Rituximab as pre-emptive treatment in patients with thrombotic thrombocytopenic purpura and evidence of anti-ADAMTS13 autoantibodies

Summary

Thrombotic thrombocytopenic purpura (TTP) is a rare and severe disease characterized by thrombocytopenia, microangiopathic haemolytic anemia, neurological and renal involvement associated with deficiency of the von Willebrand factor-cleaving protease, ADAMTS13. Persistence of high titers of anti-ADAMTS13 autoantibodies predisposes to relapsing TTP. Since relapses are associated with high morbidity and mortality rates, the optimal therapeutic option should be a pre-emptive treatment able to deplete anti-ADAMTS13 autoantibodies and avoid relapses. Five patients who presented with persistence of undetectable ADAMTS13 activity and high titers of autoantibodies, were treated with rituximab as pre-emptive therapy during remission. Four of them were affected by relapsing TTP and one was treated after the first episode. ADAMTS13 activity ranging from 15% to 75% with disappearance of inhibitors was achieved after three months in all patients, and persisted >20% without inhibitors at six months. In three patients disease-free status is still ongoing after 29, 24 and six months, respectively. Relapses were documented in two patients during follow-up: in one patient remission lasted 51 months; while in the other patient relapse occurred after 13 months. Results demonstrated that rituximab used as pre-emptive treatment may be effective in maintaining a sustained remission in patients with anti-ADAMTS13 antibodies in whom other treatments failed to limit the production of inhibitors, and suggests that re-treatment with rituximab should be considered when ADAMTS13 activity decreases and inhibitors reappear into the circulation, to avoid a new relapse.

Keywords

TTP - rituximab - ADAMTS13 - autoantibodies - rare diseases

• References

• 1 Remuzzi G, Ruggenenti P, Bertani T. Thrombotic microangiopathies. In: Renal pathology with clinical and functional correlations. Philadelphia: J.B. Lippincott Company; 1994: 1154-1184.
• 2 Moake JL, Rudy CK, Troll JH. et al. Unusually large plasma factorVIII: von Willebrand factor multimers in chronic relapsing thrombotic thrombocytopenic purpura. N Engl J Med 1982; 307: 1432-1435.
• 3 Furlan M, Robles R, Galbusera M. et al. von Wille-brand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome. N Engl J Med 1998; 339: 1578-1584.
• 4 Tsai HM, Lian ECY. Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura. N Engl J Med 1998; 339: 1585-1594.
• 5 Mannucci PM, Peyvandi F. TTP and ADAMTS13: when testing is appropriate?. Hematology Am Soc Hematol Educ Program 2007; 2007: 121-126.
• 6 Scheiflinger F, Knobl P, Trattner B. et al. Nonneutralizing IgM and IgG antibodies to von Willebrand factor-cleaving protease (ADAMTS-13) in a patient with thrombotic thrombocytopenic purpura. Blood 2003; 102: 3241-3243.
• 7 Rieger M, Mannucci PM, Kremer-Hovinga JA. et al. ADAMTS13 autoantibodies in patients with thrombotic microangiopathies and other immunomediated diseases. Blood 2005; 106: 1262-1267.
• 8 Mori Y, Wada H, Gabazza EC. et al. Predicting response to plasma exchange in patients with thrombotic thrombocytopenic purpura with measurement of vWF-cleaving protease. Transfusion 2002; 42: 572-580.
• 9 Zengh XL, Kaufman RM, Goodnough LT, Sadler JE. Effect of plasma exchange on plasma ADAMTS13 metalloprotease activity, inhibitor level, and clinical outcome in patients with idiopathic and nonidiopathic thrombotic thrombocytopenic purpura. Blood 2004; 103: 4043-4049.
• 10 Bohm M, Betz C, Miesbach W. et al. The course of ADAMTS-13 activity and inhibitor titre in the treatment of thrombotic thrombocytopenic purpura with plasma exchange and vincristine. Br J Haematol 2005; 129: 644-652.
• 11 Coppo P, Wolf M, Veyradier A. et al. Prognostic value of inhibitory anti-ADAMTS13 antibodies in adult-acquired thrombotic thrombocytopenic purpura. Br J Haematol 2006; 132: 66-74.
• 12 Veyradier A, Obert B, Houllier A. et al. Specific von Willebrand factor-cleaving protease in thrombotic microangiopathies: a study of 111 cases. Blood 2001; 98: 1765-1772.
• 13 Vesely SK, George JN, Lammle B. et al. ADAMTS13 activity in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: relation to presenting features and clinical outcome in a prospective cohort of 142 patients. Blood 2003; 102: 60-68.
• 14 Ferrari S, Scheiflinger F, Rieger M. et al. Prognostic values of anti-ADAMTS13 antibody features (Ig iso-type, titer, and inhibitory effect) in a cohort of 35 adult French patients undergoing a first episode of thrombotic microangiopathy with undetectable ADAMTS13 activity. Blood 2007; 109: 2815-2822.
• 15 Yomtovian R, Niklinski W, Silver B. et al. Rituximab for chronic recurring thrombotic thrombocytopenic purpura: a case report and review of the literature. Br J Haematol 2004; 124: 787-795.
• 16 Johnson PW, Glennie MJ. Rituximab: mechanisms and applications. Br J Cancer 2001; 85: 1619-1623.
• 17 Edwards JC, Cambridge G. B-cell targeting in rheumatoid arthritis and other autoimmune diseases. Nat Rev Immunol 2006; 6: 394-403.
• 18 Franchini M, Veneri D, Lippi G. et al. The efficacy of rituximab in the treatment of inhibitor-associated hemostatic disorders. Thromb Haemost 2006; 96: 119-125.
• 19 Heidel F, Lipka DB, von Auer C. et al. Addition of rituximab to standard therapy improves response rate and progression-free survival in relapsed or refractory thrombotic thrombocytopenic purpura and autoimmune haemolytic anaemia. Thromb Haemost 2007; 97: 228-233.
• 20 George JN, Woodson RD, Kiss JE. et al. Rituximab therapy for thrombotic thrombocytopenic purpura: a proposed study of the Transfusion Medicine/Hemostasis Clinical Trials network with a systematic review of Rituximab therapy for immune-mediated disorders. J Clin Apher 2006; 21: 49-56.
• 21 Garvey B. Rituximab in the treatment of auto-immune haematological disorders. Br J Haematol 2008; 141: 149-169.
• 22 Galbusera M, Bresin E, Noris M. et al. Rituximab prevents recurrence of thrombotic thrombocytopenic purpura: a case report. Blood 2005; 106: 925-928.
• 23 Fakhouri F, Vernant JP, Veyradier A. et al. Efficiency of curative and prophylactic treatment with rituximab in ADAMTS13-deficient thrombotic thrombocytopenic purpura: a study of 11 cases. Blood 2005; 106: 1932-1937.
• 24 Reddy PS, Deauna-Limayo D, Cook JD. et al. Rituximab in the treatment of relapsed thrombotic thrombocytopenic purpura. Ann Hematol 2005; 84: 232-235.
• 25 Benetatos L, Vassou A, Bourants KL. Effectiveness of rituximab as prophylaxis in thrombotic thrombocytopenic purpura. Clin Lab Haem 2006; 28: 288-289.
• 26 Schleinitz N, Ebbo M, Mazodier K. et al. Rituximab as preventive therapy of a clinical relapse in TTP with ADAMTS13 inhibitor. Am J Hematol 2007; 82: 417-418.
• 27 Remuzzi G, Galbusera M, Noris M. et al. von Willebrand factor cleaving protease (ADAMTS13) is deficient in recurrent and familial thrombotic thrombocytopenic purpura and haemolytic uremic syndrome. Blood 2002; 100: 778-785.
• 28 Lattuada A, Rossi E, Calzarossa C. et al. Mild to moderate reduction of a von Willebrand factor cleaving protease (ADAMTS-13) in pregnant women with HELLP microangiopathic syndrome. Haematologica 2003; 88: 1029-1034.
• 29 George JN. Thrombotic thrombocytopenic purpura. N Engl J Med 2006; 354: 1927-1935.
• 30 Kremer-Hovinga JA, Studt JD, Demarmels Biasiutti F. et al. Splenectomy in relapsing and plasma-refractory acquired thrombotic thrombocytopenic purpura. Haematologica 2004; 89: 320-324.
• 31 Scully M, Cohen H, Cavenagh J. et al. Remission in acute refractory and relapsing thrombotic thrombocytopenic purpura following rituximab is associated with a reduction in IgG antibodies to ADAMTS-13. Br J Haematol 2007; 136: 451-461.
• 32 Barbot J, Costa E, Guerra M. et al. Ten years of prophylactic treatment with fresh frozen plasma in a child with chronic relapsing thrombotic thrombocytopenic purpura as a result of a congenital deficiency of von Willebrand factor-cleaving protease. Br J Haematol 2001; 113: 649-651.
• 33 Keystone E, Fleischmann R, Emery P. et al. Safety and efficacy of additional courses of rituximab in patients with active rheumatoid arthritis: an open-label extension analysis. Arthritis Rheum 2007; 56: 3896-3908.
• 34 Lowndes S, Darby A, Mead G. et al. Stevens–Johnson syndrome after treatment with rituximab. Ann Oncol 2002; 13: 1948-1950.
• 35 Millward PM, Bandarenko N, Chang PP. et al. Cardiogenic shock complicates successful treatment of refractory thrombotic thrombocytopenic purpura with rituximab. Transfusion 2005; 45: 1481-1486.
• 36 Kandula P, Kouides PA. Rituximab-induced leukocytoclastic vasculitis: a case report. Arch Dermatol 2006; 142: 246-247.
• 37 Todd DJ, Helfgott SM. Serum sickness following treatment with rituximab. J Rheumatol 2007; 34: 430-433.
• 38 Chemnitz J, Draube C, Scheid P. et al. Successful treatment of severe thrombotic thrombocytopenic purpura with the monoclonal antibody rituximab. Am J Hematol 2002; 71: 105-108.
• 39 Sallah S, Husain A, Wan JY. et al. Rituximab in patients with refractory thrombotic thrombocytopenic purpura. J Thromb Haemost 2004; 2: 834-836.
• 40 Cravedi P, Ruggenenti P, Sghirlanzoni MC. et al. Titrating rituximab to circulating B cells to optimize lymphocytolytic therapy in idiopathic membranous nephropathy. Clin J Am Soc Nephrol 2007; 2: 932-937.