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Rheumatology - intravenous cyclophosphamide in paediatrics

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Cyclophosphamide is a cytotoxic alkylating agent which may be administered orally or intravenously. Intravenous cyclophosphamide is preferable in children.

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Starship clinical guidelines

Background

Cyclophosphamide is a cytotoxic alkylating agent which may be administered orally or intravenously. Intravenous cyclophosphamide is preferable in children.

Indications in Paediatric Rheumatology

Cyclophosphamide may be used for induction therapy of proliferative (class 3 or 4) lupus nephritis², and less commonly for the treatment of organ or life threatening manifestation of vasculitis or connective tissue disease.

  • Proliferative lupus nephritis²

  • Neuropsychiatric lupus with psychosis or coma⁸

  • ANCA associated vasculitis¹

  • Polyarteritis nodosa¹

  • Primary Central Nervous System vasculitis⁷

  • Connective tissue disease complicated by interstitial lung disease⁹

  • Severe and refractory Juvenile Dermatomyositis³

Contraindications

  1. Signs or symptoms suggestive of significant infection. These should be discussed with the appropriate consultant. The infusion may need to be deferred and antibiotics or other therapy required.

  2. Hypersensitivity to agent

  3. Significant cytopenia (leucopenia and neutropenia). Interval and/or dose may need to be adjusted.

  4. If impaired renal function the dose of cyclophosphamide may need to be adjusted.

Pre-treatment and monitoring

Prior to commencement

  1. Check that the parents have read the information and are happy to proceed.

  2. To determine dose: check full blood count 1 week before the first infusion and day 7-10 for subsequent infusions.

    1. If the nadir white count is stable or doesn't fall significantly then the dose may be increased by 250 mg/m2 (maximum 1000 mg)³

    2. If the nadir white count is < 2 or the neutrophil count is < 1 then the dose may be reduced by 25% and counts repeated prior to the next infusion to ensure adequate recovery.³

  3. Cyclophosphamide should be charted on a cytotoxic drug chart and sent to the pharmacy in advance (24-48 hours prior to the infusion). The dose should be discussed with the responsible consultant, charted by the registrar and countersigned or charted by the responsible consultant.

  4. MESNA should be charted

  5. Determine if methylprednisolone is required prior to the infusion (usually 10-30 mg/kg/dose, maximum 1 gm diluted in 100 ml of 0.9% normal saline.

  6. Antiemetics cyclizine and/or ondansetron should be charted.

Pre-treatment bloods and tests

  1. Renal function, full blood count, liver function and inflammatory markers (ESR for SLE and CRP for vasculitis).

  2. Urinalysis (MC and S, Protein:creatinine ratio)

  3. Complement (C3/C4), ANA and dsDNA every 3-6 months for all children with SLE.

  4. CK, LDH for children with JDM.

Dosage and administration

This is a cytotoxic medicine. Please ensure you follow your local policy with regards to cytotoxic competence and personal protection when preparing and administering it

The dose should be discussed with a paediatric rheumatologist and/or paediatric renal physician to ensure that the indication, initial and cumulative dosages are appropriate. The most commonly used regimens are as follows:

  1. 500-1000 mg/m2/dose (maximum 1 gram) monthly for 3-6 months

  2. 500 mg/m2/dose every 2-3 weeks (maximum 6 doses)

For all indications the maximum cyclophosphamide is 1000 mg/dose (see Recommended Dosage by Indication for further information).

Infusion

  1. An antiemetic should be administered prior to the infusion¹. IV Ondansetron (0.15 mg/kg/dose, maximum 8 mg) prior to infusion and every 8 hours as required. Cyclizine (1 mg/kg/dose, maximum 50 mg) should be given after the infusion.

  2. MESNA is given as an IV bolus over 15 minutes. If 400 mg is greater than the actual cyclophosphamide dose then reduce the MESNA dose to 60% of the cyclophosphamide dose.¹⁸

    Cyclophosphamide (CPA)  500mg/m2 750mg/m2 1000mg/m2
    MESNA dose with CPA 400mg 400mg  400mg 
    MESNA 2 hrs post CPA  NA 400mg  400mg 
    MESNA 4 hrs post CPA  NA  400mg  400mg 

  3. Fluid balance chart (if anuric or very nephrotic then discuss with consultant)* Nursing staff should ensure the urine output is >= 2-3 mL/kg/hr and contact the supervising doctor if output is not adequate.

    Prehydration fluids  125ml/m2/hr of 0.9% saline + KCL 20mmol/L for 2 hours.
    Continue until cyclophosphamide commenced
    Cyclophosphamide  infusion Chart as IV infusion in 0.9% normal saline (premade with 250-500ml of normal saline) over 2 hours
    Post hydration fluids 125ml/m2/hr of 0.9% saline + KCL 20mmol/L for 4 hours

  4. Inform medical staff if decreased urine output (<3 mL/kg/hr), macroscopic haematuria, microscopic haematuria and vomiting.

    Problem Action
    Macroscopic haematuria Increase IV fluids and consider MESNA^
    Reduced urine output Assess hydration, weight and consider increasing fluids and/or frusemide. Continue post hydration if >4 hours.
    Reduced urine output and adequate input Consider IV frusemide (0.5mg/kg/dose)
    Vomiting Anti-emetics and ensure adequate hydration

*Anuric patients may require additional fluids while nephrotic patients may require IV albumin (1mg/kg/dose over 4 hours with frusemide).

^The routine use of intravenous MESNA (2-mercaptoethanesulfonate) in rheumatology patients to reduce the risk of haemorrhagic cystitis and/or bladder cancer is controversial. If there is evidence of macroscopic haematuria or a history of haemorrhagic cystitis then administration should be considered. Dosing regimens vary but it may be given with the post hydration fluids at 100% of the cyclophosphamide dose and maybe increased in 20% increments up to 180% if required. The hydration time may be increased to 16-20 hours¹⁵

Availability

Cyclophosphamide is available in 1 gram and 2 gram vials and should be diluted in 250-500 mL of 0.9% saline.
MESNA (2-mercaptoethanesulfonate) comes in ampules at a concentration of 400 mg/4mL and 1 gram/10 mL. It may be added to cyclophosphamide or a compatible solution (sodium chloride 0.9% or glucose 5%)

Ongoing Monitoring

  1. A nadir full blood count should be arranged for 7-10 days after the infusion.

    1. These results should be discussed with the responsible consultant to determine if further monitoring is required and to determine the dose of cyclophosphamide for any subsequent infusions.

  2. Ondansetron wafers (x6) if required in addition to routine medications should be prescribed.

  3. Pneumocystis jirovecii prophylaxis with cotrimoxazole should be prescribed if not contraindicated. The usual dose is 24 mg/kg (maximum 960 mg) twice daily for 3 days of the week (consecutive or alternate days). Cotrimoxazole tablets are 480 mg (400 mg sulphamethoxazole + 80 mg trimethoprim) and syrup is 240 mg/5mL (200 mg sulphamethoxazole + 40 mg trimethoprim)

  4. A date for the next infusion should be determined prior to discharge

  5. Parents should monitor for signs and symptoms suggestive of infection and seek a medical review if indicated. All children should be treated appropriately depending on their clinical presentation (see Starship Clinical Guideline on Immunosuppression and Infection in Rheumatology patients)

Adverse effects

Short term effects include bone marrow suppression, infection, nausea, alopecia, leukopenia, thrombocytopenia, haemorrhagic cystitis, pulmonary injury (interstitial pulmonary fibrosis), cardiotoxicity (high doses) and allergic reactions.¹¹

The risk of haemorrhagic cystitis and bladder cancer with periodic IV cyclophosphamide used for rheumatologic indications is low. In addition, MESNA is given as additional bladder protection. Evidence that MESNA helps prevent haemorrhagic cystitis or bladder cancer in patients receiving cyclophosphamide for rheumatic diseases is inconclusive.¹²,¹³,¹⁴

Cyclophosphamide is associated with reduced ovarian reserve, ovarian failure and male infertility.¹ Age of treatment (pre, pubertal and post pubertal) and cumulative dosing are important risk factors for gonadal failure¹⁷. Limited case based data suggests that the average risk of amenorrhoea for women with SLE aged less than 21 years when they receive cyclophosphamide is estimated at 11%. Semen abnormalities are similarly less when therapy is initiated in pre-pubertal boys.¹⁶ Prognostic factors for persistent amenorrhea from intravenous cyclophosphamide in premenopausal women include older age with no clear link to cyclophosphamide therapy in women aged less than 32 years. In a review of 84 women receiving cyclophosphamide therapy none developed ovarian failure under the age of 25 years.¹¹

References

  1. EULAR/ERA-EDTA recommendations for the management of ANCA-associated vasculitis. Yates M, et al. Ann Rheum Dis 2016;0:1-12. doi:10.1136/annrheumdis-2016-209133.

  2. Lupus nephritis management guidelines compared. Wilhelmus et al. Nephrol Dial Transplant (2016) 31: 904-913.

  3. Intravenous cyclophosphamide pulse therapy in juvenile dermatomyositis. A review of efficacy and safety. Riley et al. Rheumatology 2004; 43:491-496.

  4. Textbook of Paediatric Rheumatology. Sixth edition. Cassidy J, Petty R, Laxer R and Lindsley C. Copyright 2011,2005 by Saunders, an imprint of Elsevier Inc.

  5. Systemic Polyarteritis Nodosa in the Young. A Single-Center Experience Over Thirty-Two Years. Eleftheriou et al. ARTHRITIS & RHEUMATISM Vol. 65, No. 9, September 2013, pp 2476-2485

  6. Theraputic advances in the treatment of Vasculitis. Eleftheriou D and Brogan P. Pediatric Rheumatology (2016) 14:26

  7. Pediatric Vasculitis. Weiss P. Pediatr Clin North Am. 2012 April ; 59(2): 407-423

  8. Neuropsychiatric manifestations in pediatric systemic lupus erythematosus: a 20-year study. Yu H-H et al. Lupus (2006) 15, 651-657

  9. Scleroderma in children. Foeldvari I. Current Opinion in Rheumatology 2002, 14:699-703.

  10. Central Nervous System Involvement in Pediatric Rheumatic Diseases: Current Concepts in Treatment. Duzova A and Bakkalogu A. Current Pharmaceutical Design, 2008, 14, 1295-1301.

  11. Acquisition of expanded indications for intravenous cyclophosphamide in the management of childhood rheumatic disease in general. Mori et al. Mod Rheumatol (2011) 21:449-457

  12. Incidence and Prevention of Bladder Toxicity From Cyclophosphamide in the Treatment of Rheumatic Diseases. Monach P, Arnold L and Merkel P. ARTHRITIS & RHEUMATISM Vol. 62, No. 1, January 2010, pp 9-21

  13. Incidence of Cyclophosphamide-induced Urotoxicity and Protective Effect of Mesna in Rheumatic Diseases. Yilmaz N, et al. Rheumatol 2015;42:1661-6.

  14. Intravenous cyclophosphamide in patients with chronic systemic inflammatory diseases: morbidity and mortality. Goransson LG et al. Scand J Rheumatol 2008;37:130-134.

  15. Paediatric Rheumatology. Foster H and Brogan P.

  16. Childhood onset systemic lupus erythematosus: how is it different from adult SLE?A. Aggarwal and P. Srivastava. International Journal of Rheumatic Diseases 2015; 18: 182-191

  17. Therapy Insight: preserving fertility in cyclophosphamide-treated patients with rheumatic disease. Dooley M and Nair R. NATURE CLINICAL PRACTICE RHEUMATOLOGY. MAY 2008 VOL 4 NO 5.

  18. Royal Children's Hospital Melbourne. Cyclophosphamide infusion protocol for non neoplastic conditions.

  19. ADHB policy for cytotoxic and hazardous medicine administration

  20. Foster H and Brogan P. Oxford Specialists Handbooks in Paediatrics. Paediatric Rheumatology. Page 234. Copyright Oxford University Press 2012.

 

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