TRANSFUSION PRACTICE Bortezomib for chronic relapsing thrombotic thrombocytopenic purpura: a case report Sean Yates,1 Karen Matevosyan,1 Cynthia Rutherford,2 Yu-Min Shen,2 and Ravi Sarode1
BACKGROUND: Acquired thrombotic thrombocytopenic purpura (TTP) is an autoimmune disorder characterized by a severe deficiency of ADAMTS13 activity. Although therapeutic plasma exchange (PLEX) is the standard of care, 30% to 50% patients develop exacerbation or relapse, requiring immunomodulatory agents. Of these agents, glucocorticoids, rituximab, and cyclosporine A are the most frequently used. CASE REPORT: We report a case of chronic relapsing TTP in a patient who had eight relapses over a 14-year period. After her seventh relapse, the patient demonstrated only partial response to glucocorticoids, two courses of rituximab, and cyclophosphamide. The eighth relapse occurred 58 days after her last PLEX and subsequent to this she received a course of bortezomib (Velcade, Millennium Pharmaceuticals, Inc.). After treatment with bortezomib the patient demonstrated a complete response with a progressive increase in ADAMTS13 activity from less than 5% to 22% accompanied by undetectable inhibitor, and she has remained PLEX free for more than 169 days. CONCLUSION: Bortezomib may serve as an adjunct treatment in patients with acquired TTP who exhibit an incomplete response or are refractory to conventional management.
ABBREVIATIONS: PLEX = plasma exchange; TTP = thrombotic thrombocytopenic purpura. From the 1Department of Pathology, Division of Transfusion Medicine and Hemostasis, and the 2Department of Internal Medicine, Division of Hematology/Oncology, University of Texas Southwestern Medical Center, Dallas, Texas. Address reprint requests to: Ravi Sarode, MD, Department of Pathology, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390; e-mail: [email protected]. Received for publication October 17, 2013; revision received December 19, 2013, and accepted December 26, 2013. doi: 10.1111/trf.12614 © 2014 AABB TRANSFUSION 2014;54:2064-2067. 2064
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hrombotic thrombocytopenic purpura (TTP) is a rare disorder characterized by microangiopathic hemolytic anemia, thrombocytopenia, and the development of von Willebrand factor (VWF)–platelet (PLT)-rich thrombi within the microvasculature of several organs.1 Acquired TTP results from the formation of polyclonal autoantibodies against ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin Type 1 motif, Member 13), an enzyme responsible for the cleavage of ultralarge VWF multimers. Despite the initial efficacy of therapeutic plasma exchange (PLEX) in most TTP patients, 30% to 50% relapse,2 with significant rates of morbidity and mortality.3 Consequently, immunosuppressant modalities (glucocorticoids, rituximab, cyclosporine A, cyclophosphamide, and vincristine) are often used as an adjunct treatment in refractory or relapsing cases. We report a case of chronic relapsing TTP in a patient refractory to glucocorticoids, rituximab, and cyclophosphamide who responded well to bortezomib.
CASE REPORT A 48-year-old Hispanic female was diagnosed with her first episode of autoimmune TTP in 1999. Over the 14 years since her initial presentation, she has experienced eight relapses, each characterized by a severe deficiency of ADAMTS13 (169 days). Volume 54, August 2014 TRANSFUSION
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Fig. 2. PLT count and LDH data before and immediately after the initiation of PLEX and bortezomib therapy. (—) PLT counts over time; (···) LDH concentration over time; (○) one PLEX; (□) one dose of rituximab; (Δ) one dose of bortezomib.
DISCUSSION Nonselective immunosuppressant agents have been used in patients with relapsing refractory TTP to inhibit the production of autoantibody. Recently, rituximab has emerged as a promising adjunct therapy with studies demonstrating significant responses (95%) in 73 patients.5 Rituximab, a monoclonal antibody, targets the CD20 antigen found on B-cell surfaces, ultimately resulting in B-cell apoptosis. However, rituximab’s effect appears to be transient in some patients.6 Despite completing a second course of rituximab 41 days earlier, our patient developed her eighth episode of relapse, indicating resistance to rituximab therapy. Therefore, she was treated with bortezomib, which resulted in a gradual increase in ADAMTS13 activity and undetectable inhibitor titers. The first appreciable level of ADAMTS13 activity of 15% in 166 days occurred 4 days after administration of bortezomib. This could be attributed to PLEX therapy, which preceded this measurement. However, interestingly, during the 28-day interval in which bortezomib was discontinued due to neutropenia, ADAMTS13 activity was less than 5%. Upon restarting bortezomib, the ADAMTS13 activity had remained in the range of 15% to 22%. To our knowledge, there are only two other cases of refractory TTP successfully treated with bortezomib.4,7 2066
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Both of these cases were characterized by persistent disease during their first presentation despite treatment with multiple immunosuppressive modalities, including rituximab. Much like our patient, both demonstrated a significant response after the initiation of bortezomib. The source of immunoglobulin G autoantibodies includes mature B cells and plasma cells. Rituximab effectively destroys B cells expressing CD20 markers; however, plasma cells do not express this antigen and can serve as a potential source of autoantibody production. Bortezomib functions through the selective inhibition of proteasomes, leading to cell cycle arrest and apoptosis. Currently, bortezomib is approved for the treatment of multiple myeloma and mantle cell lymphoma. The capacity of bortezomib to target plasma cells, amply demonstrated in the plasma cell dyscrasias,8 is of particular interest for autoimmune diseases. Bortezomib has been shown to substantially reduce circulating autoantibodies through induction of apoptosis in both B-cell and plasma cell populations.9 In addition, bortezomib may induce apoptotic cell death in immature dendritic cell populations, necessary for the activation of CD4+ T cells, which are responsible for autoantibody production.10 Moreover, in liver and kidney transplant patients bortezomib has demonstrated an ability to significantly reduce pathologic antibody titers and promote long-term organ survival in
BORTEZOMIB THERAPY IN CHRONIC RELAPSING TTP
those refractory to rituximab therapy.11-13 It is logical to assume it could serve a similar role in reducing autoantibodies in acquired TTP and may require more tailored regimen for autoimmune disorders. Before treating with bortezomib several factors should be considered, including the cost and potential adverse effects. Currently 100 mg of rituximab is available at an average wholesale price of $801.28. For an average person (1.73 m2) at a dose of 375 mg/m2, a total amount of 650 mg would be required translating to $5206 per infusion or $20,826 for a typical four-dose course. Conversely, 3.5 mg of bortezomib is available at an average wholesale price of $1852.80. For an average person (1.73 m2) at a dose of 1.3 mg/m2, a total amount of 2.25 mg would be required, translating to $1190 per infusion. Thus, per dose, bortezomib is cheaper than rituximab; however, the number of doses for TTP has not been established. There are significant toxicities that have been reported with the use of bortezomib including thrombocytopenia, peripheral neuropathy, and neutropenia.14 In conclusion, this current case report suggests that bortezomib may serve as a viable adjunct treatment in patients with acquired TTP who exhibit an incomplete response or are refractory to conventional management. CONFLICT OF INTEREST The authors report no conflicts of interest or funding sources.
REFERENCES 1. Tsai HM, Lian EC. Antibodies to von Willebrand factorcleaving protease in acute thrombotic thrombocytopenic purpura. N Engl J Med 1998;339:1585-94. 2. Jin M, Casper TC, Cataland SR, et al. Relationship between ADAMTS13 activity in clinical remission and the risk of TTP relapse. Br J Haematol 2008;141:651-8. 3. Tsai HM. Autoimmune thrombotic microangiopathy: advances in pathogenesis, diagnosis, and management. Semin Thromb Hemost 2012;38:469-82.
4. Shortt J, Oh DH, Opat SS. ADAMTS13 antibody depletion by bortezomib in thrombotic thrombocytopenic purpura. N Engl J Med 2013;368:90-2. 5. Elliott MA, Heit JA, Pruthi RK, et al. Rituximab for refractory and or relapsing thrombotic thrombocytopenic purpura related to immune-mediated severe ADAMTS13deficiency: a report of four cases and a systematic review of the literature. Eur J Haematol 2009;83:365-72. 6. Patino W, Sarode R. Successful repeat therapy with rituximab for relapsed thrombotic thrombocytopenic purpura. J Clin Apher 2007;22:17-20. 7. Balen T, Schreuder MF, Jong H, et al. Refractory thrombotic thrombocytopenic purpura in a 16-year-old girl: successful treatment with bortezomib. Eur J Haematol 2014; 92:80-2. 8. Painuly U, Kumar S. Efficacy of bortezomib as first-line treatment for patients with multiple myeloma. Clin Med Insights Oncol 2013;7:53-73. 9. Mulder A, Heidt S, Vergunst M, et al. Proteasome inhibition profoundly affects activated human B cells. Transplantation 2013;95:1331-7. 10. Park SJ, Cheong HI, Shin JI. Antibody depletion by bortezomib through blocking of antigen presentation. N Engl J Med 2013;368:1364-5. 11. Everly MJ, Everly JJ, Susskind B, et al. Bortezomib provides effective therapy for antibody- and cell-mediated acute rejection. Transplantation 2008;86:1754-61. 12. Paterno F, Shiller M, Tillery G, et al. Bortezomib for acute antibody-mediated rejection in liver transplantation. Am J Transplant 2012;12:2526-31. 13. Scully M, McDonald V, Cavenagh J, et al. A phase 2 study of the safety and efficacy of rituximab with plasma exchange in acute acquired thrombotic thrombocytopenic purpura. Blood 2011;118:1746-53. 14. Utecht K, Kolesar J. Bortezomib: a novel chemotherapeutic agent for hematologic malignancies. Am J Health Syst Pharm 2008;65:1221-31.
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BACKGROUND: Acquired thrombotic thrombocytopenic purpura (TTP) is an autoimmune disorder characterized by a severe deficiency of ADAMTS13 activity. Although therapeutic plasma exchange (PLEX) is the standard of care, 30% to 50% patients develop exacerbation or relapse, requiring immunomodulatory agents. Of these agents, glucocorticoids, rituximab, and cyclosporine A are the most frequently used. CASE REPORT: We report a case of chronic relapsing TTP in a patient who had eight relapses over a 14-year period. After her seventh relapse, the patient demonstrated only partial response to glucocorticoids, two courses of rituximab, and cyclophosphamide. The eighth relapse occurred 58 days after her last PLEX and subsequent to this she received a course of bortezomib (Velcade, Millennium Pharmaceuticals, Inc.). After treatment with bortezomib the patient demonstrated a complete response with a progressive increase in ADAMTS13 activity from less than 5% to 22% accompanied by undetectable inhibitor, and she has remained PLEX free for more than 169 days. CONCLUSION: Bortezomib may serve as an adjunct treatment in patients with acquired TTP who exhibit an incomplete response or are refractory to conventional management.
ABBREVIATIONS: PLEX = plasma exchange; TTP = thrombotic thrombocytopenic purpura. From the 1Department of Pathology, Division of Transfusion Medicine and Hemostasis, and the 2Department of Internal Medicine, Division of Hematology/Oncology, University of Texas Southwestern Medical Center, Dallas, Texas. Address reprint requests to: Ravi Sarode, MD, Department of Pathology, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390; e-mail: [email protected]. Received for publication October 17, 2013; revision received December 19, 2013, and accepted December 26, 2013. doi: 10.1111/trf.12614 © 2014 AABB TRANSFUSION 2014;54:2064-2067. 2064
TRANSFUSION Volume 54, August 2014
T
hrombotic thrombocytopenic purpura (TTP) is a rare disorder characterized by microangiopathic hemolytic anemia, thrombocytopenia, and the development of von Willebrand factor (VWF)–platelet (PLT)-rich thrombi within the microvasculature of several organs.1 Acquired TTP results from the formation of polyclonal autoantibodies against ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin Type 1 motif, Member 13), an enzyme responsible for the cleavage of ultralarge VWF multimers. Despite the initial efficacy of therapeutic plasma exchange (PLEX) in most TTP patients, 30% to 50% relapse,2 with significant rates of morbidity and mortality.3 Consequently, immunosuppressant modalities (glucocorticoids, rituximab, cyclosporine A, cyclophosphamide, and vincristine) are often used as an adjunct treatment in refractory or relapsing cases. We report a case of chronic relapsing TTP in a patient refractory to glucocorticoids, rituximab, and cyclophosphamide who responded well to bortezomib.
CASE REPORT A 48-year-old Hispanic female was diagnosed with her first episode of autoimmune TTP in 1999. Over the 14 years since her initial presentation, she has experienced eight relapses, each characterized by a severe deficiency of ADAMTS13 (169 days). Volume 54, August 2014 TRANSFUSION
2065
YATES ET AL.
Fig. 2. PLT count and LDH data before and immediately after the initiation of PLEX and bortezomib therapy. (—) PLT counts over time; (···) LDH concentration over time; (○) one PLEX; (□) one dose of rituximab; (Δ) one dose of bortezomib.
DISCUSSION Nonselective immunosuppressant agents have been used in patients with relapsing refractory TTP to inhibit the production of autoantibody. Recently, rituximab has emerged as a promising adjunct therapy with studies demonstrating significant responses (95%) in 73 patients.5 Rituximab, a monoclonal antibody, targets the CD20 antigen found on B-cell surfaces, ultimately resulting in B-cell apoptosis. However, rituximab’s effect appears to be transient in some patients.6 Despite completing a second course of rituximab 41 days earlier, our patient developed her eighth episode of relapse, indicating resistance to rituximab therapy. Therefore, she was treated with bortezomib, which resulted in a gradual increase in ADAMTS13 activity and undetectable inhibitor titers. The first appreciable level of ADAMTS13 activity of 15% in 166 days occurred 4 days after administration of bortezomib. This could be attributed to PLEX therapy, which preceded this measurement. However, interestingly, during the 28-day interval in which bortezomib was discontinued due to neutropenia, ADAMTS13 activity was less than 5%. Upon restarting bortezomib, the ADAMTS13 activity had remained in the range of 15% to 22%. To our knowledge, there are only two other cases of refractory TTP successfully treated with bortezomib.4,7 2066
TRANSFUSION Volume 54, August 2014
Both of these cases were characterized by persistent disease during their first presentation despite treatment with multiple immunosuppressive modalities, including rituximab. Much like our patient, both demonstrated a significant response after the initiation of bortezomib. The source of immunoglobulin G autoantibodies includes mature B cells and plasma cells. Rituximab effectively destroys B cells expressing CD20 markers; however, plasma cells do not express this antigen and can serve as a potential source of autoantibody production. Bortezomib functions through the selective inhibition of proteasomes, leading to cell cycle arrest and apoptosis. Currently, bortezomib is approved for the treatment of multiple myeloma and mantle cell lymphoma. The capacity of bortezomib to target plasma cells, amply demonstrated in the plasma cell dyscrasias,8 is of particular interest for autoimmune diseases. Bortezomib has been shown to substantially reduce circulating autoantibodies through induction of apoptosis in both B-cell and plasma cell populations.9 In addition, bortezomib may induce apoptotic cell death in immature dendritic cell populations, necessary for the activation of CD4+ T cells, which are responsible for autoantibody production.10 Moreover, in liver and kidney transplant patients bortezomib has demonstrated an ability to significantly reduce pathologic antibody titers and promote long-term organ survival in
BORTEZOMIB THERAPY IN CHRONIC RELAPSING TTP
those refractory to rituximab therapy.11-13 It is logical to assume it could serve a similar role in reducing autoantibodies in acquired TTP and may require more tailored regimen for autoimmune disorders. Before treating with bortezomib several factors should be considered, including the cost and potential adverse effects. Currently 100 mg of rituximab is available at an average wholesale price of $801.28. For an average person (1.73 m2) at a dose of 375 mg/m2, a total amount of 650 mg would be required translating to $5206 per infusion or $20,826 for a typical four-dose course. Conversely, 3.5 mg of bortezomib is available at an average wholesale price of $1852.80. For an average person (1.73 m2) at a dose of 1.3 mg/m2, a total amount of 2.25 mg would be required, translating to $1190 per infusion. Thus, per dose, bortezomib is cheaper than rituximab; however, the number of doses for TTP has not been established. There are significant toxicities that have been reported with the use of bortezomib including thrombocytopenia, peripheral neuropathy, and neutropenia.14 In conclusion, this current case report suggests that bortezomib may serve as a viable adjunct treatment in patients with acquired TTP who exhibit an incomplete response or are refractory to conventional management. CONFLICT OF INTEREST The authors report no conflicts of interest or funding sources.
REFERENCES 1. Tsai HM, Lian EC. Antibodies to von Willebrand factorcleaving protease in acute thrombotic thrombocytopenic purpura. N Engl J Med 1998;339:1585-94. 2. Jin M, Casper TC, Cataland SR, et al. Relationship between ADAMTS13 activity in clinical remission and the risk of TTP relapse. Br J Haematol 2008;141:651-8. 3. Tsai HM. Autoimmune thrombotic microangiopathy: advances in pathogenesis, diagnosis, and management. Semin Thromb Hemost 2012;38:469-82.
4. Shortt J, Oh DH, Opat SS. ADAMTS13 antibody depletion by bortezomib in thrombotic thrombocytopenic purpura. N Engl J Med 2013;368:90-2. 5. Elliott MA, Heit JA, Pruthi RK, et al. Rituximab for refractory and or relapsing thrombotic thrombocytopenic purpura related to immune-mediated severe ADAMTS13deficiency: a report of four cases and a systematic review of the literature. Eur J Haematol 2009;83:365-72. 6. Patino W, Sarode R. Successful repeat therapy with rituximab for relapsed thrombotic thrombocytopenic purpura. J Clin Apher 2007;22:17-20. 7. Balen T, Schreuder MF, Jong H, et al. Refractory thrombotic thrombocytopenic purpura in a 16-year-old girl: successful treatment with bortezomib. Eur J Haematol 2014; 92:80-2. 8. Painuly U, Kumar S. Efficacy of bortezomib as first-line treatment for patients with multiple myeloma. Clin Med Insights Oncol 2013;7:53-73. 9. Mulder A, Heidt S, Vergunst M, et al. Proteasome inhibition profoundly affects activated human B cells. Transplantation 2013;95:1331-7. 10. Park SJ, Cheong HI, Shin JI. Antibody depletion by bortezomib through blocking of antigen presentation. N Engl J Med 2013;368:1364-5. 11. Everly MJ, Everly JJ, Susskind B, et al. Bortezomib provides effective therapy for antibody- and cell-mediated acute rejection. Transplantation 2008;86:1754-61. 12. Paterno F, Shiller M, Tillery G, et al. Bortezomib for acute antibody-mediated rejection in liver transplantation. Am J Transplant 2012;12:2526-31. 13. Scully M, McDonald V, Cavenagh J, et al. A phase 2 study of the safety and efficacy of rituximab with plasma exchange in acute acquired thrombotic thrombocytopenic purpura. Blood 2011;118:1746-53. 14. Utecht K, Kolesar J. Bortezomib: a novel chemotherapeutic agent for hematologic malignancies. Am J Health Syst Pharm 2008;65:1221-31.
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