Abstract L13: Mycophenolate Mofetil and Intravenous Cyclophosphamide in the Aspreva Lupus Management Study (ALMS): Efficacy by Racial Group
Alan N. Baer, MD
Authors:
E. M. Ginzler, G. B. Appel, M. A. Dooley, D. Isenberg, D. Jayne, N. Solomons, D. Wofsy
Background:
The Aspreva Lupus Management Study (ALMS) was designed to assess the efficacy of oral mycophenolate mofetil (MMF) compared to intravenous cyclophosphamide (IVC) in the initial treatment of patients with active class III-V lupus nephritis and to assess the long-term efficacy of MMF compared to azathioprine in maintaining remission and renal function. It is the largest study of mycophenolate mofetil (MMF) in lupus nephritis. The results of the induction treatment phase of the study are reported here.
Methods:
A multiracial group of 370 patients from multiple different countries were enrolled in the study. The patients entering the 24-week induction phase were randomized to open-label MMF with a target dose of 3 g/day, or IVC, 0.5-1.0 g/m2 in monthly pulses. Both groups received prednisone, tapered from a maximum starting dose of 60 mg/day. Response to treatment was defined as a decrease in proteinuria (as measured by the urine protein/creatinine ratio) and improvem ent and/or stabilization in serum creatinine.
Results:
Overall, 104/185 (56%) of the lupus nephritis patients treated with MMF responded, compared with 98/185 (53%) of the patients treated with IVC (p=0.575). The study therefore did not meet its primary objective of showing a superior response rate with MMF than with IVC.
40% of the patients reported themselves as Caucasian, 33% as Asian (mostly in China) and 27% as ‘Other’, a group mostly comprising black and mixed-race patients. Across all racial groups, 35% stated their ethnicity as Hispanic and 65% as non-Hispanic. There was a significant interaction between treatment regimen and race (p=0.047). Response rates with MMF and IVC were similar for Caucasian and Asian patients. Of the patients classified as ‘Other’, 60% responded with MMF and 39% with IVC (p=0.033). The response rates among Hispanic patients were 61% for MMF and 39% for IVC (p=0.011). There were no clinically important differences in baseline disease that might explain the variation by race and ethnicity.
Adverse events (AEs), serious AEs and infection rates were comparable between the treatment groups over the 24-week induction phase. AEs accounted for 24 withdrawals in the MMF group (12 due to infections) compared with 13 in the IVC group (4 due to infections). Of the 9 deaths in the MMF group and 5 in the IVC group, 7 and 2 were due to infections, and 0 and 2 were due to systemic lupus erythematosus, respectively.
Conclusions:
In this large, multiracial study, overall response rates of MMF and IVC were comparable, but there were notable differences in response rates based on race and ethnicity. More non-Caucasian non-Asian patients responded to MMF than IVC, the current standard treatment. This is a notable finding since patients in this racial group tend to have more severe LN.
Editorial Comments:
In an earlier 24-week, randomized, open-label multicenter noninferiority study of 140 patients with active lupus nephritis, therapy with mycophenolate mofetil was superior to intravenous cyclophosphamide in inducing complete remissions of lupus nephritis and was also better tolerated with fewer severe side effects. The results of the ALMS study are thus disappointing in that they do not confirm the superiority of mycophenolate mofetil over intravenous cyclophosphamide in the induction therapy of lupus nephritis. In the initial study, the primary endpoint was complete remission, a more rigorous one than was employed in the ALMS study. It is thus possible that the results of the ALMS study would have been different if the same, more rigorous, response criteria had been used.
Importantly, mycophenolate was equivalent in efficacy to the potentially more toxic cyclophosphamide regimen. Such toxicities were not apparent in the current study, but have been observed in earlier studies and include gonadal failure, hemorrhagic cystitis and serious infections. In addition, a particular racial group was not identified that responded better to cyclophosphamide than to mycophenolate. Thus, this study supports the use of mycophenolate mofetil as first-line therapy for lupus nephritis.
