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 Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 43  |  Issue : 1  |  Page : 5-9

The use of anti-CD20 in management of Egyptian children with chronic immune thrombocytopenic purpura


Pediatric Hematology, Oncology and Bone Marrow Transplantation Unit, Pediatric Department, Faculty of Medicine, Mansoura University, Egypt

Date of Submission07-Oct-2017
Date of Acceptance14-Nov-2018
Date of Web Publication3-Aug-2018

Correspondence Address:
Suzy Abdelmabood
Pediatric Hematology, Oncology & Bone Marrow Transplantation Unit, Pediatric Department, Faculty of Medicine, Mansoura University, Egypt, Mansoura University Children Hospital, 35516, Mansoura
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ejh.ejh_44_17

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  Abstract 


Background/aim Chronic immune thrombocytopenic purpura (ITP) is an immune-mediated platelet destruction, with decreased platelet count to less than 100×109/l for more than 12 months. Overall, 5–10% of children with chronic ITP experience serious bleeding, and their treatment is challenging. Rituximab is one of treatment options. Our aim is to evaluate low-dose rituximab in the management of childhood chronic ITP.
Patients and methods Twenty-eight children with primary chronic ITP were prospectively administered rituximab at a dose of 100 mg/week for 4 weeks and followed up for 1 year.
Results The initial response showed that 12/28 (42.8%) achieved complete remission, 2/28 (7%) minimal remission and 14/28 (50%) no remission. No significant differences were detected between responders and nonresponders regarding age and sex (P=0.94 and 0.59, respectively), except that the duration of the disease was significantly longer among nonresponders (P=0.025). The outcome after 1-year follow-up was as follows: one patient lost to follow-up, 14/28 (50%) were nonresponders, 8/28 (28%) relapsed, and 6/28 (21%) maintain sustained remission.
Conclusion Rituximab is one of treatment choices for chronic ITP in children with convincing initial results; however, failure to achieve sustained remission is still a problem.

Keywords: immune thrombocytopenic purpura, platelet count, rituximab, thrombocytopenia


How to cite this article:
Abdelmabood S, Sarhan MM. The use of anti-CD20 in management of Egyptian children with chronic immune thrombocytopenic purpura. Egypt J Haematol 2018;43:5-9

How to cite this URL:
Abdelmabood S, Sarhan MM. The use of anti-CD20 in management of Egyptian children with chronic immune thrombocytopenic purpura. Egypt J Haematol [serial online] 2018 [cited 2019 Dec 13];43:5-9. Available from: http://www.ehj.eg.net/text.asp?2018/43/1/5/238543




  Introduction Top


Immune thrombocytopenic purpura (ITP) is defined as an immune-mediated destruction of the platelets, with resulting decreased platelet count and increased bleeding tendency [1]. It affects 4–6/100 000 children per year [2]. Chronic ITP refers to platelet count of less than 100 000/mm3 for more than 12 months [3]. Chronic ITP in children usually carries less severe course than adults, with increased likelihood of spontaneous resolution within 1–2 years; therefore, many hematologists prefer to keep those having no major bleeding episodes only under observation. However, 5–10% of children with chronic ITP experience serious bleeding, and their treatment remains a real challenge, as there is limited experience about the best second-line therapy [2]. Many treatment options considering different mechanisms of chronic ITP for severe chronic and/refractory cases are suggested such as splenectomy, rituximab, and thrombopoietin receptor agonists [4],[5]. Rituximab is a monoclonal anti-CD20 antibody. It attacks B lymphocytes, causing their depletion, to eradicate antiplatelet antibody production and thus sparing platelets from destruction [6],[7],[8]. In this work, we studied the effect of administration of once weekly low dose of rituximab for four doses for treatment of children with chronic primary ITP as a second-line therapy.


  Patients and methods Top


A prospective study was conducted on 28 nonsplenectomized children (<18 years) with severe chronic ITP whose platelet count was less than 30×109/l in spite of previous treatment with corticosteroids, intravenous immunoglobulin (Ig) and anti-D-Ig. The study protocol was approved before conducting the research work by Institutional Review Board (IRB) of Faculty of Medicine, Mansoura University. They were recruited from Pediatric Hematology Unit, Mansoura University Children Hospital, Egypt. They were reevaluated by bone marrow examination, serological test for HIV, hepatitis C and B, and immunological profile to exclude secondary causes of thrombocytopenia. All patients’ parents were consented in accordance with the declaration of Helsinki before starting rituximab as a second-line therapy for their children. Rituximab was administered to all patients in a low dose of 100 mg once per week for consecutive 4 weeks. It was diluted in 250 ml of 5% dextrose − water solution and administered over a period of 4 h intravenously. Antipyretic and antihistaminic drugs were administered 30 min before rituximab infusion as premedication preparations. They were scheduled for outpatient monthly follow-up visits for at least 12 months using platelet count. Patients were considered to achieve complete remission when platelet count is more than 100×109/l, partial remission when platelet count was ranging from 50×109/l to less than 100×109/l, minimal response when platelet count was less than 50×109/l and more than 30×109/l, and no response when platelet count was still less than 30×109/l [1].

Statistical analysis

Statistical analysis was carried out using statistical package for social sciences, version 16 (Statistical Package for the Social Sciences, SPSS Inc., Chicago, IL, USA). Numerical variables were expressed in median and range. Comparison between groups was done using Mann–Whitney U-test or Pearson’s χ2-test. P value less than 0.05 was considered to be statistically significant.


  Results Top


Twenty-eight patients (14/28 were males and 14/28 were females) participated in this study and received weekly doses of rituximab for 4 consecutive weeks. Patients’ characteristics are shown in [Table 1]. The median age of the patient group was 8.6 years (ranging from 5.6–17.00). The patients manifested different types of bleeding (18 mucocutaneous bleeding, 12 bleeding per gum, eight epistaxis, four hematemesis, and four by abnormal uterine bleeding). Disease characteristics and initial response to rituximab are demonstrated in [Table 2]. The median baseline platelet count was 12×109/l (ranging from 1 to 19). The median duration since ITP diagnosis was 2.4 years (ranging from 1.25 to 5.8). The median period lapsed since first dose of rituximab till achievement of response in initial responders was 21 days (ranging from 7 to 28). Overall, 50% of the patients (14 of 28) were initially responders to rituximab (12 achieved complete remission and two achieved minimal response) whereas the other half of the patients (14) failed to achieve any increment in their platelet count (no response). [Table 3] compares between initial responders and nonresponders regarding patient and disease characteristics. Neither age nor sex was significantly different between responders and nonresponders groups (P=0.94 and 0.59, respectively), whereas the duration of the disease was significantly shorter in responders versus nonresponders groups (P=0.025). [Figure 1] illustrates the scheme for patients with chronic ITP receiving rituximab and their outcome after 1-year follow-up. [Figure 2] demonstrates the duration of remission for initial responders to rituximab and the time of their relapse (two relapsed at the fifth month, one at the seventh month, and one at the eighth month of follow-up), and 21% of patients succeeded to maintain sustained remission till the 12th month of follow-up.
Table 1 Characteristics of patients with chronic immune thrombocytopenic purpura

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Table 2 Disease characteristics and initial response to therapy

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Table 3 Comparison between initial responders and nonresponders to rituximab according to patient and disease characteristics

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Figure 1 Scheme for response to rituximab treatment in patients with chronic immune thrombocytopenic purpura (ITP) and their follow-up. CR, complete remission; MR, minimal response.

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Figure 2 One-year follow-up for initial rituximab responders.

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  Discussion Top


Although chronic ITP in children usually leads a benign course than does in adults, management of severe symptomatic cases represents a difficult task for hematologists [2]. Many treatment strategies involving different mechanisms of chronic ITP were recommended for those patients [4],[5]. The American Society of Hematology consensus review in 2010 considered splenectomy, cyclosporine A, cyclophosphamide, danazol, azathioprine, rituximab, mycophenolate mofetil, and thrombopoietin receptor agonists, eltrombobag or romiplostim, as second lines [9]. Each medication has its own potential adverse effect; therefore, hematologists should select thoroughly those patients who are actually in need for second-line therapy and discuss promptly with them and their caregivers these issues [9].

In the current work, we tried to evaluate the efficacy of rituximab in the management of chronic ITP in children. Half of the patients showed initial remission. This is more or less similar to the results of a multicenter study in which initial remission was reported in 57% of the patients [10]. Although rituximab dose in our study is different from that of aforementioned study, the initial response seemed to be similar. This supports the results of Zaja et al. [11] who concluded that lower dose of rituximab (four weekly doses of 100 mg intravenously) had similar effect to standard dose (four weekly doses of 375 mg/m2).

Neither the age nor the sex was significantly different among responder and nonresponder groups to rituximab therapy; this is similar to the previous studies [10],[12]. However, the duration of ITP was significantly longer among nonresponder group. Garcia-Chavez et al. [12] reported similar finding, as the patients with longer duration of ITP and who were intensively treated before had worse response to ITP. The possible explanation for that is the refractory course of the immune system of those patients with longer duration of ITP receiving repeated intensive courses of immune-suppressive therapies. Furthermore, different mechanisms emerged to take place in the pathogenesis of chronic ITP other than the immune mechanism (such as decreased platelet production by bone marrow) [13].

Median time to attain response to rituximab was 21 days (ranging from 7 to 28). These results are more or less consistent with those of two previous studies using rituximab in children with chronic ITP [14],[15]. However, they are different from the results of a systematic review about the efficacy of rituximab in adults, which found longer median time required to achieve rituximab response (5.5 weeks) [16]. This is may be related to an important factor influencing the response to treatment in adulthood, which is splenectomy, especially more than half of their patients (53.8%) underwent splenectomy and splenectomy was associated with delayed response to rituximab [16]. Unlike the aforementioned systematic review, none of our patient underwent splenectomy.

Splenectomy was not done for anyone of our patients because of many reasons: first, although splenectomy is a well-known line of treatment in adults with chronic ITP, there is limited experience about its effectiveness in children. Furthermore, after splenectomy, overwhelming bacterial infection is still a challenge for clinicians inspite of antimicrobial prophylaxis and vaccinations [17]. Lastly, rituximab is considered as an alternative to splenectomy in children and adolescent with chronic ITP [18].

Rituximab therapy during the current study was well tolerated with no serious adverse events being reported. Only mild adverse effects were faced such as fever, flushing, and itching, which responded well to anti-inflammatory and antipyretic drugs. This was agreed by previous studies that did not document major toxicities or severe adverse effects [10],[12].

The elevation in the platelet count in response to rituximab administration in the responders seemed to be a fast response. In most of the patients, this occurred within the first 3 weeks. Such rapid response was explained by Stasi et al. [19] to be secondary to inhibition of the macrophage Fc-receptor function and prevention of IgG-coated platelets clearance by opsonized B cells rather than decrease in the antiplatelet antibody production in the circulation. Their hypothesis was supported by a few of their patients (6/25) who had low level of IgM and IgG, and flow cytometric analysis confirmed reduction of the circulating B cells after the first infusion of rituximab.

Although the initial response to rituximab as a second-line therapy for children with chronic ITP seems to be convincing for hematologists, the sustained remission for responders is still disappointing. This was explained by Coopamah et al. [20] who suggested that the normalization of Tcell upsets [e.g. elevated Th1/Th2 (and Tc1/Tc2) cytokine ratios, elevated CD4, Tcell-associated Bcl-2/ Baxm RNA levels, and oligoclonal T-cell expansion] in chronic ITP can be normalized by modifying B cell activity using anti-CD20 with transient efficacy lasting for 6–12 months only; nevertheless, the mechanism on how B-cell population can modulate the activity of T cells is still a matter of research.


  Conclusion Top


Treatment choices of chronic ITP in children are diverse. Rituximab is one of them, with convincing initial results; however, failure to achieve sustained remission is still a challenge. Further researches are required to understand the mechanism of chronicity of ITP and thus offering more treatment options for indicated individuals.

Acknowledgements

The authors thank patients, their families, nurses, and physicians in Mansoura University Children Hospital, Mansoura, Egypt for their trust and cooperation to accomplish this work.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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