789 - Immunoglobulin Concentrations and Infection Risk Among Patients with ANCA-Associated Vasculitis Treated with Rituximab or Cyclophosphamide

Sunday, November 6, 2011: 2:30 PM
W192b (McCormick Place West)
Ulrich Specks1, Peter A. Merkel2, Philip Seo3, Robert F. Spiera4, Carol A. Langford5, Gary S. Hoffman5, Cees G.M. Kallenberg6, E. William St. Clair7, Swati Tole8, Paul Brunetta9, Shuyi Shen8, Nadia Tchao10, Barri J. Fessler11, Lisa Webber12, Linna Ding13, Lourdes P. Sejismundo14, Kathleen Mieras1, Deborah J. Phippard10, Adam Asare10, Noha Lim10, David Ikle15, Brett Jepson15, Alice Lail15 and Mark Mueller16, 1Mayo Clinic, Rochester, MN, 2Boston University School of Medicine, Boston, MA, 3Johns Hopkins Vasculitis Center, Baltimore, MD, 4Hospital for Special Surgery, New York, NY, 5Cleveland Clinic, Cleveland, OH, 6University Medical Center Groningen, Groningen, Netherlands, 7Duke University Medical Center, Durham, 8Genentech, Inc., South San Francisco, CA, 9Genentech, So San Francisco, CA, 10Immune Tolerance Network, Bethesda, MD, 11University of Alabama at Birmingham, Birmingham, AL, 12National Institute of Allergy and Infectious Diseases, 13NIAID, Bethesda, MD, 14Johns Hopkins University, Baltimore, MD, 15Rho, Chapel Hill, NC, 16Food & Drug Administration, Bethesda, MD
Presentation Number: 789

Immunoglobulin Concentrations and Infection Risk Among Patients with ANCA-Associated Vasculitis Treated with Rituximab or Cyclophosphamide

Background/Purpose: Patients (pts) with ANCA-associated vasculitis (AAV) are treated with immunosuppression and are at increased risk of infection.  The incidence of low immunoglobulin (Ig) concentrations observed with rituximab (RTX) and cyclophosphamide (CYC) is therefore a potential concern.  Limited data exist on the incidence and risk for infection of low Ig concentrations in AAV.  We evaluated changes in Ig concentrations among patients (pts) treated with either RTX or CYC followed by azathioprine (CYC/AZA) in the RAVE trial (NEJM 2010), and investigated the impact of these changes on infection.

Methods: Post hoc analysis of RAVE, a trial of 197 pts with severe AAV randomized and treated with RTX followed by placebo (n=99) or CYC followed by AZA (n=98).  Quantitative assays for IgM, IgG, and IgA were performed at baseline, 6 months (M), and 18M.  Proportions of pts with low Ig (<lower limit of normal (LLN)) at each time point and the median changes in Ig at 6M and 18M were assessed, along with the rates of overall and serious infections.

Results: Of the 56 pts who had low Ig of any isotype at baseline, 36 (64%) entered with relapsing disease.  Pts in both treatment groups had low Ig at baseline and the proportions with low Ig increased at 6M and 18M (Table 1).  Median changes from baseline in Ig concentrations were similar in the RTX and CYC/AZA groups.  In the RTX group, pts with low Ig levels at any time had received numerically higher quantities of glucocorticoids (GC) at baseline compared to those who did not have low Ig (IgM: 1.51 g prednisone or equivalent vs 1.03; IgG: 1.31 vs 1.27; IgA 1.73 vs 1.11; p=0.07, 0.45, 0.32, respectively).  Rates of overall and serious infections were similar in pts with low Ig at any time compared to those with normal Ig levels (Table 2).

Conclusions: A substantial proportion of pts with AAV receiving either RTX or CYC/AZA had low Ig concentrations at baseline, perhaps resulting from immunosuppression prior to trial entry.  The proportions of pts with low Ig increased at 6M and 18M in both groups, and median changes in Ig levels were similar in both groups.  Low Ig was not associated with increased rates of infections.

Table 1: Change from Baseline and Proportion of Patients with Low Ig (< LLN&) by Visit

 

 

RTX

CYC/AZA

 

 

 

Baseline (n*)

99

94

   IgM <LLN

16 (16.2%)

6 (6.4%)

   IgG <LLN

18 (18.2%)

20 (21.3%)

   IgA <LLN

5 (5.1%)

10 (10.6%)

6M (n*)

83

77

   IgM

 

 

      Median Change from baseline (mg/dL)

-42.0

-42.5

      < LLN

49 (59.0%)

36 (46.8%)

   IgG

 

 

      Median change from baseline (mg/dL)

-259

-252

      < LLN

54 (65.1%)

43 (55.8%)

   IgA

 

 

      Median change from baseline (mg/dL)

-48

-59

      < LLN

25 (30.1%)

24 (31.2%)

18M (n*)

69

60

   IgM

 

 

      Median Change from baseline (mg/dL)

-38.0

-23.5

      < LLN

27 (39.1%)

17 (28.3%)

   IgG

 

 

      Median Change from baseline (mg/dL)

-185

-131

      < LLN

31 (44.9%)

19 (31.7%)

   IgA

 

 

      Median Change from baseline (mg/dL)

-44

-42

      < LLN

19 (27.5%)

16 (26.7%)

& LLN: IgM 23 mg/dL (16 – 19 yrs), 40 mg/dL (≥20 yrs); IgG 549 mg/dL, 700 mg/dL; IgA 61 mg/dL, 70 mg/dL 

                       

* n indicates number of subjects with available data at the corresponding visits.

Table 2: Rates of overall and serious infectious events (SIE) in patients with low and normal Ig levels

 

RTX

CYC/AZA

 

Normal IgM

IgM < LLN at any time

Normal IgM

IgM < LLN at any time

N (pt-year)

45 (51.5)

54 (74.7)

57 (66.5)

39 (51.2)

rate of infection per

patient year

1.61

1.28

1.08

1.56

rate of SIE per

patient year

0.17

0.08

0.17

0.18

 

Normal IgG

IgG < LLN at anytime

Normal IgG

IgG < LLN at anytime

N (pt-year)

36 (37.1)

63 (89.1)

43 (48.4)

53 (69.3)

rate of infection per

patient year

1.86

1.23

1.16

1.38

rate of SIE per

patient year

0.22

0.08

0.19

0.16

 

Normal IgA

IgA < LLN at anytime

Normal IgA

IgA < LLN at any time

N (pt-year)

70 (86.3)

29 (39.9)

66 (77.4)

30 (40.3)

rate of infection per

patient year

1.30

1.68

1.24

1.39

rate of SIE per

patient year

0.14

0.08

0.18

0.15

 


Keywords: clinical trials, immunoglobulin (IG), infection and rituximab

Disclosure: U. Specks, Genentech and Biogen-IDEC, Inc., 2 ; P. A. Merkel, Genentech and Biogen IDEC Inc., 2 ; P. Seo, Genentech and Biogen IDEC Inc., 5 ; R. F. Spiera, Genentech and Biogen IDEC Inc., 2 ; C. A. Langford, Genentech and Biogen IDEC Inc., 2 ; G. S. Hoffman, Genentech and Biogen IDEC Inc., 2 ; C. G. M. Kallenberg, None; E. W. St. Clair, Genentech and Biogen IDEC Inc., 2 ; S. Tole, Roche Pharmaceuticals, 1, Genentech, Inc., 3 ; P. Brunetta, Genentech/, 3 ; S. Shen, Genentech/, 3 ; N. Tchao, None; B. J. Fessler, Genentech and Biogen IDEC Inc., 2 ; L. Webber, None; L. Ding, None; L. P. Sejismundo, None; K. Mieras, None; D. J. Phippard, None; A. Asare, None; N. Lim, None; D. Ikle, None; B. Jepson, None; A. Lail, None; M. Mueller, None.