CYCLOPS

CYCLOPS, http://trialguru.org/

1. CYCLOPS OVMC Landmark trials series de Groot K, et al. "Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody-associated vasculitis: A randomized trial".  Annals of Internal Medicine . 2009. 150(10): 670-680.

2. (CYCLOPS)

3. BACKGROUND SOME FACTS: ANCA-associated vasculitis used to be fatal until Fauci et al introduced cyclophosphamide and glucocorticoid therapy ANCA-associated small-vessel vasculitis include microscopic polyangiitis , Wegener's granulomatosis, Churg -Strauss syndrome, and drug-induced vasculitis. Cyclophosphamide is an alkylating agent of the nitrogen mustard type, which add alkyl group to DNA and interferes with DNA replication. It is used in treating cancers, autoimmune disorders, and amyloidosis. PRIOR TO THIS TRIAL: Prior to the CYCLOPS , dosing for cyclophosphamide trial was still unclear for patients with ANCA-associated vasculitis

4. Clinical question Among patients with newly-diagnosed ANCA-associated vasculitis with renal involvement, is pulse cyclophosphamide superior to daily oral cyclophosphamide for the induction of remission?

5. DESIGN Analysis: Intention-to-treat Multicenter , open-label, parallel-group, randomized, controlled trial N=149 (160 screened) Pulse cyclophosphamide (n=76) Daily oral cyclophosphamide (n=73) Setting: 42 centers in Europe and Mexico Median follow-up: 18 months Primary outcome: Time to remission

6. Population Inclusion Criteria Age 18-80 years New diagnosis of ANCA Renal involvement of the disease, defined by ≥1 of the following: Creatinine > 1.69 mg/ dL but < 5.6 mg/ dL Biopsy showing necrotizing glomerulonephritis RBC casts Urine showing >30 RBC/high-powered field and proteinuria (>1 gram/day) Confirmatory histology or ANCA positive serology Exclusion Criteria >2 weeks of prior cyclophosphamide or other cytotoxic drug therapy in the prior year or corticosteroids for >4 weeks Other multisystem autoimmune disease Hepatitis B, C, or HIV HIV Life-threatening organ dysfunction Prior malignancy Pregnancy Anti-GBM Ab+

7. Interventions Randomized to a group: Pulse cyclophosphamide : 15 mg/kg IV pulses q2 weeks x 6 weeks, then 15 mg/kg IV pulses q 3 weeks until remission, and then for 3 months following remission adjusted for WBC level, age, and renal function Weeks 7-25 could be be administered orally as 5 mg/kg/day for 3 days per week Daily oral cyclophosphamide : 2 mg/kg/day until remission (generally about 3 months), then 1.5 mg/kg/day for 3 months following remission adjusted for WBC count, age, and renal function Additional immunosuppression (administered to both groups): Prednisolone 1 mg/kg/day oral, tapered to 0.4 mg/kg/day by month 3 and 5 mg/kg/day by month 15 Azathioprine 2 mg/kg/day starting 3 months after remission, continued until the end of the study

8. criticisms Unclear generalizability to areas with endemic TB because pulse cyclophosphamide can lead to worse outcomes for those with latent TB Daily oral therapy may have been more effective than pulse therapy for renal function recovery Contrary to the author's comments, pulse therapy is not likely more convenient No report of proteinuria

9. Bottom line Among patients with newly-diagnosed ANCA-associated vasculitis with renal involvement, there was no difference in rates of, or time to remission when comparing pulse cyclophosphamide to daily oral cyclophosphamide. Those receiving pulse cyclophosphamide required a lower cumulative dose and had a lower risk of leukopenia . Follow-up study in 2012 by same authors showed higher relapse in pulse cyclophosphamide group than daily oral group.

10. Discussion questions According to the CYCLOPS study, what is the benefit in receiving pulse cyclophosphamide rather than daily dosing of cyclophosphamide? In areas with endemic TB, which is worse: pulse cyclophosphamide or daily cyclophosphamide? What was the final conclusion in terms of pulse vs. daily cyclophosphamide in the CYCLOPS trial?

11. Discussion questions/ANSWERS According to the CYCLOPS study, what is the benefit in receiving pulse cyclophosphamide rather than daily dosing of cyclophosphamide ? ANSWER: Receiving pulse cyclophosphamide required a lower cumulative dose and had a lower risk of leukopenia . In areas with endemic TB, which is worse: pulse cyclophosphamide or daily cyclophosphamide ? ANSWER: Pulse cyclophosphamide leads to worse outcomes for TB edemic areas due to high rate of latent TB What was the final conclusion in terms of pulse vs. daily cyclophosphamide in the CYCLOPS trial ? ANSWER: There is no difference in rates/time of remission between pulse vs. daily. However, pulse cyclophosphamide (while may lead to decreased cumulative dose) is associated with higher relapse rates.

12. BOARD-LIKE Question 42yo Female presents to her primary care doctor’s office. She reports that she had 2 episodes of hemoptysis within the past week in setting of chronic fevers. She also reports chronic sinus infections, weight loss. Physical exam: T 37.0°C, HR 60, BP 137/79. BMI is 22 No abnormalities Labs: Hg 11, ESR 35 Urinalysis: Trace protein, 10-20 RBC, 0-2 WBC, no casts QUESTION What is the best treatment regimen to start in this patient? Glucocorticoids Pulse dose Cyclophosphamide + Glucocortioids Daily dose cyclophosphamide + Glucocorticoids Rituximab Either B or C

13. BOARD-LIKE Question Educational Objective: Knowledge of treatment for ANCA-associated vasculitis Key Point: This patient suffers from granulomatosis with polyangiitis ( Priorly known as Wegener’s) First line treatment option is usually corticosteroids and cyclophosphamide (either pulse or daily dosing) ANSWER What is the best treatment regimen to start in this patient? Glucocorticoids Pulse dose Cyclophosphamide + Glucocortioids Daily dose cyclophosphamide + G lucocorticoids Rituximab Either B or C

14. BOARD-LIKE Question A 60yo female presents for painless blood urine for past 2 months. History is significant for eosinophilic granulomatosis with polyangiitis (previously known as Churg -Strauss) diagnosed 10 years ago, which is now in remission. She was treated with prednisone for 3 years and oral cyclophosphamide for 1 year. She uses albuterol PRN for her asthma. Physical exam: T 37.0°C, HR 60, BP 138/81. BMI is 28. No abnormalities Labs: Hg 12, ESR 35 Urinalysis: Trace protein, 10-20 RBC, 0-2 WBC, no casts. Urine culture: Negative (Adapted from MKSAP 17) QUESTION Which of the following is the most appropriate diagnostic test to perform next? CT abdomen/pelvis w/o contrast Cytoscopy Kidney/Bladder US Urine eosinophil measurement Urine protein/creatinine ratio

15. BOARD-LIKE Question Educational Objective: Know the association between bladder cancer and cyclophosphamide Key Point: The use of cyclophosphamide is associated with increased risk of malignancy, especially bladder cancer, and patients should be evaluated accordingly. ANSWER Which of the following is the most appropriate diagnostic test to perform next? CT abdomen/pelvis w/o contrast Cytoscopy Kidney/Bladder US Urine eosinophil measurement Urine protein/creatinine ratio