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Allografting

Engraftment syndrome, but not acute GVHD, younger age, CYP3A5 or MDR1 polymorphisms, increases tacrolimus clearance in pediatric hematopoietic SCT

Abstract

We investigated clinical factors that affected the clearance of tacrolimus (FK506) administered by continuous drip infusion to children who had received allogeneic hematopoietic SCT. Blood FK506 levels were measured every day in 27 patients in an attempt to adjust the dose to maintain the target range (10–15 ng/mL). Patients who developed engraftment syndrome (ES) and acute GVHD and patients less than 7 years of age showed a higher FK506 clearance calculated from body weight (BW) for 5 or more consecutive days compared with the control groups. A time-course study showed that the occurrence of ES, but not acute GVHD, was related to increased clearance of FK506. When calculated from body surface area (BSA), a significant increase in FK506 clearance was observed in patients with ES, but not in those less than 7 years of age. FK506 clearance was not influenced by CYP3A5, multidrug resistance 1 or ABCG2 genotypes. None of the clinical parameters affected blood FK506 levels. Determination of the FK506 dose on the basis of frequent monitoring of the blood concentration seems to minimize the serious adverse effects induced by the immunosuppressant. It may be more accurate to dose FK506 according to BSA rather than BW for pediatric patients.

Introduction

Tacrolimus (FK506), a heterocyclic macrolide antibiotic isolated from the broth of Streptomyces tsukubaensis, is an agent used for GVHD prophylaxis. This immunosuppressant is 50–200 times more potent than cyclosporine.1, 2 FK506 suppresses calcineurin, causing an inhibition of IL-2 production and a decrease of Ag-specific T-lymphocyte proliferation.1, 2 In randomized human trials, FK506 in combination with standard-dose MTX led to a significantly lower incidence of acute GVHD, compared with cyclosporine plus MTX in BMT.3, 4, 5

Initially, it was proposed that the target blood FK506 level should be set at 10–30 ng/mL.3, 4, 5 However, as high concentrations of FK506 increased the incidence of adverse effects such as renal dysfunction, concentrations of 10–20 ng/mL have been considered appropriate.6, 7 For pediatric patients, it is recommended that FK506 be started at 0.03–0.04 mg/kg/day, and the target blood level be set at 5–158, 9 or 10–20 ng/mL.10 The frequent adverse effects are hypomagnesemia, hypertension, nephrotoxicity and tremor.8

Cytochrome P450 (CYP)3A4 and CYP3A5 are the most important contributors to FK506 metabolism whereas the P-glycoprotein pump (multidrug resistance 1, MDR1) modulates its bioavailability. Both CYP3A5 and MDR1 genes have multiple single-nucleotide polymorphisms (SNPs). Recent studies have elucidated the effects of SNPs on the pharmacokinetics and adverse effects of FK506 in organ transplant patients.11, 12, 13, 14

The factors affecting clearance of FK506 administered by continuous drip infusion remain to be fully understood in pediatric and adult hematopoietic SCT (HSCT). In the present study, blood FK506 levels were measured every day in an attempt to adjust the dose to maintain the target range (10–15 ng/mL) after allogeneic HSCT in 27 pediatric patients with blood disorders. The results showed a higher FK506 clearance in patients with engraftment syndrome (ES) at HSCT. However, the occurrence of acute GVHD, younger age, CYP3A5, MDR1, and ABCG2 genotypes did not influence the clearance.

Materials and methods

Patient selection

A total of 27 children with leukemia (n=25), myelodysplastic syndrome (n=1) and aplastic anemia (n=1), 1–13 years of age, underwent HSCT between December 2002 and February 2009. When the conditioning treatment was initiated, three, seven and three patients with ALL were in CR1, CR2 and non-CR (>30% marrow blasts), respectively. Two, four and four patients with AML were transplanted in CR1, CR2 and non-CR (10–63% marrow blasts), respectively. One patient with plasmacytoid DC leukemia was in CR1. One patient with juvenile myelomonocytic leukemia was in non-CR. The study protocol was approved by the institutional review board of Shinshu University School of Medicine. Written informed consent was obtained from parents and from patients over 12 years of age. Before HSCT, all patients had a Lansky score of 80%, and no problems regarding major organs. Pretransplant median serum creatinine level and creatinine clearance in 27 patients were within normal limits: 0.24 (range, 0.13–0.44) mg/dL and 129.6 (range, 93.9–238.9) mL/min per 1.73m2, respectively.

Donor selection

HLA antigens for A, B and DRB1 were determined by high-resolution DNA typing.15 The primary criterion for donor selection was HLA compatibility, defined as a 6/6 allele match (at the A, B and DRB1 loci) or a 5/6 allele match (single-Ag mismatch at the A, B or DRB1 locus), with preference for the 6/6 match. If matched related donors were not available, unrelated donors were sought. When the patient lacked an available related or unrelated donor who had at least five of six HLA Ags that matched the recipient at the allelic level, an HLA-haploidentical related donor was selected. If a transplant was urgently needed, unrelated umbilical cord blood was chosen according to the number of nucleated cells based on the recipient's body weight (BW) and HLA compatibility.

Conditioning regimen and transplantation

Preparative conditioning consisted of TBI (4.5–12. Gy), fludarabine at 150 mg/m2 and CY at 120 mg/kg. The source of stem cells for transplantation was the BM and umbilical cord blood in 23 and 4 patients, respectively. Three related and four unrelated donors were completely HLA-matched with their recipients. One sibling, two related and five unrelated donors were one-locus-mismatched with their recipients. The remaining eight patients were transplanted with marrow cells from related donors with mismatches of two or three HLA antigens (HLA-haploidentical). All cord blood transplants were from HLA-mismatched unrelated donors.

GVHD prophylaxis and treatment

We used short-term MTX (15 mg/m2 i.v. on day 1 and 10 mg/m2 on days 3, 6 and 11) and FK506 (starting at 0.03 mg/kg/day on day −1). In addition, methylprednisolone was given at 0.5–1 mg/kg/day in most of the transplants from HLA-mismatched donors. After engraftment, the dose of methylprednisolone was tapered and discontinued up to day 30 in the absence of acute GVHD. In cord blood transplantation, FK506 and methylprednisolone were given i.v. as prophylactics.

During continuous drip infusion we measured the blood FK506 levels almost every day, and endeavored to adjust the dose to maintain the target range (10–15 ng/mL). In all patients, whenever the blood concentration was outside the target range (<10 ng/mL or >15 ng/mL), the FK506 dose was changed the same day. We also altered the FK506 dose when the blood level showed a change >1 ng/mL compared with the value shown 1 day before, and was simultaneously expected to become outside the target range by the next day. As we tapered FK506 in patients who showed no acute GVHD or whose acute GVHD was improved, the FK506 clearance was analyzed until day 60 after HSCT excluding the tapering period.

Diagnosis of acute GVHD was based on clinical manifestations and the histology of biopsy samples of affected tissues. Acute GVHD was graded according to standard criteria.16 Grade II or higher acute GVHD was treated with 1–2 mg/kg/day of methylprednisolone.

Supportive care

G-CSF (5 μg/kg/day) was administered i.v. to ALL patients from day 5, and its use was discontinued when the neutrophil count exceeded 1500/μL. Oral antibiotics were administered to sterilize the bowel. Acyclovir (10 mg/kg, daily) and micafungin (2 mg/kg, daily) were given i.v. during the peritransplant period. I.v. γ-globulin was administered at 200 mg/kg for every 2 weeks up to day 60.

Trimethoprim or sulfamethoxazole was used after engraftment for prophylaxis against Pneumocystis jirovecii infection.

Nineteen patients who developed febrile neutropenia were treated with fourth-generation cephalosporins (depending on the drug-susceptibility profile of isolates) or a carbapenem. When the monotherapy was not effective, teicoplanin was added. We did not use aminoglycosides. There were no patients who developed clinically or microbiologically documented bacterial or fungal infection during the clinical course.

Definition of ES

ES was defined using the diagnostic criteria described previously,17 which included the development of two or more of the following symptoms 4 days before and after the start of neutrophil recovery (ANC>100/μL): (1) fever (temperature >38.5 °C) without an identifiable infectious cause; (2) weight gain 2.5% over the pretransplantation baseline weight; (3) erythematous rash not attributable to a medication and (4) hypoxia, pulmonary infiltrates, or both, not attributable to infection, thromboembolism, pulmonary hemorrhage, fluid overload or cardiac disease.

FK506 assay and measurement of clearance

Blood samples were obtained from the central venous catheter. Before blood collection was initiated, we stopped infusion of FK506 and clamped the infusion lumen. The distal lumen was dedicated to FK506 infusion, whereas the proximal lumen was used for blood sampling. There were no apparent differences in FK506 levels between the central venous catheter and peripheral blood draw.

The concentration of FK506 in whole blood was measured with a microparticle enzyme immunoassay using the IMx analyzer (Abbott Japan, Tokyo, Japan);18 FK506 clearance (L/h/kg) was calculated daily using the following formula:

FK506 clearance (L/h/m2) was calculated with the following formula:

Determination of cytokine concentration

The patient's serum was stained using the Cytometric Bead Array system (BD Biosciences, San Jose, CA, USA), and cytokines such as IL-1β, IFN-γ, IL-6 and IL-8 were measured by flow cytometric analysis according to the manufacturer's instructions, as described previously.19

Genotyping of CYP3A5, MDR1 and ABCG2 polymorphisms

DNA was extracted from peripheral blood or BM cells before HSCT using the QIAamp DNA Blood Mini Kit (Qiagen, Tokyo, Japan). The concentration of genomic DNA was prepared at 10–15 ng/μL for the TaqMan SNP genotyping assay. SNPs in the CYP3A5 gene (A6986G in intron 3) and MDR1 gene (T-129C in exon 1, G2677A/T in exon 21 and C3435T in exon 26) were genotyped using the SNP Genotyping Kit (Applied Biosystems, Tokyo, Japan). The ABCG2 gene (C421A in exon 5) associated with the pharmacokinetics of mycophenolic acid was also genotyped.20 PCR was performed using a TaqMan Assay for Real-Time PCR (7500 Real-Time PCR System; Applied Biosystems), following the manufacturer's instructions.

Toxicity grading of adverse events

Adverse events were assessed according to the Common Terminology Criteria for Adverse Events (CTCAE; version 3.0;. http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf). Grade 0 indicated no organ toxicity, and grades 1–4 indicated increasing levels of toxicity, such as hypertension, hyperkalemia, hyperglycemia, hypercholesteremia, hypertriglyceridemia, hyperuricemia, thrombotic microangiopathy, seizure and tremor. Thrombotic microangiopathy (grade III or higher) and hyperuricemia (grade I or higher) were considered as indications of toxicity. A twofold or greater increase in the pre-transplant creatinine level was defined as indicating nephrotoxicity. Other grade II or higher adverse events were defined as showing toxicity.

Statistical analysis

Analysis was performed using SPSS version 11.0. (SPSS, Inc., Chicago, IL, USA). Post-transplant changes in clearance, dose and blood concentration of FK506 were analyzed using the paired t-test. The effect of clinical parameters on the clearance, dose and blood level of FK506 was evaluated by the unpaired t-test. The association between genotypes and the adverse effects of FK506 were analyzed by using Fisher's exact test. Statistical significance was defined if the values for consecutively 5 days or more showed a P-value of <0.05.

Results

The clearance, dose and blood concentration of FK506 administered by a continuous drip infusion

A continuous drip infusion of FK506 (0.03 mg/kg/day) was given from day 1 before HSCT, and the target blood FK506 level was set at 10–15 ng/mL. It took 2–5 days for FK506 to reach a blood level 10 ng/mL (Figure 1). The blood FK506 levels in the 27 patients were in the range of 10–15 ng/mL on 821 (69.2%) of 1186 days, <10 ng/mL on 126 days (10.6%) and >15 ng/mL on 239 days (20.2%). In all, 7 days (0.6%) showed >20 ng/mL of FK506 levels. The mean calculated FK506 clearance was 0.085±0.030 L/h/kg on day 5, reached a peak of 0.112±0.042 L/h/kg on day 11 and, thereafter, gradually decreased to 0.087±0.029 L/h/kg on day 20, 0.073±0.021 L/h/kg on day 30 and 0.062±0.021 L/h/kg on day 60. The FK506 dose was reduced to 0.025±0.008 mg/kg/day on day 5, and, subsequently, a dose of 0.031±0.013 mg/kg/day was required on day 11. Thereafter, the dose was decreased to 0.028±0.009, 0.022±0.007 and 0.017±0.006 g/kg/day on days 20, 30 and 60, respectively.

Figure 1
figure1

The mean clearance, dose and blood concentration of FK506 in 27 children who underwent HSCT. The clearance and dose were calculated according to BW.

Association of clinical parameters with the clearance, dose and blood concentrations of FK506

Next, the association between various clinical parameters and FK506 clearance and dose was analyzed. ES developed on a median of 11 days (range, 5–22 days) in 19 of 27 patients. Nine patients had fever and one other symptom, whereas 10 patients had three or more of the symptoms listed in the diagnostic criteria. As shown in Figure 2a, patients who developed ES showed a higher FK506 clearance calculated according to BW for a period of 12 consecutive days from days 7 to 18 compared with the clearance in those who did not develop ES. Patients with ES required a higher FK506 dose for 9 consecutive days from days 10 to 18 than those without. We then examined whether clearance and dose of FK506 increased after the occurrence of ES. Compared with the mean value of FK506 clearance (0.099±0.034 L/h/kg) 4 days before the onset of ES, FK506 clearance substantially increased to 0.134±0.048 L/h/kg 1 day after the onset, and thereafter decreased to 0.112±0.044 L/h/kg on day 5, 0.090±0.029 L/h/kg on day 10 and 0.062±0.027 L/h/kg on day 30, as shown in Figure 3a. There was also a significant difference in FK506 dose on comparison of the values obtained before and after the occurrence of ES: 0.028±0.012 mg/kg/day 4 days before the onset of ES, 0.034±0.012 mg/kg/day on day 5 after the onset, 0.030±0.011 mg/kg/day on day 10 and 0.019±0.007 mg/kg/day on day 30.

Figure 2
figure2

Association of various clinical parameters with the clearance, dose and blood concentration of FK506.The clearance, dose and blood concentration of FK506 were compared (a) in the presence or absence of ES; (b) in the presence or absence of acute GVHD (grade II); (c) between patients less than 7 years of age and those 7 years or older; and (d) between carriers of the CYP3A5*3*3 genotype and carriers of the *1*3/*1*1 genotype. The clearance and dose were calculated from BW.

Figure 3
figure3

The clearance, dose and blood concentration of FK506 before and after the occurrence of ES or that of acute GVHD. We defined ‘day 0’ as the first day that a patient developed ES or acute GVHD (grade II). The clearance and dose were calculated from BW.

Acute GVHD (grade II) developed on a median of 26 days (range, 12–58 days) in 15 of 27 patients. FK506 clearance calculated from BW was substantially greater between days 9 and 14 and days 17 and 21 in patients who had acute GVHD than in those who did not. The FK506 dose for patients with acute GVHD was higher on 33 consecutive days from days 7 to 39, as compared with the values of patients who did not (Figure 2b). Nevertheless, neither clearance nor dose of FK506 increased after the occurrence of acute GVHD, as shown in Figure 3b. Clearance was 0.098±0.031 L/h/kg 4 days before the onset, 0.095±0.027 L/h/kg on day 5 after the onset, 0.079±0.038 L/h/kg on day 10 and 0.071±0.032 L/h/kg on day 30. The FK506 dose was 0.031±0.011 mg/kg/day 4 days before the onset, 0.026±0.009 mg/kg/day on day 5 after the onset, 0.024±0.009 mg/kg/day on day 10 and 0.019±0.008 mg/kg/day on day 30.

Patients less than 7 years of age had a significantly greater FK506 clearance calculated from BW on 12 consecutive days from days 12 to 23 than those 7 years of age or older, but showed no difference from day 30 onward (Figure 2c). In patients less than 7 years old, more FK506 was required on 8 consecutive days from days 14 to 21. We then evaluated whether the occurrence of ES and younger age increased the clearance and dose of FK506 calculated according to BSA. The results are presented in Figure 4. Patients who developed ES showed a higher FK506 clearance for a period of 8 consecutive days from days 7 to 14 compared with the clearance of those who did not develop ES. Patients with ES required a higher FK506 dose for 6 consecutive days from days 11 to 16 than those without. On the other hand, there were no significant differences in FK506 clearance and dose between patients less than 7 years of age and those 7 years of age or older.

Figure 4
figure4

The clearance and dose of FK506 calculated from BSA. (a) The mean clearance and dose of FK506 calculated from BSA in 27 children who underwent HSCT are shown. The clearance and dose of FK506 were compared (b) in the presence or absence of ES; and (c) between patients less than 7 years of age and those 7 years or older.

The FK506 clearance and dose calculated from BW were not influenced by the patient's gender, donor source, whether the donor was related or unrelated, whether the donor was HLA-mismatched at 2 or more loci, and whether G-CSF was used or not. Patients who underwent HSCT in non-CR did not significantly differ in FK506 clearance from those who underwent HSCT in remission but required a higher FK506 dose from days 10 through 24. No patients developed complications that were expected to influence the clearance of FK506 (for example, venoocclusive disease). In addition, the patients did not receive any medications that were known to interfere with FK506 clearance (for example, administration of azoles, macrolide antibiotics and anticonvulsants). As shown in Figure 2d, CYP3A5, MDR1 or ABCG2 genotypes did not influence FK506 clearance or dose requirement. It is of particular interest that none of the clinical parameters, including ES, acute GVHD, age less than 7 years, and HSCT in non-CR, affected the blood FK506 levels.

The incidence of adverse effects in the first 2 months after HSCT was as follows: hyperuricemia, 29.6%; hypertension, 22.2%; hyperglycemia, 22.2%; hypertriglyceridemia, 7.4%; nephrotoxicity, 7.4%; hyperkalemia, 7.4%; hypercholesteremia, 3.7%; thrombotic microangiopathy, 3.7%; seizure, 0%; and tremor, 0%. All adverse effects were reversible, and no fatal complications occurred. The incidence of these adverse effects was not associated with CYP3A5, MDR1 or ABCG2 genotypes. There was no correlation of the frequencies of hypertension and nephrotoxicity with FK506 concentration. Therefore, hypertension as well as hyperglycemia, hypercholesterolemia and hyperlipemia might be largely due to corticosteroids that were used for more than 90% of patients.

Discussion

It is reported that, in adult BMT, when 0.03 mg/kg/day of FK506 is administered by continuous drip infusion, FK506 clearance is 0.055–0.075 L/h/kg on day 11 after BMT, and is not affected by the concomitant use of short-term MTX or methylprednisolone.21, 22 However, it is unclear whether post-transplant complications influence FK506 clearance. The present study revealed that FK506 clearance calculated from BW was higher from days 7 to 18 after HSCT in patients with ES, as compared with patients without ES. Similarly, the clearance between days 9 and 14 and days 17 and 21 after HSCT was greater in patients who developed acute GVHD (grade II) than in those who did not. The time-course study demonstrated that only the occurrence of ES was related to increases in clearance and dose of FK506. A possible explanation is that 12 of 15 patients with acute GVHD had also demonstrated ES; as a result, clearance and dose of FK506 might have already increased during the pre-acute GVHD period. Proinflammatory cytokines such as IL-1, TNF-α, and IFN-γ, released as a consequence of tissue injury from preparative conditioning or from recovering neutrophils, have been demonstrated to have a role in the development of ES.23 Actually, significant numbers of our patients showed high serum cytokine levels at the beginning of ES according to flow cytometric analyses: IL-1β (51.7–97.1 pg/mL in 7 of 16 patients), IFN-γ (38.1–44.2 pg/mL in 2 of 16 patients), IL-6 (28.1–310.9 pg/mL in 11 of 16 patients) and IL-8 (46.4–1691.0 pg/mL in all 16 patients). As FK506 exerts inhibitory effects on the synthesis of various cytokines by T cells,24 hypercytokinemia in the development of ES may influence FK506 clearance.

Several investigators reported the clearance of FK506 in children who received HSCT. In a study of 55 children (6 months to 18 years of age), Przepiorka et al.9 noted that FK506 clearance at 2 weeks after HSCT in children <6, 6–12 and >12 years of age was 0.159±0.082, 0.109±0.053 and 0.104±0.068 L/h/kg, respectively. In the present study, patients younger than 7 years of age showed a significantly higher FK506 clearance calculated from BW between days 12 and 23 after HSCT than those 7 years of age or older. However, from day 30 onward, FK506 clearance decreased in both groups, showing no intergroup differences. One possible explanation for the age-dependent difference in FK506 clearance was majorly the calculation based on BW, as there was no significant difference in FK506 clearance calculated from BSA between patients less than 7 years of age and those 7 years of age or older. The results of the comparative analysis suggest that it is more accurate to dose FK506 according to BSA rather than BW for children who receive HSCT.

Patients with the CYP3A5*3*3 genotype require less FK506 to achieve target trough blood concentrations than carriers with the CYP3A5*1 allele in organ transplantation.13 Regarding pediatric patients at 1 year post-heart transplantation, recipients with GT/TT for MDR1 G2677T require a lower dose of FK506 than GG patients to reach the same blood levels. A substantial difference was also observed between CC patients and CT/TT patients for MDR1 C3435T.12 In adult renal transplantation, recipients with the ABCG2 421A allele (CA/AA) showed mycophenolic acid-pharmacokinetics differing from those with the CC allele.20 In the present study, there was no significant difference in FK506 clearance calculated from BW between CYP3A5 expressers and non-expressers. Neither MDR1 nor ABCG2 genotype was related to FK506 clearance. In HSCT, the influence of genotypes on FK506 clearance may be hidden by other factors such as ES and age. Nevertheless, the possible effects of methylprednisolone on the expression of CYP3A and p-glycoprotein25, 26, 27 cannot be excluded, because more than 90% of the patients received corticosteroid.

Although a greater dose of FK506 calculated from BW was given to patients with ES and to those with a younger age, the circulating concentrations were maintained at levels comparable to those in the control groups. As a result, there were no severe adverse effects during the first 2 months after HSCT. Consecutive adjustment of FK506 dose based on frequent monitoring of the blood concentration may be able to minimize the serious adverse complications induced by the immunosuppressant.

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Yanagisawa, R., Katsuyama, Y., Shigemura, T. et al. Engraftment syndrome, but not acute GVHD, younger age, CYP3A5 or MDR1 polymorphisms, increases tacrolimus clearance in pediatric hematopoietic SCT. Bone Marrow Transplant 46, 90–97 (2011). https://doi.org/10.1038/bmt.2010.64

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Keywords

  • tacrolimus (FK506)
  • engraftment syndrome
  • GVHD
  • CYP3A5
  • MDR1 (ABCB1)

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