Caroline Helwick

June 02, 2009

June 2, 2009 (Milan, Italy) — For the treatment of antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis, a pulse cyclophosphamide regimen is as effective as standard treatment with oral daily cyclophosphamide in inducing remission, and may be safer, Italian investigators reported here at the World Congress of Nephrology, a Joint Meeting of the European Renal Association–European Dialysis and Transplant Association and the International Society of Nephrology.

"The pulse regimen produced a similar response rate, necessitated less total dose of the cyclophosphamide, and produced less leucopenia," said Lorraine Harper, MD, from the University of Birmingham, in the United Kingdom, who presented the results of the CYCLOPS study.

The goals of modern therapy for this condition are to achieve rapid resolution with therapy tailored to disease severity, producing sustained remission, with minimal toxicity. For generalized disease, with renal or other organ involvement, standard treatment is oral daily cyclophosphamide for 3 to 4 months, followed by maintenance azathioprine, she explained.

The randomized double-blind study consisted of 149 patients with newly diagnosed generalized ANCA-associated vasculitis and renal involvement, accrued at 42 centers in 12 European countries. Patients were randomized to pulse cyclophosphamide (15 mg/kg every 2 to 3 weeks) or to daily oral cyclophosphamide (2 mg/kg, tapering to 1.5 mg/kg). Both groups also received prednisolone in standard 12.5-mg doses.

The primary end point was time to remission; secondary outcomes were change in renal function, adverse events, and cumulative dose of cyclophosphamide.

"At 9 month follow-up, the majority of patients in both arms had achieved remission, and there was no difference between the groups," she reported (hazard ratio [HR], 1.098; 95% confidence interval [CI], 0.78 - 1.55; P = .594). The proportion of patients achieving remission at 9 months was also similar — 88.1% with pulse cyclophosphamide and 87.7% with daily oral treatment.

"The outcomes were similar, in spite of the fact that the pulse group received half the amount of cyclophosphamide," she noted. The absolute cumulative cyclophosphamide dose in the daily oral group was nearly twice that in the pulse group (15.9 g vs 8.2 g; P = .001).

Relapses occurring after the achievement of remission were observed in 13 patients receiving pulse and 6 receiving daily oral cyclophosphamide, which was not statistically significant. This was also not a predefined end point, and the study was not powered to detect a difference in relapse rates between the groups, she said.

Renal function was also similar between the groups at 9 months, as was the incidence of end-stage renal disease and the mortality rate. The mortality rate of 9% at 18 months is higher than that seen in some series, but this population of patients was a very ill group with very poor renal function at entry.

The 1 difference between the groups was in the risk for leucopenia, which was significantly less in the pulse group (26% vs 45% with standard treatment; HR, 0.41; 95% CI, 0.23 - 0.71; P = .016).

Dr. Harper maintained that, based on the similar response rates of 14% in each group, 3 months of consolidation cyclophosphamide probably has little benefit.

The comoderators of the late-breaking trials session, where the data were presented, commented on the importance of these findings. "This information could change clinical practice," said Adrian Covic, MD, PhD, professor of nephrology at Parhon University Hospital in Iasi, Romania.

"But first, we need to answer the most important question of relapse," added Piergeorgio Messa, MD, professor of nephrology at Ospedale Maggiore Policlinico in Milan, Italy. "The relapse rate was still high with the IV regimen; in fact, it was double that of the oral regimen. Even if this difference was not statistically significant, in my opinion it is still a concern. If you can avoid giving so much cyclophosphamide initially, you may still have to give it later, when you retreat. It is an open question that needs further evaluation."

World Congress of Nephrology 2009: A Joint Meeting of the European Renal Association–European Dialysis and Transplant Association (ERA-EDTA) and the International Society of Nephrology (ISN): Abstract Sa774. Presented May 24, 2009.


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