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This special supplement to Oncology NewsInternational includes updated results ofstudies with anti-CD20 therapy and othertargeted therapies in the treatment oflymphomas, chronic lymphocytic leukemia,and immune thrombocytopenic purpura. Theresults were presented at the American Societyof Hematology 44th Annual Meeting inPhiladelphia, December 6 to 10, 2002.
PHILADELPHIA-Immune thrombocytopenic purpura (ITP) is an autoimmune disease characterized by low platelet counts and resultant mucocutaneous bleeding. The first-line treatment for ITP is typically prednisone (1.0 to 1.5 mg/kg/day), and response rates range from 50% to 75%. The optimal duration of therapy has not been determined, however, and many patients relapse. In addition, no standard second-line agent has been established. Splenectomy is currently the only curative treatment for ITP. Rituximab (Rituxan), a B-cell- depleting monoclonal antibody with well-characterized activity in non- Hodgkin's lymphoma, has recently been reported to be effective in patients with refractory ITP.[3-5] Data from a study of 57 patients with ITP refractory to at least two previous treatment regimens including splenectomy suggest that rituximab can induce durable responses in such patients, with minimal treatment-related toxicity (ASH abstract 1871). Study investigators included Nichola Cooper, MD, fellow, and James Bussel, MD, professor of pediatrics, at the Weill Medical College of Cornell University in New York, and Robert Stasi, MD, of the Regina Apostolorum Hospital in Albano Laziale, Italy.
Duration of Response
Adult patients with ITP refractory to standard therapy and platelet counts < 30,000/Î¼L were administered 4 weekly infusions of rituximab 375 mg/m2 and followed for a median duration of 11 months. Treatment with rituximab produced responses in 72% of patients (see Table 1), including complete responses (platelet count > 150,000/Î¼L)in 32% of patients. In addition, 23% of patients achieved a good response, defined as platelet count > 50,000/Î¼L but < 150,000/Î¼L). The overall median time to response from the start of therapy was 3 weeks (range, 1 to 19 weeks), whereas the median time to complete response was 8 weeks (range, 1 to 40 weeks). Notably, patients with a complete response had a significantly longer duration of response than did patients with a good response (P < .001). Sixteen of 18 (89%) patients who achieved a complete response maintained normal platelet counts for 16 to 136 weeks from the start of therapy (median duration, 49 weeks). Dr. Cooper reported that prior treatment with splenectomy did not correlate with response to therapy, timing, or duration of response. Rituximab was safe and well tolerated. Mild to moderate infusion reactions were reported in 33 (58%) patients, but no discontinuations were attributed to infusion reactions. Administration of prednisone before rituximab infusion significantly decreased the incidence of infusion reactions, particularly fevers and chills. All patients completed all four infusions of rituximab. There were no reports of serious infections in this patient population. All patients achieved a decrease in their B-cell count to < 30 * 106 cells/L by week 4 of the study. B-cell levels began to return to normal between weeks 11 and 25. By week 52, only 1 of 33 (3%) patients had B-cell levels lower than the normal range (approximately 75 to 700 cells/Î¼L).
Mechanism of Action
Although there has been a great deal of speculation regarding the mechanism of action of rituximab in treating ITP, no definitive answers have yet emerged. Dr. Cooper and colleagues investigated the mechanism of action of rituximab in 23 patients with treatment-refractory ITP (ASH abstract 1860). Patients were treated with rituximab 375 mg/m2 weekly for 4 weeks. At week 5, 6 of 11 (55%) patients who responded to therapy and 10 of 11 (91%) who did not respond to therapy lacked detectable B cells. B-cell levels began to recover by weeks 12 to 26 and all but one patient had normal B-cell levels by week 52. Five of seven (71%) patients who responded to rituximab therapy had prestudy antiplatelet immunoglobin G (IgG) antibodies to the platelet membrane glycoproteins IIB/IIIA, IBIX, and IA/IIA. Of these five patients, four had a decrease in two to three of these antibodies at week 5. However, 9 of 10 nonresponders did not have a reduced titer for any of the three antiplatelet antibodies after rituximab treatment. One late responder had no change in antiplatelet antibody titers at week 5. Pretreatment thrombopoietin levels were significantly higher in nonresponders compared with responders and in late responders compared with early responders. These data suggest that a higher thrombopoietin level in nonresponders was caused by lower platelet production, an indication of disease activity. Overall, it appears that patients who respond to rituximab have an immediate reduction in platelet-associated IgG antibodies. The authors speculated that the IgG depletion may be related to rituximab depletion of antibody-producing cells. Slow onset of responses to rituximab may be related to a slower rate of antibody depletion. To date, rituximab has not demonstrated the ability to deplete plasma cells. New data on the mechanisms of action are intriguing, Dr. Cooper noted, and suggest that further investigation of the mechanism of action of rituximab in ITP is needed.
1. Cines DB, Blanchette VS. Immune thrombocytopenic purpura. N Engl J Med 346:995-1008, 2002.
2. Schwartz J, Leber MD, Gillis S, et al: Long term follow-up after splenectomy performed for immune thrombocytopenic purpura (ITP). Am J Hematol 72: 94-98, 2003.
3. Hedge UP, Wilson WH, White T, et al: Rituximab treatment of refractory fludarabine-associated immune thrombocytopenia in chronic lymphocytic leukemia. Blood 100:2260-2262, 2002.
4. Saleh MN, Gutheil J, Moore M, et al: A pilot study of the anti-CD20 monoclonal antibody rituximab in patients with refractory immune thrombocytopenia. Semin Oncol 27:99-103, 2000.
5. Bussel JB. Overview of idiopathic thrombocytopenic purpura: New approach to refractory patients. Semin Oncol 27:91-98, 2000.
6. Cooper N, Stasi R, Feuerstein M, et al: Transient B cell depletion with rituximab, an anti CD20 monoclonal antibody, resulted in lasting complete responses in 16 of 57 adults with refractory immune thrombocytopenic purpura (abstract 187). Blood 100:52a, 2002.
7. Cooper N, Feuerstein M, McFarland J, et al: Investigating the mechanism of action of rituximab, an anti-CD20 monoclonal antibody in adults with immune thrombocytopenic purpura (abstract 1860). Blood 100:479a, 2002.