Rituximab treatment for ANCA-associated vasculitis in childhood

Transcription

1 Rituximab treatment for ANCA-associated vasculitis in childhood DISCLOSURE I have no relevant financial relationships to disclose Katharine Moore MD Nov 14, 2012 University of Colorado School of Medicine Colorado Childrens Hospital Seattle Children s Hospital / University of Washington EVIDENCE BASED MEDICINE Eleftheriou D, Melo M, Marks SD, Tullus K, Sills J, Cleary G, et al. Biologic therapy in primary systemic vasculitis of the young. Rheumatology 2009; 48: Jones RB, Tervaert JWC, Hauser T, Luqmani R, Morgan MD, Peh CA, et al, for the European Vasculitis Study Group. Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis. N Engl J Med 2010; 363: Stone JH, Merkel PA, Spiera R, Seo P, Langford CA, Hoffman GS, et al, for the RAVE-ITN Research Group. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med 2010; 363: ANCA-Associated Vasculitis (AAV) in Children Granulomatosis with polyangiitis (GPA, formerly Wegener s), microscopic polyangiitis (MPA) and Churg-Strauss vasculitis Small and medium sized blood vessels; propensity to affect kidneys and respiratory tract Antibodies against proteinase 3 (PR3) or myeloperoxidase (MPO) Often life threatening with pulmonary hemorrhage and airway granulomas Treatment of AAV in Children Standard of care: cyclophosphamide (CYC) and high-dose glucocorticoids (GC) for severe disease Methotrexate (MTX) in limited / less severe disease The Problem with the standard of care: Large cumulative dose of CYC due to repeated treatment Dose dependent adverse effects Cytopenias, sepsis, infertility, hemorrhagic cystitis, malignancy Cyclophosphamide-sparing regimens are needed B-cell Targeted Therapies for AAV Rituximab Chimeric monoclonal antibody against CD20 Depletes certain peripheral B- lymphocytes? Disrupts communication with T-lymphocytes? Disrupts production of inflammatory cytokines 1

2 Rituximab for ANCA vasculitis 2005: as adjunctive therapy in severe pediatric AAV at Children s Hospital Colorado 2010: RAVE 1 and RITUXVAS 2 trials as a CYC sparing agent in adult ANCA vasculitis Did not include children During this time, regularly used in treating childhood AAV 2011: FDA approves for use in AAV STUDY OBJECTIVE To share the experience of a tertiarycare children s hospital treating a cohort of children with antineutrophil cytoplasmic antibody (ANCA)- associated vasculitis (AAV) with rituximab as a part of the therapeutic regimen. 1 Stone et al, NEJM Jones et al, NEJM 2010 STUDY DESIGN TYPE OF STUDY: Single-Center retrospective case series Tertiary care children s hospital with multi-state catchment area Patients identified through search of EMR INCLUSION CRITERIA: Age 3 ys 17 yrs at diagnosis Diagnosed with ANCA-associated vasculitis between Received a full 4-week course of rituximab as part of treatment regimen OUTCOME MEASURES PRIMARY OUTCOME MEASURE: Total cumulative dose of CYC SECONDARY OUTCOME MEASURES: Scores on Birmingham Vasculitis Activity Score for Wegener s Granulomatosis (BVAS/WG) Scores on the Vasculitis Damage Index (VDI) Time to Remission (Remission = BVAS/WG score of 0) Adverse effects of PATIENT CHARACTERISTICS CLINICAL FEATURES Total Patients (N) MPA (N) 2 GPA (N) (7 female) Mean age at diagnosis 13 years (range 8-15) Mean BVAS/WG score at dx 7.8 (range 1-12) Severe Disease (N) 11 (73%) Treated before adding (N) 6 Average duration previous treatment Average length of follow-up after 1.7 years (range 5 mo 2 yrs) 2.5 years (range 3 mo 5.5 yrs) Pulmonary hemorrhage 9 Respiratory Failure 6 Sinus disease 5 Kidney Disease Purpura 6 Arthritis 6 Arthralgia 6 Other Admitted to Intensive Care Unit 11 (hematuria, proteinuria, renal failure) Pulmonary cavitation, Pulmonary nodules, oral ulcers, SN hearing loss, cognitive change, chronic otitis, episcleritis 7 2

3 INITIAL TREATMENT REGIMENS POST- TREATMENT REGIMEN For N = 12: Rituximab 375 mg/m 2 /wk x 4 Glucocorticoids Pulse, hi-dose, taper Cyclophosphamide 2 mg/kg/day oral PICU admission for n = 7 Plasma Exchange for n = 6 For N = 3: Rituximab 375 mg/m 2 /wk x 4 Glucocorticoids Pulse, hi-dose, taper Methotrexate Receiving CYC, GC and : CYC discontinued when clinically improved Prednisone tapered, then discontinued No additional medications added Receiving MTX, GC and : MTX discontinued when clinically improved Prednisone tapered, then discontinued Lower Mean Cumulative CYC Dose When Given at Diagnosis Total Cumulative Dose (g) g BVAS/WG and VDI Scores Reflect Clinical Improvement Score Mean BVAS/WG Scores: Mean VDI Scores 3 months: 0.7 (range 0-3) 6 months: 0.8 (range 0-3) g at Dx later N = 9 N = Time of 3 mo 0.4 THERAPEUTIC RESPONSE: REMISSION Mean follow-up: 2.5 yrs (range 3 mo 5.1 yrs) Every patient achieved remission (Absence of clinical disease activity) 12 wks THERAPEUTIC RESPONSE: RELAPSE 9 patients (60%) never relapsed 6 patients (40%) relapsed at mean of 18.5 months 4 of these had refractory disease prior to & PREDNISONE 10 mg/d MEAN DURATION CYC 16 wks 11.3 wks 3

4 RESULTS: ADVERSE EVENTS No deaths No documented infectious complications No hemorrhagic cystitis Leukopenia in 1 pt (ANC 0, ALC 0.3) d/c CYC 6 Infusion reactions: Hives/itching, itching without rash, hypotension, tooth sensitivity, chills without fever, infusion-related anxiety attack LIMITATIONS Retrospective Review: Small cohort To date: largest single institution case series of in pediatric AAV Use of BVAS/WG in MPA and in children SUMMARY FUTURE STUDY QUESTION: Total CYC dose less when treated with at diagnosis 8.6 g vs 62 g 86% reduction All patients achieved remission (mean of 12 weeks) Can rituximab be given without concomitant CYC for severe, life-threatening pediatric disease? Patients previously refractory to standard therapy responded to CONCLUSION shows promise as a CYC sparing agent when given at diagnosis in severe pediatric AAV ACKNOWLEDGEMENTS J. Roger Hollister, MD Leonard Dragone, MD, PhD Jennifer Soep, MD 4

5 BVAS/WG and VDI Birmingham Vasculitis Activity Score for Wegener s Granulomatosis (BVAS-WG) Validated measure of disease activity in adult GPA Includes determinants of severe disease Scleritis, retinal hemorrhage, sensorineural deafness, mesenteric ischemia, gangrene, alveolar hemorrhage, respiratory failure, RBC casts, rise in Cr >30%, meningitis, spinal cord lesion, stroke, cranial nerve palsy, sensory peripheral neuropathy, mononeuritis multiplex Vasculitis Damage Index (VDI) Reflects long term damage, not active disease List of 64 items by organ system, 1 point each To be assigned no more often than every 3 months Both scored retrospectively RESULTS: THERAPEUTIC RESPONSE ALL AT DX LATER 12 wks 6.8 wks 24 wks WITH PREDNISONE 10 MG/DAY ALL AT DX LATER 16 wks 13.4 wks 25 wks RESULTS: Total CYC dose ANCA monitoring Total Cumulative Dose of CYC (mg/kg) in patients not initially treated with vs. patients treated with from the beginning of therapy No initial initially Total Cum dose Dose after added Time to Negative ANCA 6 patients never had negative ANCA For other 9, at mean time 15.2 weeks Not always checked regularly 5

6 Treatment of flares Flares treated with: Prednisone burst alone (n = 1) AZA (n=1) alone (n=2) + prednisone (n=1) + prednisone + CYC (n=1) RESULTS: Patient Characteristics Previous Treatment Before Rituximab 5 patients previously treated 4 with CYC, alone or in combination with others 1 presented with arthritis alone, MTX x2 yrs before other vasculitis sx emerged 1 patient received a single 375 mg/m2 dose without the other 3, due to severe infusion-related anxiety; tried other therapies, then ultimately back to and completed full course For these 6 patients, mean duration of therapy prior to was 1.7 years (range 5 mo 2 yrs) 6