CYCLOPSOVMC 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.

(CYCLOPS)

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

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?

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

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+

INTERVENTIONS

Randomized to a group: Pulse cyclophosphamide: 15 mg/kg IV pulses q2 weeks x 6 weeks, then 15 mg/kg

IV pulses q3 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

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

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.

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?

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.

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 abnormalitiesLabs:Hg 11, ESR 35Urinalysis: Trace protein, 10-20 RBC, 0-2 WBC, no casts

QUESTIONWhat is the best treatment regimen to start in this patient?A. GlucocorticoidsB. Pulse dose Cyclophosphamide + GlucocortioidsC. Daily dose cyclophosphamide + GlucocorticoidsD. RituximabE. Either B or C

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)

ANSWERWhat is the best treatment regimen to start in this patient?A. GlucocorticoidsB. Pulse dose Cyclophosphamide + GlucocortioidsC. Daily dose cyclophosphamide + GlucocorticoidsD. RituximabE. Either B or C

BOARD-LIKE QUESTIONA 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 abnormalitiesLabs:Hg 12, ESR 35Urinalysis: Trace protein, 10-20 RBC, 0-2 WBC, no casts. Urine culture: Negative

(Adapted from MKSAP 17)

QUESTIONWhich of the following is the most appropriate diagnostic test to perform next?A. CT abdomen/pelvis w/o contrastB. CytoscopyC. Kidney/Bladder USD. Urine eosinophil measurementE. Urine protein/creatinine ratio

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.

ANSWERWhich of the following is the most appropriate diagnostic test to perform next?A. CT abdomen/pelvis w/o contrastB. CytoscopyC. Kidney/Bladder USD. Urine eosinophil measurementE. Urine protein/creatinine ratio