Can rituximab replace splenectomy in immune thrombocytopenic ...

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Indian J Hematol Blood Transfus 25(1):6–9


ORIGINAL ARTICLE

Can rituximab replace splenectomy in immune thrombocytopenic purpura? Vrushali Dabak · Amr Hanbali · Philip Kuriakose

Received: 16 January 2009 / Accepted: 25 February 2009 © Indian Society of Hematology and Transfusion Medicine 2009

Abstract Aim Immune thrombocytopenic purpura (ITP) is an autoimmune disorder characterized by premature platelet destruction. Standard practice is to initiate treatment with corticosteroids, followed by splenectomy. Most published literature for responses from rituximab is in patients with chronic refractory ITP, who have failed multiple prior treatments, including splenectomy. We therefore decided to analyze our patient population with ITP who had been treated with rituximab, mainly as a second line treatment regimen prior to splenectomy. Methods We performed a retrospective chart review of patients with a diagnosis of ITP who had been treated with rituximab between January 2001 and December 2006 at our institution. Results 18/29 patients (62%) had a CR, 2/29 (7%) patients had a PR, representing an overall response rate of 69%. The average time to response was 5 weeks and all patients have maintained their response for more than 12 months after treatment with rituximab. Conclusion Our study shows higher CR, comparable overall response rates, but with a longer duration of response when compared to the published literature. V. Dabak · A. Hanbali · P. Kuriakose Henry Ford Hospital, 2799 West Grand Blvd, Detroit, MI - 48202, USA V. Dabak () E-mail: [email protected]

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Keywords Rituximab · Treatment · Immune thrombocytopenia

Introduction Immune thrombocytopenic purpura is an acquired hematological disorder, presenting as an isolated, idiopathic thrombocytopenia [1]. A presumptive diagnosis is made when the history, physical examination, complete blood count, and examination of peripheral blood smear do not suggest other etiologies for patient’s isolated thrombocytopenia. There is marked interpatient variability in the clinical presentation, with bleeding in symptomatic patients ranging from severe to only petechiae and easy bruising. Older patients can have more severe bleeding manifestations, such as gastrointestinal bleeding, and possibly intracranial hemorrhage. Hence, major goal for treatment of ITP is to provide safe platelet count to prevent major bleeding, which primarily occurs with platelet counts < 10,000/microL [2, 3]. In adults, standard practice is to initiate treatment with corticosteroids followed by a slow taper. About half of such patients relapse within 6 months of initial taper [3]; those who do not respond to the first or second courses of steroids are treated with intravenous immunoglobulins (IVIG) and/or other immunosuppressant’s, or for long term control with splenectomy. Splenectomy is the traditional second-line treatment in adults with ITP, with complete remission in about 65–70 percent of patients [4, 5]. Although splenectomy has an impressive response rate, it is associated with approximately 1 percent operative mortality, and a lifelong increased risk of opportunistic infections [6]. Additionally, ITP recurs in about one-third of patients undergoing splenectomy [7, 8] and hence many patients would like to avoid splenectomy in preference to other treatment modalities.


Rituximab is a monoclonal antibody targeting CD20 surface antigen on B-lymphocytes. It is approved for use in Non Hodgkin’s lymphoma (NHL), and is being used in other conditions like chronic lymphocytic leukemia (CLL) and autoimmune hemolytic anemia, including ITP. In patients with ITP, major responses (i.e. platelet counts >50,000/ microL) are seen in approximately 50 percent, with complete remissions (i.e., platelet counts >150,000/microL) in about one-third [9]. Two systematic reviews of case series describing rituximab treatment of patients with chronic refractory ITP have documented a 30–43 percent complete remission rate [10, 11], with an overall response rate of 62 percent [11]. The median response duration was about 10.5 months in one review while the median follow-up was 9.5 months in the other; hence durability of these responses still remains uncertain. Although rituximab is clearly a useful agent in ITP, published data is currently sparse. Also most of the available literature on the use of Rituximab is in patients with chronic refractory ITP, who have failed multiple prior treatments, including splenectomy [12, 13, 14]. Hence more studies are needed to better define role rituximab use early on in ITP. Most studies have suggested the usefulness of rituximab both in splenectomized and non-splenectomized patients; a Spanish study, published in Annals of hematology in 2006, showed a better early response rate in non splenectomized patients as compared with those who underwent prior splenectomy. This suggests a potential role for rituximab as an early therapeutic option, even as an alternative to splenectomy [15]. We therefore analyzed our patients with ITP who had been treated with rituximab, mainly as a second line treatment prior to splenectomy.

Patients and methods We performed a retrospective chart review of patients with ITP who were treated with rituximab between January 2001 and December 2006 at Henry Ford hospital, Detroit, Michigan. The collected data included age, sex, diagnosis, date of diagnosis, previous treatment for ITP including splenectomy, platelet counts before and after treatment with rituximab, dose of rituximab administered, type of response if any, duration of response, and date of relapse or last follow up or death. In our review, we included only those patients who were treated with steroids alone and were either unresponsive or refractory to them, and hence were offered rituximab as second line of treatment. Treatment with IVIG for emergent stabilization of platelet counts until patients received definitive treatment with rituximab was allowed. Patients with ITP secondary to autoimmune conditions like Lupus and rheumatoid arthritis were included, but patients with thrombocytopenia and concomitant Lymphoma or CLL were excluded from this analysis. Platelet counts were

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evaluated at the time of initial and maximum response. Based on literature review, we defined complete response (CR) as achievement of platelet count greater than 150 × 109 cell/l and partial response as a platelet count between 50 and 150 × 109. Based on median duration of response of 10.5 months as reported in the literature, we choose the cut off of 12 months for our study.

Rituximab dose and duration Rituximab has been approved at a dose of 375 mg/m2 for patients with lymphoma. Hence in our patients rituximab was administered as weekly infusion of 375 mg/m2 for 4 consecutive weeks in all except 1 patient, who received only 1 treatment of rituximab, on account of his ongoing cardiac issues (he however achieved CR with just 1 treatment).

Results We identified a total of 29 patients with a diagnosis of ITP, who were treated with rituximab in the second line setting prior to splenectomy. All except one patient received rituximab for a total of 4 weeks of treatment. Eighteen patients (62%) had a CR which lasted for more than 12 months or longer, 2/29 (another 7%) patients had a PR which was also lasted for at least 12 months, thus with an overall response rate of 69%, as shown in Figure 1. Three out of 29 patients (10%) achieved a CR which was short lived and they had to be treated with other modalities of treatment, with 6/29 (21%) patients not responding to rituximab at all. While the average time to response was 5 weeks, most patients responded within 4 weeks as shown in Fig. 2, and all patients with either a CR or PR maintained their response for more than 12 months after treatment. Side effects like fatigue and tiredness were seen in 2/29 patients and facial rash in 1/29 of our patient population. In our review, age, race or sex of the patients were not significant predictors of response to treatment. Analyzing further we did not find any difference in response between patients who were either steroid dependent or refractory. However, amongst patients who responded to rituximab, responses were seen mostly if they received rituximab soon after their diagnosis, usually within a year. This data was presented at the American society of Hematology conference in December 2007 and since then we have had a longer follow up data on these 29 patients [16]. All patients who achieved a CR still continue to be in remission. The duration of CR in all our patients is now more than 18 months. The patient with the longest CR is now about 57 months since his treatment with rituximab. Of those patients who had a CR, although 2 patients relapsed, one after 12 months and other after 2 and half years, both received retreatment with rituximab and continue to be in second remis-

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Response to Rituximab as second line therapy 70

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Rate of response

60 50 40 31 30 20 7

10 0 CR

PR

No response

Type of response Fig. 1 Response rate in patients treated with Rituximab as second line therapy

Time to response after rituximab 12

Patients, responders

10 8 6 4 2 0 1

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Weeks after rituximab therapy

Fig. 2 Timing of response to rituximab therapy. Most patients responded within 4 weeks

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sion. Among 2 patients with PR, one relapsed after 2 years, while other one continues to be in PR at 2 and half years. 2.

Discussion Our study is a retrospective study with a small number of patients, hence with limitations. It is however one of the few studies looking at the role of rituximab in replacing splenectomy in patients with ITP. Comparing our results to the published data, our study shows comparable overall response rates, with higher CR rates and longer duration of response, even better with longer follow up. This could be due to the fact that our patients received rituximab as second line treatment, earlier in their disease course, prior to splenectomy. This concurs with some prior reports comparing effectiveness of rituximab in splenectomized and heavily pre treated patients versus non-splenectomized patients. Also 2 patients responded to retreatment in spite of relapsing after the first course of rituximab, though a small number may further point towards usefulness of rituximab in this patient population prior to splenectomy. The optimal dosing schedule for rituximab in ITP has not been established. In most reported series, it is used at 375 mg/m2 weekly for 4 weeks. In our patient series also, most received the above doses of rituximab, and it was well tolerated with minimal toxicity. However according to a study reported at ASH this year from Italy looking at rituximab in ITP at a lower fixed dose of 100 mg weekly for 4 weeks, showed comparable response rates though were short lived and delayed [17]. This definitely opens an area where more research needs to be done. We believe our study would support clinical trials like the one by Ostfold Hospital in Norway, which is currently looking prospectively to determine whether early treatment with rituximab can result in durable remissions, and consequently, lead to avoidance of splenectomy in a significant number of patients.

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Conclusion Based on our study we could conclude that rituximab is an effective option as a second line in patients with ITP, achieving higher durable response rates with minimal toxicity, especially prior to splenectomy, thereby avoiding the need for splenectomy. The optimal dosing in patients with ITP remains to be determined with future prospective clinical trials.

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