异体骨髓移植/脐血移植/造血干细胞移植环孢素应用指南（英语版）

Cyclosporine (CSP) Administration Guidelines for Allogeneic Transplantation

 Introduction    Cyclosporine, a cyclic undecapeptide of fungal origin, is an effective immunosuppressive agent in preventing graft-versus-host disease (GVHD) after allogeneic transplantation by inhibiting T cell function. (Note: Cyclosporine should not be infused concurrently with bone marrow) Patients may be discharged to the Outpatient Department on either oral or IV cyclosporine, depending on the clinical situation and the overall condition of the patient. However, it is important that the patient be on a stable cyclosporine dose with stable renal function and documented drug levels at the time of discharge. Patients discharged at the end of the week will not necessarily be seen (or have labs drawn) until the following Monday unless specified in the discharge orders.郑州大学一附院血液内科万鼎铭

Administration

Intravenous    1. Sterile solution of 250 mg/5 ml ampules.

2. Store at room temperature.

3. Dilute in D₅W (Dextrose 5% in Water, In China called 5% glucose solution/5%GS) or NS(normal saline).

4. Final dilution volume: 25, 50, 100 ml.

5. Infusion time: standard time ? 1 hour. If hand/foot pain or burning is present, infuse over 2-6 hours; Infuse total daily dose of D₅W in glass bottle as 24 hours infusion if burning persists with 6 hours infusion.

6. Patients may be discharged on intravenous cyclosporine.

Oral          1. Liquid-100 mg/ml in 50 ml multidose vial.

2. 25 or 100 mg gelatin capsules.

3. Dose vomited: (1) Within 1 hour, repeat dose. (2) Persistent vomiting: Change to IV administration.

4. Conversion from IV to PO dosing of cyclosporine:

(1). 24 hour Oral dose CSP = 4×24 hour IV dosage, or as protocol indicated.

(2). Serum electrolytes, BUN, and creatinine should be checked within 48 hours after the changeover. These laboratory parameters should be monitored at least twice weekly while patients are in Seattle and at NCCH in Japan, but at The First Affiliated Hospital of Zhengzhou University once weekly or more.

(3) Steady state blood levels of cyclosporine will not be achieved for at least 48 to 72 hours after any change in dosing (assuming normal hepatic function?even longer if abnormal), so blood levels before this time are not helpful unless acute toxicity, e.g., seizures, is suspected.

Dosage          The prescribed dose of cyclosporine is determined by the research protocol on which the patient is treated. Most protocols will prescribe cyclosporine 1.5 mg/kg q12h. Intravenously, and when the oral dose is tolerated, 6.0 mg/kg q12h. Both intravenous and oral doses of cyclosporine will be calculated for non-obese patients using actual body weight. For obese patients （>125% ideal body weight）use of the adjusted ideal body weight is recommended.

Taper         1. Determined by the research protocol on which the patient is treated.

2. Patients with no evidence of GVHD and no protocol for tapering CSP begin the taper of 5%/week after day +50 and will receive their last dose of CSP at day +180.

3. Patients with acute GVHD (graft-versus-host disease) will begin the taper of cyclosporine after the prednisone therapy is completed. The dose of cyclosporine at the discontinuation of prednisone will be tapered at the rate of 5% per week. Assessment of chronic GVHD is done before day +100, and if present, the patients’ management will be outlined by the current treatment protocol or policy.

Cyclosporine Levels  Cyclosporine is metabolized by the cytochrome P-450 system in the liver and small intestinal mucosa. Renal excretion and metabolism is essentially negligible. Liver dysfunction as a result of VOD or GVHD can result in decreased metabolism and subsequently a rapid rise in cyclosporine plasma levels if doses are not adjusted. Other drugs can either inhibit or enhance the metabolism of cyclosporine.

    Drug Interactions   (1) Drugs that may increase CSP levels: Fluconazole, itraconazole, ketoconazole, erythromycin, H₂ blockers, Verapamil, Diltiazem, nicardipine, danazol, bromocriptine, metoclopramide, methylprednisolone, somatostatin (octreotide) .

                            (2) Drugs that may decrease CSP levels: Rifampicin, Phenobarbital, phenytoin, carbamazepine. Octreotide may lower serum levels by decreasing intestinal absorption of the oral drug.

    Drugs that may result in additive nephrotoxicity: Aminoglycosides, Amphotericin B, Acyclovir, Furosemide, TMP-SMZ (trimethoprim-sulfamethoxazole). For questions regarding CSP level, consult attending.

Assay          Cyclosporine levels in plasma are performed routinely on all patients in The First Affiliated Hospital of Zhengzhou University by a fluorescence polarization immunoassay (FPIA). This assay measures both parent compound and metabolites. In general, cyclosporine levels between 50-600ng/ml which are documented in patient’s chart without evidence of toxicity or GVHD is acceptable. Another assay that is available by a specific monoclonal antibody that measures only parent compound and demonstrated no significant cross-reactivity with the metabolites. Thus the levels between the two methods are not interchangeable. It is rarely necessary to maintain levers>600ng/ml and the probability of major toxic events is greatly increased at these levels.

Timing of levels   It is essential that plasma cyclosporine levels represent trough values.

                 1. Trough plasma cyclosporine levels should be drawn 10-12 hours after the last dose. Levels drawn at other times are generally not interpretable.

               2. If cyclosporine is being administered by 24 hour continuous IV infusion, the levels can be drawn at any time. Cyclosporine levels should not be drawn from the catheter lumen used for the intravenous infusion of cyclosporine.

                 3. Date and time of both the sample collection and last dose must be noted on the test requisition forms.

Frequency of Levels   1. Cyclosporine Levels should be done routinely on a weekly basis until week 8 after Allo-Transplantation.

2. Subsequently routine cyclosporine levels will then be measured every month while patients are receiving >50% of the calculated full?dose of cyclosporine.

3. Cyclosporine levels should also be measured at the time of suspected drug toxicity and at the time of the diagnosis of GVHD. Cyclosporine levels may be required more frequently in unstable patients.

4. Routine cyclosporine levels can be discontinued when patients are receiving < 50% of the calculated full-dose of cyclosporine.

Cyclosporine Dose Adjustments

Rationale: Minimize toxicity while maintaining adequate doses of cyclosporine to prevent or treat GVHD.

Adjustment of cyclosporine dose should not be based exclusively on plasma levels. Studies have demonstrated only a weak relationship between cyclosporine levels (plasma serum or whole blood) and the occurrence of GVHD or solid organ graft rejection. A better but still weak relationship between cyclosporine levels and toxicity has been demonstrated. Other factors may be important in determining clinical outcome. Biologic availability of the drug to the cells may be determined by the serum lipid concentration and profile (HDL, LDL. VLDL). Cellular factors (cyclophilin, calmodulin, calcineurin) determining the biologic effectiveness of cyclosporine may also vary between patients. Therefore cyclosporine levels should be used as a guide in conjunction with clinical observations of the biologic effects of the drug i.e. Toxicity and immunosuppression.

Doses should be adjusted based on the presence or absence of toxicity and the risk for clinical GVHD. In these cases plasma CSP levels should generally be supportive of the clinical hypothesis that cyclosporine is a contributing agent in the pathogenesis of organ disfunction or that inadequate dosing of cyclosporine is resulting in inadequate immunosuppression. A high plasma CSP level would support the hypothesis that CSP is contributing to toxicity. A test of this hypothesis would be a reduction in the CSP dose to determine if toxicity resolves. In the latter situation, the onset of GVHD might result from inadequate immunosuppression. A low plasma CSP level would support this clinical hypothesis. A test of this hypothesis would be to increase the CSP dose to determine if the GVHD improves or is controlled. In any patient, a change in the dose of CSP should be carefully considered, but this should be even more so with dose reductions in those patients at high risk of GVHD, such as patients transplanted from unrelated or HLA-mismatched donors.

Toxicities        Many toxicities may result from treatment with cyclosporine.

Renal              Increase in serum creatinine

Neurological       Peripheral ? paresthesia, severe tremor

                     Central ? seizures, visual disorder, paresis, disorientation, depression, confusion, somnolence, coma.

Gastrointestinal   Hepatotoxicity, nausea, vomiting and pancreatitis

Vascular + Hematologic  Hypertension

                      Hemolytic ? uremic syndrome (HUS)

                      Thrombo-embolism

Endocrine            Hyperglycemia

                      Gynecomastia

Dermal               Hypertrichosis

                      Gingival hypertrophy

Almost all patients will have some decrease in renal function. The dose adjustment of cyclosporine will depend on the severity of the toxicity (see following table).

Isolated increases in serum bilirubin may occur as a result of inhibition of the multi-drug resistance (MDR) gene by CSP. This has been suggested because of observations of a transiently increased bilirubin after short high-dose CSP administered during chemotherapy. This effect of CSP on bilirubin excretion is in addition to hepatotoxicity which has been previously described.

 

Cyclosporine Dose Adjustment Guidelines

Plasma Level1	GVHD or High risk of GVHD2	Toxicity Grade3	Cyclosporine Dose
<50ng/ml4	0	0	Increase 25%5
<150ng/ml	+	0	Increase 25%
50-150ng/ml	0	0	No change
150-600ng/ml	0	Ⅰ	No change
150-600ng/ml	0	Ⅱ	Decrease 25-50%
150-600ng/ml	0	Ⅲ	Decrease 75-100%
150-600ng/ml	0	Ⅳ	Stop 100%
150-600ng/ml	+	Ⅰ	No change
150-600ng/ml	+	Ⅱ	No change or Decrease 25%
150-600ng/ml	+	Ⅲ	Decrease 50-75%
150-600ng/ml	+	Ⅳ	Stop 100%
>600ng/ml	0	0	Decrease 10-25% every 3-4days
>600ng/ml	+	0	No change

1  Level should be repeated to confirm result before dose change.

2  High risk of  GVHD:  ① all mismatched haploidentical    ② all URD-SCT (unrelated donor stem cell transplantation)    ③ HLA matched siblings (>40 y.o.)

3. Toxicities can be observed even with low serum levels. The general guidelines for the toxicity scale of cyclosporine are:  Grade Ⅰ - Development of chemical or clinical abnormalities which are not of major clinical consequence and which reverse without requiring major medical intervention.  Grade Ⅱ - Development of chemical or clinical abnormalities which are persistent and represent target organ damage which may not be readily reversed. The toxicity at this level would be manageable by clinical methods but may interfere with other therapies.  Grade Ⅲ -Development of major clinical or chemical abnormalities which represent maximum toxicities of target organ without a significant probability of fatal outcome.  Grade Ⅳ - Development of major clinical or chemical abnormalities with significant probability of fatal outcome.

4. Levels can only be detected with confidence above 50ng/ml.

5. In young children, increase CSP doses by 50% increments above the baseline of 3 mg/kg/day to a maximum of 9 mg/kg/day to achieve satisfaction blood levels. If levels are still low, increase the frequency of the administration from q12h to q6h.

Toxicity criteria for grading in Common Adverse Events e.g. renal and neurological dysfunction

Organ dysfunction: Renal: 1. 1.5-2 X baseline serum creatinine.1 2. 2-3 X baseline or > 2.0 mg/dl (176.8mmol/L) serum creatinine.2 3. >3 X baseline or renal failure requiring hemodialysis.	Grade Ⅰ Grade Ⅱ   Grade Ⅲ
Neurological: Disorientation, depression, confusion, somnolence, paresthesia, tremor. Visual disturbance, paresis, aphasia. Intractable seizures, coma.	Grade Ⅰ-Ⅱ   Grade Ⅲ Grade Ⅳ

1. baseline serum creatinine is from pre-admit OPD (Outpatient Department) or hospital admit.

2. a serum creatinine >2.0 mg/dl is less serious in a >70 kg 45 y.o. male than in a 50 kg 45 y.o. female or in a child.

Rate of cyclosporine dose change    To decrease the cyclosporine dose because of toxicity (GradeⅡ) or elevated plasma levels unassociated with toxicity, it is recommended that there should be 25-50% or smaller decrements in the dose at 3-4 day intervals. If cyclosporine is stopped because of toxicity, the drug can be re-started at 25-50% of the full-dose when toxicity is resolving. To increase the CSP dose because of GVHD associated with low plasma levels or very low plasma levels not associated with GVHD, it is recommended that there be 10-25% increments in the dose at 3-4 day intervals. Young children frequently have serum levels <50ng/ml on 3 mg/kg/day, in these cases, the dose can be increased to 9 mg/kg/day in 50% increments. If levels are still low increase the frequency of administration from q12h to q6h. a gradual decrease or increase in CSP dose will allow a new steady-state concentration of the drug to develop such that repeat plasma cyclosporine levels are interpretable.

Alternate prophylaxis if CSP stopped for Toxicity    If more than one dose of cyclosporine is held because of severe toxicity, methylprednisolone should be considered for prophylaxis at 1 mg/kg/day. In those patients without significant renal dysfunction (serum creatinine < 2X baseline), ascites or pleural effusion, methotrexate may be considered as prophylaxis instead of methylprednisolone.