Vinblastine in the treatment of children and adolescents with refractory immune thrombocytopenia
Authors: Brice Fresneau, Arnaud Petit, Mary‐France Courcoux, Marie‐Dominique Tabone, Anne Auvrignon, Judith Landman‐Parker, Guy Leverger
Journal: American Journal of Hematology (2011)

Childhood immune thrombocytopenia (ITP) has a favorable outcome in most cases but severe bleeding may occur, mostly in children with very low platelet counts. Although first-line therapies are well defined, management of refractory ITP is not consensual. Vinblastine (VBL) is one second-line treatment in adult series. We reported all childhood refractory ITP treated with VBL in our unit in past 10 years. VBL was administered by four weekly injections (6 mg/m2/dose) in initial phase, followed by maintenance phase according to response and tolerance. Seventeen patients with refractory ITP, significant clinical bleeding (Buchanan bleeding score = 3), and platelet-count <20 × 109/L were treated with VBL. In the initial phase, response rate was 11/17. In these 11 patients, response rate in maintenance was 8/11 (in combination therapies in three cases) with a median duration of VBL treatment of 13 months (2–83); 1/11 had a loss of response and 2/11 stopped treatment because of side effect. Eleven patients had side effects, mainly neuropathic pain, completely reversible after dose reduction or treatment interruption. We conclude that VBL could be considered in the treatment schedule of childhood ITP: it could rapidly increase platelet count and sustain response, if necessary in combination therapies. ITP is an autoimmune disorder of adults and children [1]. Pathogenesis is multifactorial with increased platelet destruction and impaired thrombopoiesis [2]. Incidence of childhood ITP is 4.0–5.5 per 100,000 per year [3, 4]. In most cases it resolves spontaneously within 6 months. But 15–25% of children with primary ITP develop a chronic form [3, 4]. An international working group recently described three phases of the disease: newly diagnosed ITP, within 3 months from diagnosis; persistent ITP, between 3 and 12 months from diagnosis; and chronic ITP, for more than 12 months [1]. In persistent and chronic ITP, many children have a platelet count of more than 20 × 109/L. They are not symptomatic and need specific therapy only in case of surgery, dental extraction, or injury [5]. But when platelet count is less than 20 × 109/L, severe bleeding, in particular intracranial hemorrhage (ICH), may occur [6]. First-line therapies in childhood ITP are polyclonal intravenous immunoglobulin and corticosteroids [5, 7] but in case of no response or loss of response following these therapies, choice of treatment is not consensual [1]. In second-line therapies, medical treatments as rituximab, danazol, colchicine, azathioprine, or cyclosporine have been tried with variable efficiency [7, 8] but surgical treatment by splenectomy has still the best results with complete remission in 70% of patients [9], which is counter-balanced by side effects like infectious and thrombotic complications [10, 11]. As far as some results have been reported with vinca alkaloids (e.g., vincristine and VBL) in adult [12, 13] and childhood [14, 15] refractory ITP, we decided in 2001 to use VBL in our Pediatric Department of Hematology as a modality of standard care in second-line therapies of symptomatic persistent childhood ITP. Ten years later, while new therapies are available in ITP, we would like to report a monocentric retrospective analysis of VBL results in the treatment of children and adolescents with refractory primary ITP. Detailed results are presented in Table SI (Supporting Information). Seventeen patients with refractory ITP, ten males and seven females, median age at diagnosis 8 years (range 1–16), were treated by VBL in our department. Three children had no typical primary ITP: one of them (patient 4) suffered from Evans syndrome with autoimmune hemolytic anemia diagnosed and treated without recurrence at the age of five, 1 year before thrombocytopenia appeared; two other children (patients 9 and 11) had autoimmune neutropenia diagnosed in the same time period as ITP. Median time between diagnosis of ITP and VBL onset was 6 months (range 2–54). Twelve patients had persistent ITP (3–12 months), four had chronic ITP (>12 months) and one had acute ITP (treated before 3 months of evolution because of frequent hemorrhagic symptoms and early failure of intravenous immunoglobulin (IvIg) and corticosteroids). Median number of prior therapies was 2 (range 2–4): all patients received IvIg and prednisone before VBL onset. All patients suffered from significant clinical bleeding (Buchanan bleeding score = 3) with cutaneous and mucous membrane bleeding (with wet purpura on oral mucosa or epistaxis) and a platelet count <20 × 109/L at time of VBL onset (median 10 × 109/L, range 3–20 × 109/L). In 5/17 cases, VBL treatment was initiated in combination with prior insufficient therapies (IvIg: 3; IvIg-cyclosporine-prednisone: 1; prednisone: 1). Responses were classified as follows [1]: complete response (CR): platelet count >100 × 109/L and absence of bleeding; partial response (PR): platelet count >30 × 109/L and at least twofold increase in the baseline count and absence of bleeding; no response (NR): platelet count <30 × 109/L or less than twofold increase of baseline platelet count or bleeding. VBL-dependence was defined as the need for ongoing VBL injections in mono-therapy for at least 3 months to maintain platelet count at or above 30 × 109/L and to avoid bleeding. Responses were evaluated in initial and in maintenance phases. In initial phase, 1 week after the fourth injection, response rate was 11/17 (CR: 8; PR: 3; median platelet count: 151 × 109/L [range 41–250 × 109/L]). All but one occurred after first VBL injection. One more patient responded after first VBL injection but he did not maintain response after four injections. In maintenance, in these 11 patients, response rate was 8/11 with a median duration of VBL treatment of 13 months (range 2–83). 5/11 responded with a VBL mono-therapy maintenance regimen in a VBL-dependent manner (CR: 2; PR:3). 3/11 responded with drugs combination in maintenance regimen. 1/11 responded in maintenance with VBL and IvIg during 6 months before a loss of response leading to stop VBL treatment. 2/11 stopped VBL treatment in maintenance because of potential side effects. Regarding toxicity, VBL administration resulted in side effects in 11 children. Neurological toxicity was observed in five patients (mainly neuropathic pain). Neutropenia occurred in five patients (<0.5 × 109/L in two cases and between 0.5 and 1 × 109/L in three cases). Nausea occurred in three cases and partial hair loss in one case. All these side effects appeared after 1–6 injections, mostly in older children (3 children <5 years, 2 children 5–10 years, 6 children >10 years,) and were rapidly and completely reversed after dose reduction or treatment interruption. Due to their platelet-binding property, vinca alkaloids have been used in refractory ITP treatment [8]. VBL binds to tubulin [16] and concentrates mostly in platelets [17]; the antibody-coated platelet-drug complexes are then phagocytized by macrophages which are destroyed by the drug [18]. This action on the reticuloendothelial system explains why VBL is used in Langherans cell histiocytosis [19], as well as in ITP [20]. Recently, a previously unrecognized activity of VBL was described: this chemotherapeutic agent is able to induce phenotypic and functional maturation of dendritic cells in vitro [21]. In vivo, VBL could increase both humoral and cellular immune responses via dendritic cells [22]. These effects on dendritic cell maturation and host immunity could be implied in VBL response in ITP, but studies on dendritic cell roles in ITP pathophysiology are needed to explore this hypothesis. In adult patients, weekly vinca alkaloids slow infusions or bolus injections improve platelet count 7–10 days after first injection and lead to a sustained response rate of 15–50% [12, 13, 23-25]. In our retrospective monocentric study of VBL in children and adolescents with refractory ITP, it appears that VBL could control bleeding symptoms and rapidly increase platelet count (response rate in initial phase: 11/17). Afterward, response could be sustained with on-going VBL injections in mono-therapy (five cases) or in combination with intravenous immunoglobulin +/−cyclosporine (three cases). Differences in response rate based on clinical characteristics of treated patients (sex, age, anterior therapies, duration before VBL onset, platelets, and symptoms at VBL onset) were not significant given the limited sample size. This limited sample size is one limitation of the study. It is explained by low frequency of refractory ITP with significant clinical bleeding and very low platelet count. Other limitations are the retrospective nature of the study (e.g., lack of standardization of the criteria for VBL treatment, in particular number of prior therapies) and the use of drug combinations (difficulty to appropriately assess the impact of VBL on the therapeutic efficacy). Nevertheless, this article reports some cases of childhood ITP treated with VBL, a second-line therapy little studied in pediatrics patients [14, 15, 26]. Choudhry et al. [15] reported 10/16 partial to complete response in children with chronic ITP treated with weekly VBL bolus injection for 8 weeks and then monthly for 6 months, in association with danazol. Sustained remission occurred in 5 of these 10 patients after cessation oftherapy. Besides, in adult patients, vinca alkaloids have already been used successfully in combination with chemotherapies (cyclophosphamide, procarbazine, etoposide) [27] or with immunomodulators or immunosuppressive drugs (intravenous immunoglobulin, anti-D, corticosteroids, danazol, and azathioprine) [28]. In our experience, combination of VBL and intravenous immunoglobulin (+/−cyclosporine) could be used successfully in childhood refractory ITP with different action mechanisms (on reticuloendothelial system and on cellular immunity with autoreactive T cells). Regarding toxicity, in our report, side effects (in particular neuropathic pain and neutropenia) occurred in 11 children, mostly in initial phase. In all cases, they resolved completely and rapidly after a 33% dose reduction or after treatment interruption. In previous studies, side effects were less frequent. In conclusion, VBL could be considered in the treatment schedule in childhood ITP after failure of first-line therapies. It could control bleeding symptoms and increase rapidly platelet count after one injection. Prolonged response could be obtained with a maintenance regimen with gradually spaced injections of VBL (in combination with IvIg in case of insufficient response). However, further prospective studies are necessary to better assess VBL response in mono- and multi-agent therapies in childhood refractory ITP. While new treatments like thrombopoietin agonists or rituximab are now available in ITP, it is also necessary to evaluate which place it could be conferred on VBL in ITP treatment strategy. This report is a monocentric retrospective analysis of data recorded in medical files, for children and adolescents aged 0–18 years with refractory primary ITP who received one or several course(s) of VBL in their ITP specific treatment between 2001 and 2010 in the Pediatric Department of Hematology (Armand Trousseau Hospital, Paris, France). Diagnosis of ITP was made according to the guidelines of the American Society of Hematology [29]. First-line therapies used in our Pediatric Department of Hematology were IvIg and conventional or high-dose oral prednisone. In case of refractory ITP [1], various second-line therapies could have been used before VBL: intravenous anti-D rhesus immunoglobulin, rituximab monoclonal antibody, colchicine, hydroxychloroquine, dapsone, and cyclosporine. VBL was used in children and adolescents with primary persistent or chronic ITP who failed to respond to first-line therapies, with a platelet count of less than 20 × 109/L and cutaneous and mucous membrane bleeding symptoms (Buchanan bleeding score >2) [30]. In all cases, decision-making involved medical staff and parents who were well informed of potential benefits and harms of this treatment. VBL was administered at the dose of 6 mg/m2 of body surface area (maximal dose administered: 10 mg) by bolus intravenous injection. Four weekly injections were scheduled in initial phase. In most severe cases, VBL was initiated in combination with prior treatments. Continuation in maintenance regimen was dependent of response and tolerance. In responders, VBL injections were gradually spaced (from weekly to monthly) according to platelet count. In case of loss of response, IvIg were added. In case of adverse effects, a 33% VBL dose reduction was applied. If serious adverse effects occurred, or if side effects were badly tolerated by patient, VBL was stopped. In data analysis, criteria for assessing response to VBL were: bleeding symptoms (Buchanan bleeding score), platelet count, duration of VBL treatment, number of VBL injections, and drugs combinations. Authors thank G. Sebille, MD, for assistance in preparing the manuscript and helpful discussion. Additional Supporting Information may be found in the online version of this article. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. Brice Fresneau [email protected]*, Arnaud Petit* , Mary-France Courcoux*, Marie-Dominique Tabone*, Anne Auvrignon* , Judith Landman-Parker* , Guy Leverger* , * Pediatric Hematology Unit, Armand-Trousseau University Hospital, Paris, France, UPMC Université Pierre et Marie Curie, UMR S 938, Saint-Antoine research centre, Paris, France.