruption was primarily caused by involvement of the sweat glands and hair follicles. Although a direct toxic effect may play some role, the histologic features suggest that the dominant mechanism is a graft-versus-host-like or host-versus-altered-host-type reaction.

Topics: Antineoplastic Combined Chemotherapy Protocols; Drug Eruptions; Erythema; Female; Fluorouracil; Graft vs Host Disease; Humans; Interferon alpha-2; Interferon-alpha; Keratosis; Leucovorin; Male; Middle Aged; Pigmentation Disorders; Recombinant Proteins

Topics: Bone Marrow Transplantation; Graft vs Host Disease; Humans; Leucovorin; Methotrexate

Thirty-two patients undergoing related-donor bone marrow transplantation (BMT) received cyclosporine (CSP) and methotrexate (MTX) with folinic acid rescue (FAR) as graft-versus-host disease (GVHD) prophylaxis. Fifty consecutive related-donor BMT patients given the CSP/MTX combination without FAR were utilized as historical controls. Patients receiving FAR experienced earlier engraftment, with absolute neutrophil count greater than 0.5 x 10(9)/l at a median of 17 days (vs 21 days in controls, p = 0.002). The day of last platelet transfusion was earlier in the FAR group (median of 14 days vs 17 days in controls, p = 0.01). Compared with the control group, patients receiving FAR had a lower incidence of grade II-IV stomatic (53% vs 78%, p = 0.04) and hepatic (25% vs 56%, p = 0.01) regimen-related toxicity. In the FAR group, 70% required total parenteral nutrition vs 92% of controls (p = 0.02). Broad-spectrum antibiotics were given to FAR patients for a median of 21 days (vs 23 days in controls, p = 0.09). The incidence of grade II-IV acute GVHD was similar in the FAR and control populations (45% and 35%, respectively, p = NS) as was the incidence of chronic GVHD (62% vs 55%, respectively, p = NS). Estimated event-free survival is 59% for FAR patients (median follow-up 64 weeks) and 58% for controls (median follow-up 109 weeks, p = NS). FAR reduces regimen-related toxicity in patients receiving CSP/MTX acute GVHD prophylaxis without significantly influencing GVHD incidence or event-free survival.

Topics: Adolescent; Adult; Blood Cell Count; Bone Marrow Transplantation; Dose-Response Relationship, Drug; Female; Graft vs Host Disease; Humans; Leucovorin; Liver; Male; Methotrexate; Middle Aged; Mouth Mucosa; Neutrophils; Prospective Studies; Salvage Therapy; Transplantation, Homologous