Addition of rituximab to standard therapy improves response rate and progression-free survival in relapsed or refractory thrombotic thrombocytopenic purpura and autoimmune haemolytic anaemia

Florian Heidel; Daniel B. Lipka; Charis von Auer; Christoph Huber; Inge Scharrer; Georg Hess

doi:10.1160/TH06-09-0499

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2007; 97(02): 228-233
DOI: 10.1160/TH06-09-0499

Platelets and Blood Cells

Schattauer GmbH

Addition of rituximab to standard therapy improves response rate and progression-free survival in relapsed or refractory thrombotic thrombocytopenic purpura and autoimmune haemolytic anaemia

Authors

Florian Heidel^*

¹Department of Hematology/Oncology, Johannes Gutenberg-University, Mainz, Germany
Daniel B. Lipka^*

¹Department of Hematology/Oncology, Johannes Gutenberg-University, Mainz, Germany
Charis von Auer

¹Department of Hematology/Oncology, Johannes Gutenberg-University, Mainz, Germany
Christoph Huber

¹Department of Hematology/Oncology, Johannes Gutenberg-University, Mainz, Germany
Inge Scharrer

¹Department of Hematology/Oncology, Johannes Gutenberg-University, Mainz, Germany
Georg Hess

¹Department of Hematology/Oncology, Johannes Gutenberg-University, Mainz, Germany

Abstract

Summary

Treatment of relapsed or refractory autoimmune mediated haemolytic syndromes, such as autoimmune haemolytic anaemia (AIHA) and thrombotic thrombocytopenic purpura (TTP), represents a therapeutic challenge. Here we report on our experience with the monoclonal anti-CD20 antibody rituximab (R) compared to standard treatment in these diseases. Patients with non-familialTTP orAIHA and no underlying malignancy were included in our analysis. Safety and efficacy of R-treatment were compared to results obtained in standard treatment approaches. Altogether, 27 patients were analyzed, comprising 15 patients withTTP and 12 patients with AIHA. The patients’ average age at the time of diagnosis was 54 years. Eleven patients received antibody treatment (8 TTP, 3 AIHA). No acute or late WHO grade III/IV toxicity associated with rituximab was noted. With standard therapy, the overall response rate (ORR) was 66.7% for AIHA and 65.8% for TTP, respectively. For the R-containing regimens the ORR was 100%. In patients with TTP, median progression free survival (PFS) with R-treatment was 3.8 years, as compared to 0.1 years in the standard-treatment group. In patients with AIHA median PFS was not reached for R-containing treatment; all patients are in sustained remissions with a median follow up of 12.5 months. In the absence of prospective trials, our data underline the safety and efficacy of rituximab in relapsed and refractory autoimmune anaemias with favourable response rates and promising long-term progressionfree survival. Therefore, prospective clinical trials evaluating rituximab as salvage- and first-line-therapy are clearly warranted.

Keywords

Rituximab - TTP - AIHA

Full Text

References

References
1 Gehrs B, Friedberg R. Autoimmune hemolytic anemia. Am J Hematol 2002; 69: 258-271.
2 Böhm M, von Auer C, Asmelash M. et al. The clinical evaluation of an ELISA-based method for measuring ADAMTS13 autoantibodies and the comparison with ADAMTS 13 inhibitors as measured by conventional mixing studies. Hämostaseologie. 2006. Abstract 46.
3 Antoine G, Zimmermann K, Plaimauer B. et al. ADAMTS13 gene defects in two brothers with constitutional thrombotic thrombocytopenic purpura and normalization of von Willebrand factor-cleaving protease activity by recombinant human ADAMTS13. Br J Haematol 2003; 120: 821-824.
4 Upshaw JD. Congenital deficiency of a factor in normal plasma that reverses microangiopathic hemolysis and thrombocytopenia. N Engl J Med 1978; 298: 1350-1352.
5 Levy GG, Nichols WC, Lian EC. et al. Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura. Nature 2001; 413: 488-494.
6 Rock GA, Shumak KH, Buskard NA. et al. Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura. Canadian Apheresis Study Group. N Engl J Med 1991; 325: 393-397.
7 Moake JL. Thrombotic thrombocytopenic purpura: the systemic clumping „plague“. Annu Rev Med 2002; 53: 75-88.
8 Shumak KH, Rock GA, Nair RC. Late relapses in patients successfully treated for thrombotic thrombocytopenic purpura. Canadian Apheresis Group. Ann Intern Med 1995; 122: 569-572.
9 Zheng XL, Kaufman RM, Goodnough LT. et al. 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 Bernard RP, Bauman AW, Schwartz SI. Splenectomy for thrombotic thrombocytopenic purpura. Ann Surg 1969; 169: 616-624.
11 Rutkow IM. Thrombotic thrombocytopenic purpura (TTP) and splenectomy: a current appraisal. Ann Surg 1978; 188: 701-705.
12 Cuttner J. Thrombotic thrombocytopenic purpura: a ten-year experience. Blood 1980; 56: 302-306.
13 Nosari A, Muti G, Busnach G. et al. Intravenous gamma globulin in refractory thrombotic thrombocytopenic purpura. Acta Haematol 1996; 96: 255-257.
14 Chemnitz J, Schulz A, Diehl V. et al. Thromboticthrombocytopenic purpura (Moschcowitz syndrome). Med Klin (Munich) 2001; 96: 343-350.
15 Darabi K, Berg AH. Rituximab can be combined with daily plasma exchange to achieve effective B-cell depletion and clinical improvement in acute autoimmune TTP. Am J Clin Pathol 2006; 125: 592-597.
16 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.
17 Koulova L, Alexandrescu D, Dutcher JP. et al. Rituximab for the treatment of refractory idiopathic thrombocytopenic purpura (ITP) and thrombotic thrombocytopenic purpura (TTP): report of three cases. Am J Hematol 2005; 78: 49-54.
18 Narat S, Gandla J, Hoffbrand AV. et al. Rituximab in the treatment of refractory autoimmune cytopenias in adults. Haematologica 2005; 90: 1273-1274.
19 Quartier P, Brethon B, Philippet P. et al. Treatment of childhood autoimmune haemolytic anaemia with rituximab. Lancet 2001; 358: 1511-1513.
20 Ramanathan S, Koutts J, Hertzberg MS. Two cases of refractory warm autoimmune hemolytic anemia treated with rituximab. Am J Hematol 2005; 78: 123-126.
21 Reddy PS, Deauna-Limayo D, Cook JD. et al. Rituximab in the treatment of relapsed thrombotic thrombocytopenic purpura. Ann Hematol 2005; 84: 232-235.
22 Rock G. The management of thrombotic thrombocytopenic purpura in 2005. Semin Thromb Hemost 2005; 31: 709-716.
23 Sallah S, Husain A, Wan JY. et al. Rituximab in patients with refractory thrombotic thrombocytopenic purpura. J Thromb Haemost 2004; 2: 834-836.
24 Scott SM, Szczepiorkowski ZM. Rituximab for TTP. Am J Hematol 2005; 80: 87-88.
25 Shanafelt TD, Madueme HL, Wolf RC. et al. Rituximab for immune cytopenia in adults: idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, and Evans syndrome. Mayo Clin Proc 2003; 78: 1340-1346.
26 Fakhouri F, Vernant J-P, 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.
27 Berentsen S, Tjonnfjord GE, Brudevold R. et al. Favourable response to therapy with the anti-CD20 monoclonal antibody rituximab in primary chronic cold agglutinin disease. Br J Haematol 2001; 115: 79-83.
28 Berentsen S, Ulvestad E, Gjertsen BT. et al. Rituximab for primary chronic cold agglutinin disease: a prospective study of 37 courses of therapy in 27 patients. Blood 2004; 103: 2925-2928.
29 Zecca M, Nobili B, Ramenghi U. et al. Rituximab for the treatment of refractory autoimmune hemolytic anemia in children. Blood 2003; 101: 3857-3861.
30 Bohm M, Vigh T, Scharrer I. Evaluation and clinical application of a new method for measuring activity of von Willebrand factor-cleaving metalloprotease (ADAMTS13). Ann Hematol 2002; 81: 430-435.
31 Jones J, Robinson M, Parciany R. et al. Therapeutic plasmapheresis in systemic lupus erythematosus. Effect on immune complexes and antibodies to DNA. Arthritis Rheum. 1981; 24: 1113-1120.
32 Mannucci PM, Böhm M, Scharrer I. et al. Patterns of changes of anti-ADAMTS13 after plasma exchange. J Thromb Haemost 2006; 4: 1405-1437.
33 Böhm M, Betz C, Vigh T. et al. The effect of plasma exchange therapy on ADAMTS13 activity and on corresponding inhibitor levels in index episodes and relapses of TTP. Ann Hematol 2003; 82 Abstract 011.