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Rituximab: an anti-CD20 antibody for the treatment of chronic refractory immune thrombocytopenic purpura.

ABSTRACT

Immune thrombocytopenic purpura (ITP) is an autoimmune disease characterized by antibody-mediated platelet destruction. Despite initial response to corticosteroids, most adults relapse during steroid taper, and splenectomy is the treatment of choice for these patients. Those whom splenectomy fails to cure present a therapeutic challenge. Subsequent management usually involves some form of chronic immune suppression, which has serious side effects and long-term morbidity, Rituximab, a recently-approved anti-CD2O chimeric monoclonal antibody, has shown efficacy in preliminary studies. We report the cases of 3 patients with refractory ITP who achieved acceptable platelet counts after treatment with rituximab.

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IMMUNE THROMBOCYTOPENIC PURPURA (ITP) is a relatively common autoimmune disease characterized by antibody-mediated platelet destruction resulting in an increased risk for bleeding. Treatment is generally not recommended until the platelet count is <30,000/[micro]L, bleeding occurs, or there are other predisposing comorbid conditions. (1)

The mainstay of initial therapy has included steroids, usually prednisone at 1 to 2 mg/kg/day, which results in an improvement in the platelet count in approximately 60% to 90% of patients, depending on the intensity and duration of treatment. After prednisone is tapered, 15% to 25% of adults with chronic ITP will show a durable response. (1,2) In steroid-refractory patients, splenectomy has been the treatment of choice. Two thirds of patients have an initial response to splenectomy, but approximately 15% of these patients relapse. (3) Although splenectomy is thought to be curative in chronic ITP, the long-term outcome for these patients is not well documented.

A single dose of intravenous [gamma]-globulin (IVIG) (1 g/kg/day) has resulted in a significant increase in the platelet counts of 85% of patients, and these patients continued to respond with repeated courses of IVIG. (4,5) Similar results have been reported with the use of WinRho. (6,7) Both WIG and WinRho are expensive measures and are not without systemic side effects.

Treatment with vinca alkaloids has resulted in a 10% to 20% response rate, but sustained complete responses are uncommon. (8) Uncontrolled and selected-case series have reported response rates of 20% to 40% with cyclophosphamide, with response occurring after 1 to 6 months of daily oral treatment. (8,9) Despite initial reports of efficacy, most of these agents have not shown consistent responses when used in larger groups of patients, and they possess potentially hazardous side effects.

Immunosuppressive agents, such as pulse dexamethasone, (10) azathioprine (Imuran), cyclosporin A (Sandimmune) and mycophenolate moefetil (MMF) (Cellcept) have been used in the treatment of ITP.

Recently, a novel approach using rituximab, an anti-CD2O chimeric monoclonal antibody, has shown promising results in patients with refractory ITP. (11-13) Rituximab is a genetically-engineered, humanized, mouse monoclonal antibody directed against the CD2O antigen found on the surface of normal and malignant B cells. Rituximab is used in the treatment of recurrent or refractory low-grade non-Hodgkin's lymphoma (NHL). (14,15) Based on these initial promising reports, we used rituximab at the approved dose of 375 mg/[m.sup.2]/week for 4 weeks to treat 3 patients with chronic refractory ITP.

CASE REPORTS

Case 1. A 49-year-old woman with a long history of refractory ITP was initially treated with prednisone and subsequently had splenectomy. Without treatment, her thrombocytopenia was severe, with platelet counts between 5,000 and 10,000/[micro]L, accompanied by recurrent bouts of epistaxis and gingival hemorrhage. She required weekly infusion of WIG to maintain her platelet count above 10,000/[micro]L, Treatment with pulse dexamethasone, trials of cyclosporin A (July to September 1996 and January to March 1999), multiple courses of vincristine, danazol (October 1996 to June 1997), Imuran (April to November 1998), pulse cyclophosphamide (November to December 1998), and MMF (March to August 1999), were all without significant or prolonged response. An experimental protocol using high-dose chemotherapy with autologous stem-cell rescue was offered, but the patient declined that treatment. After nearly 3 years of weekly IVIG and the other treatments described, the patient received 4 weekly doses of intravenous ritu ximab at a dose of 375 mg/[m.sup.2]. Her platelet count before rituximab treatment was <10,000/[micro]L, Within the first 4 weeks of treatment, her platelet count rose above 20,000/[micro]L, ultimately climbing to [greater than or equal to]30,000/[micro]L, where it was maintained for 6 months. During this period, the patient was asymptomatic and did not require additional therapy (Figure); however, she did require retreatment after 6 months for a platelet count of 11,000/[micro]L, which resulted in an additional sustained response. Her most recent platelet count (7 months after retreatment) was 104,000/[micro]L.

Case 2. An 87-year-old woman with a significant history of cardiac disease and a 6-month history of epistaxis was found to have a platelet count of 12,000/[micro]L. Other hematologic malignancies were ruled out by normal bone marrow biopsy and cytogenetic testing. Mild hematochezia developed, but a platelet transfusion did not result in an appropriate increase in the platelet count. She was started on 60 mg of prednisone, but her platelet count remained at 8,000/[micro]L after 2 weeks of therapy. Prednisone was discontinued, and WinRho was administered at a dose of 50[micro]g/kg, but her platelet count did not improve. The patient was given 1 dose of vincristine (2 mg), which did not produce any effect. Purpuric oral lesions and petechiae developed on her extremities; at that point, WIG, which had been held because of her precarious cardiac status, was administered for a total dose of 2 g/kg over 4 days. This resulted in her platelet count briefly increasing to 40,000/[micro]L, but this was sustained for less than 2 days. Splenectomy was deemed too risky due to the patient's poor cardiac function. She was then treated with 4 weekly doses of rituximab at 375 mg/[m.sup.2] intravenously. After an initially slow response, her platelet count rose to 45,000/[micro]L by the fourth week of infusion (Figure). A week after the last dose of rituximab, her platelet count had risen to 175,000/[micro]L. Two months later, her platelet count was 68,000/[micro]L and had remained stable thereafter.

Case 3. A 75-year-old man with a remote history of earlystage Hodgkin's disease treated with radiation therapy alone presented with a history of chronic ITP, diagnosed by bone marrow biopsy at an outside facility. He had 2 episodes of severe thrombocytopenia in 1993 and 1995, both of which responded to treatment with corticosteroids. In September 1997, his platelet count fell to approximately 20,000/[micro]L. The patient was started on 80 mg of prednisone daily for 2 weeks without a response. After prednisone was tapered slowly, he was treated with IVIG, 1 g/kg biweekly, for a total of 4 doses. His platelet count improved to 100,000/[micro]L but then promptly fell back to between 10,000/[micro]L and 20,000/[micro]L. He was then treated with WinRho, to which he initially responded, with his platelet count rising to 142,000/[micro]L. His platelet count stabilized at approximately 40,000/[micro]L until October 1999, when it dropped to 17,000/[micro]L. He was retreated with WinRho, and the platelet count rose to an acceptable range for 2 months. He subsequently required frequent retreatments with WinRho, and there was a gradual decrease in the duration of response (duration time decreasing to 1 to 2 weeks). He also received doses of vincristine and prednisone without any effect. The option of splenectomy was considered, but the patient was judged to be at too great a risk for surgery because of severe aortic stenosis. He was then treated with 4 weekly doses of rituximab at 375 mg/[m.sup.2] By the second week of treatment, his platetlet count had improved to approximately 50,000/[micro]L, and it has remained stable ever since, now more than 7 months after therapy (Figure).

DISCUSSION

After the failure of a variety of therapeutic modalities to cure their chronic ITP, there was a sustained, significant improvement in the platelet counts of all 3 patients treated with 4 weekly doses of rituximab. The Table summarizes the treatment of these patients.

Use of rituximab for refractory ITP has been reported recently. (11-13) Saleh et al (13) reported an update on their ongoing phase 1/phase 2 study of rituximab in patients with refractory ITP. Nineteen patients with refractory ITP and platelet counts of 75,000/[micro]L or less were treated with 4 weekly doses of rituximab (50 to 375 mg/mL). Three of the 13 evaluable patients treated with rituximab at a dose 375 mg/[m.sup.2] responded; 2 had complete responses (CR) and 1 had a partial response (PR). Response criteria were strict, however, with CR defined as a normal platelet count and PR defined as a platelet count>100,000/[micro]L. Two of these responders had ITP that was refractory to splenectomy. Time to response was approximately 4 weeks after the last dose of rituximab, but duration of response was not reported. Ratanatharathoin et al (12) described a patient with chronic graft-versus-host disease and ITP who responded to rituximab. We treated 3 patients with rituximab whose ITP was refractory to other tr eatment modalities. All 3 patients responded with an increase in the platelet count to an acceptable level. The mean time to response was 3 to 4 weeks from the start of treatment and was sustained for a minimum of 6 months. During this time, these patients did not require any other conventional treatment for ITP and did not have any episodes of bleeding. The platelet counts of patient 3 are stable more than 7 months after treatment. After 4 weekly doses of rituximab, the platelet counts of patient 1 remained stable for approximately 6 months, after which time she required retreatment. Retreatment resulted in an increase in her platelet count to above 30,000/[micro]L, where it has remained stable for several months. This finding is in accord with data from patients with low-grade NHL who, following relapse after initial treatment with rituximab, respond to retreatment.

The exact role of rituximab in autoimmune diseases is unknown. Rituximab binds to the CD2O antigen on B cells and is highly effective in depletion of these cells, ostensibly by complement-dependent cell lysis, (16) antibody-dependent cellular toxicity, (17) and possibly through induction of apoptosis. As a result of this depletion of B cells, a decrease in antiplatelet autoantibodies probably occurs, thus abrogating the thrombocytopenia. Circulating B cells become undetectable after a single dose of rituximab, but these cells recover in 3 to 6 months. Rituximab can also be detected in the serum of patients 3 to 6 months after treatment. The duration of-persistence of rituximab in the serum appears to correlate with a stable response in the platelet counts.

The acute toxicities of rituximab are modest and include fever, chills, and body aches, which usually occur with the first infusion and are successfully managed with acetaminophine, diphenhydramine, and a decrease in the rate of infusion. Rituximab was well tolerated by our patients, and no serious reactions were seen, even with the first infusion. These results suggest that rituximab has clinically significant activity in the treatment of chronic refractory ITP, and in the future may have a role in the initial management of this disease.
TABLE

Characteristics of 3 Patients With Refractory Immune Thrombocytopenic
Purpura


 Pretreatment
Case Age/Sex Previous Treatments Platelets/[micro]L

1 49/F Prednisone, splenectomy, IVIC, <10,000
 WinRho, cyclosporin A,
 Cytoxan, Cellcept
2 87/F Prednisone, WinRho, <15,000
 vincristine, IVIG
3 75/M Prednisone, IVIG, WinRho <20,000

 Posttreatment Duration of
 Highest Response
Case Platelets/[micro]L (months) Retreatment

1 37,000 6 Yes


2 175,000 [less than or equal to]3 No

3 59,000 [less than or equal to]7 No


References

(1.) George JN, woolf SH, Raskob GE, et al: Idiopathic thrombocytopenic purpura: a practice guideline developed by explicit methods for American Society of Hematology. Blood 1996; 88:3-40

(2.) McMillan R: Therapy for adults with refractory chronic immune thrombocytopenic purpura. Ann Intern Med 1997; 126:307-314

(3.) Julia A, Araguas C, Rossello J, et al: Lack of useful clinical predictors of response to splenectomy in patients with chronic idiopathic thrombocytopenic purpura (ITP). Br J Hematol 1990; 42:250-254

(4.) Imbach P, Barandun S, d' Apuzzo V, et al: High-dose intravenous gammaglobulin for idiopathic thrombocytopenic purpura in childhood Lancet 1981; 1:1228-1231

(5.) Blanchette VS, Semple JW, Freedman JJL: Intravenous immunoglobulin and Rh immunoglobulin as immunomodulators of autoimmunity to blood elements. Autoimmune Disorders of Blood. Silberstein LE (ed). Bethesda, Md, American Association of Blood Banks, 1996, pp 35-77

(6.) Bussel JB, Granziano JN, Kimberly RR, et al: IV anti-D treatment of immune thrombocytopenic purpura: analysis of efficacy, toxicity, and mechanism of effect. Blood 1991;77:1884-1893

(7.) Scaradavou A, Woo B, Woloski BMR, et al: Intravenous anti-D treatment of immune thrombocytopenic purpura: experience in 272 patients. Blood 1997; 89:2689-2700

(8.) Pizzuto J, Ambriz R: Therapeutic experience on 934 adults with idiopathic thrombocytopenic purpura: multicentric trial of the cooperative Latin American Group on Hemostasis and Thrombosis. Blood 1984; 64:1179-1183

(9.) Verlin M, Laros RK Jr, Penner JA: Treatment of refractory thrombocytopenic purpura with cyclophosphamide. Am J Hematol 1976; 1:97-104

(10.) Anderson JC: Response of resistant idiopathic thrombocytopenic purpura to pulsed high-dose dexamethasone therapy. N Engl J Med 1994; 330:1560-1564

(11.) Perotta A, Sunneberg TA, Scott J, et al: Rituxan in the treatment of chronic idiopathic thrombocytopenic purpura (ITP). Blood 1999; 94: (suppl 1) 14a

(12.) Ratanatharathom V, Carson E, Reynolds C, et al: Anti-CD20 chimeric monoclonal antibody treatment of refractory immune-mediated thrombocytopenia in a patient with chronic graft-versus-host disease. Ann Intern Med 2000; 133:275-279

(13.) Saleh MM, Gutheil J, Moore M, et al: A pilot study of antiCD20 MoAb Rituximab in patients with refractory immune thrombocytopenic purpura (ITP). Blood 2000; 96:252a

(14.) McLaughlin P, Grillo-Lopez AJ, Link BK, et al: Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to four-dose treatment program. J Clin Oncol 1998; 16:2825-2833

(15.) Leget GA, Czuczman MS: Use of rituxomab, the new FDA-approved antibody. Curr Opin Oncol 1998; 10:548-551

(16.) Emilia G, Messora C, Longo G, et al: Long-term salvage treatment by cyclosporin in refractory autoimmune haematological disorders. Br J Haematol 1996; 93:341-344

(17.) Maloney DG, Smith B, Applebaum FR: The antitumor effect of monoclonal anti CD-20 antibody therapy includes anti-proliferation activity and induction of apoptosis in CD2O positive NHL cell lines. Blood 1996; 88:637a

RELATED ARTICLE: KEY POINTS

* Rituximab is a chimeric monoclonal antibody directed against CD2O antigen present on B cells.

* Refractory immune thrombocytopenic purpura may respond to treatment with rituximab.

* Respose to rituximab is sustained for 6 months.

* Retreatment with rituximab after relapse may result in further sustained responses.

* Rituximab is well tolerated, with mainly infusion-related side effects.

From the Department of Medical Oncology/Hematology, Washington Cancer Institute, Washington, DC.

Reprint requests to Anita Aggarwal, DO, PhD, Washington Cancer Institute, Washington Hospital Center, 110 Irving St NW, Suite C-2151, Washington, DC 20010.
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Author:Catlett, Joseph P.
Publication:Southern Medical Journal
Geographic Code:1USA
Date:Oct 1, 2002
Words:2531
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