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- Material and methods
We report the long-term follow-up (median 39·5 months) of 49 paediatric patients (33 females and 16 males) with refractory symptomatic immune thrombocytopenic purpura (ITP) treated with rituximab. The overall response rate was 69% (34/49 patients). Twenty-one responders had a platelet count >50 × 109/l at a median 20·2 months from treatment. Kaplan–Meier analysis showed a probability of relapse-free survival (RFS) of 60% at 36 months from the first rituximab infusion. The number of infusions and a previous splenectomy did not influence overall response rate. Patients who achieved complete response were significantly older at diagnosis and first rituximab infusion than partial responders (P = 0·027). Older children displayed a significantly greater probability of sustained response (RFS) at 36 months than younger children (88·9% vs. 56·7%, P = 0·037). Earlier responses (within 20 d from treatment) were significantly associated with both complete (P = 0·004) and sustained response (P = 0·002). Only mild and transient side-effects were observed in 9/49 children; no major infections nor delayed toxicities were recorded during the follow-up.
Immune thrombocytopenic purpura (ITP) is an autoimmune disorder characterised by low platelet count and mucocutaneous bleeding; during childhood, the disease is usually benign and resolves spontaneously 6–18 months after diagnosis in most cases (Blanchette & Bolton-Maggs, 2008). Few patients fail to achieve an increase in platelet count in response to first-line treatments with intravenous immunoglobulin (IVIG) or steroids. A few children with refractory ITP present with repeated haemorrhages and must be aggressively treated with second-line therapies, such as vincristine, cyclophosphamide, azathioprine and cyclosporin A (Kalpatthi & Bussel, 2008).
Rituximab is a chimeric humanised IgG1/κ monoclonal antibody (Reff et al, 1994) first developed for the treatment of adult B-cell non-Hodgkin lymphoma (Cvetkovic & Perry, 2006). It targets the CD20 antigen on the surface of normal and malignant premature and mature B lymphocytes, and induces B cells destruction by means of both complement-mediated lysis and antibody-dependent cellular cytotoxicity. Induction of apoptosis has also been demonstrated (Flieger et al, 2000; Shan et al, 2000; Alas et al, 2001).
On the assumption that selective B-cell depletion stops the production of autoantibodies, in the past 10 years the use of rituximab has been extended to the treatment of autoimmune diseases (Garcia Hernandez et al, 2007; Garvey, 2008). Its efficacy and tolerability in the treatment of ITP have been shown in adults (Arnold et al, 2007) and children (Taube et al, 2005; Wang et al, 2005; Bennett et al, 2006; Parodi et al, 2006; Penalver et al, 2006; Rao et al, 2008), though its exact mechanism is still unknown. Few data are available regarding long-term follow-up analysis and prognostic factors in children.
This paper reports the long-term follow-up of all paediatric patients with refractory ITP treated with rituximab in the Haematology Units affiliated to the AIEOP (Italian Association of Paediatric Haematology and Oncology) to date.
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- Material and methods
The clinical data for 49 paediatric patients with refractory ITP who underwent rituximab treatment are reported. The efficacy and tolerability of this drug in both adult and childhood ITP have been already proven, but few data are available regarding long-term follow-up and prognostic factors in children. To our knowledge, this is the largest paediatric series and with the longest follow-up reported to date.
Overall response was observed in about 2/3 of patients. More than half of patients achieved a CR with the platelet count returning to normal levels.
The efficacy of treatment was consistent with data previously reported by Wang et al (2005) and Taube et al (2005), although both of these studies defined response as an increase in the platelet count to 30 × 109/l. However, in the series reported by Bennett et al (2006), a platelet count >50 × 109/l was reached by only 31%.
Our OR could be an expression of the natural course of the disease since some patients were treated in its very early stages when refractory to first-line treatments and seriously symptomatic. However, the absence of a correlation between duration of ITP prior to rituximab and sustained response (i.e. the presence of relapse in responding patients with a short disease duration) does not support the hypothesis of a spontaneous remission.
Twenty-one of the 34 (62%) of responders continued to maintain a normal platelet count at a median 20·2 months from rituximab administration. For some of them, the remission is the longest in the literature.
During the long follow-up, no delayed toxicities were registered. Only mild and transient side effects were observed in 18% of patients.
Most patients received four weekly infusions, according to the treatment schedule developed for oncology patients. However, the number of the infusions administered (i.e. the total dose of drug) did not influence the response rate. Our data match those previously reported in children treated with a single infusion (Taube et al, 2005), and adults treated with a single, fixed 100 mg dose (Provan et al, 2007).
These data confirm that further studies are warranted in order to determine the treatment schedule with the best cost:effectiveness ratio.
None of our responding patients required a further rituximab infusion and all displayed B-cell reconstitution (data not shown). If these data are confirmed in more patients and with a longer follow-up, this therapeutic option should be considered prior to splenectomy in order to defer or even avoid it (Godeau et al, 2006).
In spite of all the limitations because of the number of patients enrolled and the retrospective analysis of data, some factors predictive of complete response, i.e. older age and older age at time of rituximab administration, have been identified. Furthermore, patients that were pubertal at treatment presented a higher probability of sustained response than younger children.
The short time to achieving the cut-off platelet count of 50 × 109/l and the magnitude of the response were significantly associated with remission duration (sustained remission with return to normal platelet count).
As previously reported (Wang et al, 2005; Parodi et al, 2006; Penalver et al, 2006), two patterns of response were observed, confirming that rituximab acts through two or perhaps more mechanisms. If later responses may be related to the blockage of autoantibodies production secondary to the B-cell compartment depletion, other mechanisms may be implicated in earlier responses observed in the first days after the infusion.
An immunomodulant mechanism, i.e. a competitive blockade of FCγ receptors in the reticular endothelial system (the immune-complex decoy hypothesis) has been postulated (Taylor & Lindorfer, 2007). However, in our cohort, earlier responses were significantly associated with both a complete and a sustained response; these long-term remissions cannot be simply explained by this hypothesis. The exact mechanism of action of rituximab remains to be elucidated.
In conclusion, our data provide further evidence of the efficacy and safety of rituximab administration in refractory symptomatic paediatric ITP. Despite the small size of this study, the results suggest that rituximab is more effective in older paediatric patients, and that earlier responses are associated with a higher probability of a long-lasting response.