Intravenous immunoglobulin with prednisone and risk-adapted chemotherapy for children with opsoclonus myoclonus ataxia syndrome associated with neuroblastoma (ANBL00P3): a randomised, open-label, phase 3 trial

Pedro A de Alarcon, Katherine K Matthay, Wendy B London, Arlene Naranjo, Sheena C Tenney, Jessica A Panzer, Michael D Hogarty, Julie R Park, John M Maris, Susan L Cohn, Pedro A de Alarcon, Katherine K Matthay, Wendy B London, Arlene Naranjo, Sheena C Tenney, Jessica A Panzer, Michael D Hogarty, Julie R Park, John M Maris, Susan L Cohn

Abstract

Purpose: No previous clinical trial has been conducted for patients with neuroblastoma associated opsoclonus myoclonus ataxia syndrome (OMA), and current treatment is based on case reports. To evaluate the OMA response to prednisone and risk-adapted chemotherapy and determine if the addition of intravenous gammaglobulin (IVIG) further improves response, the Children's Oncology Group designed a randomized therapeutic trial.

Patient and methods: Eligible subjects were randomized to receive twelve cycles of IVIG (IVIG+) or no IVIG (NO-IVIG) in addition to prednisone and neuroblastoma risk-adapted chemotherapy. All low-risk patients were treated with cyclophosphamide. The severity of OMA symptoms was evaluated at 2, 6, and 12 months using a scale developed by Mitchell and Pike and baseline versus best response scores were compared. A single patient who did not undergo neurologic assessment was excluded from OMA response analysis. This study is registered with Clinical Trials.gov (identifier NCT00033293).

Results: Of the 53 patients enrolled in the study, 62% (33/53) were female. There were 44 low-risk, 7 intermediate-risk, and 2 high-risk neuroblastoma patients. Twenty-six subjects were randomized to receive IVIG+ and 27 were randomized to NO-IVIG. The neuroblastoma 3-year event-free survival (95% confidence interval (CI)) was 94.1% (87.3%, 100%) and overall survival was 98.0% (94.1%, 100%). Significantly higher rates of OMA response were observed in patients randomized to IVIG+ compared to NO-IVIG [21/26=80.8% for IVIG+; 11/27=40.7% for NO-IVIG (odds ratio=6.1; 95% CI: (1.5, 25.9), p=0.0029)]. For the majority of patients, the IVIG+ OMA regimen combined with cytoxan or other risk-based chemotherapy was well tolerated, although there was one toxic death in a high-risk subject.

Conclusion: This is the only randomized prospective therapeutic clinical trial in children with neuroblastoma-associated OMA. The addition of IVIG to prednisone and risk-adapted chemotherapy significantly improves OMA response rate. IVIG+ constitutes a back-bone upon which to build additional therapy.

Conflict of interest statement

Declaration of Interests: All the authors equally contributed to the preparation of this manuscript. The authors have no conflicts of interest to declear.

Figures

Figure 1
Figure 1
Study Design Schema for COG Study ANBL00P3 * OMA evaluation time points include: at Dx, monthly for 6 months, then every other month until 1 year, 18 months, 2 years and yearly thereafter two months, six months and one year.
Figure 2
Figure 2
CONSORT Diagram for COG Study ANBL00P3
Figure 3
Figure 3
a. Neuroblastoma event-free, OMA progression-free, and overall survival of the overall patient cohort (n=53) b. OMA progression-free survival for IVIG+ (n=26) versus NO-IVIG (n=27)

References

    1. Matthay KK, Blaes F, Hero B, Plantaz D, de AP, Mitchell WG, et al. Opsoclonus myoclonus syndrome in neuroblastoma a report from a workshop on the dancing eyes syndrome at the advances in neuroblastoma meeting in Genoa, Italy, 2004. Cancer Lett. 2005;228(1–2):275–282.
    1. Howlader N, Noone AM, Krapcho M, Miller D, Bishop K, Kosary CL, et al. SEER Cancer Statistics Review, 1975–2014. National Cancer Institute; Bethesda, MD: 2017.
    1. Pang KK, de SC, Lang B, Pike MG. A prospective study of the presentation and management of dancing eye syndrome/opsoclonus-myoclonus syndrome in the United Kingdom. Eur J Paediatr Neurol. 2010;14(2):156–161.
    1. Krug P, Schleiermacher G, Michon J, Valteau-Couanet D, Brisse H, Peuchmaur M, et al. Opsoclonus-myoclonus in children associated or not with neuroblastoma. Eur J Paediatr Neurol. 2010;14(5):400–409.
    1. De Grandis E, Parodi S, Conte M, Angelini P, Battaglia F, Gandolfo C, et al. Long-term follow-up of neuroblastoma-associated opsoclonus-myoclonus-ataxia syndrome. Neuropediatrics. 2009;40(3):103–111.
    1. Russo C, Cohn SL, Petruzzi MJ, de Alarcon PA. Long-term neurologic outcome in children with opsoclonus-myoclonus associated with neuroblastoma: a report from the Pediatric Oncology Group. Med Pediatr Oncol. 1997;28(4):284–288.
    1. Blaes F, Fuhlhuber V, Korfei M, Tschernatsch M, Behnisch W, Rostasy K, et al. Surface-binding autoantibodies to cerebellar neurons in opsoclonus syndrome. Ann Neurol. 2005;58(2):313–317.
    1. Blaes F, Pike MG, Lang B. Autoantibodies in childhood opsoclonus-myoclonus syndrome. J Neuroimmunol. 2008;201–202:221–226.
    1. Pranzatelli MR, Travelstead AL, Tate ED, Allison TJ, Moticka EJ, Franz DN, et al. B- and T-cell markers in opsoclonus-myoclonus syndrome: immunophenotyping of CSF lymphocytes. Neurology. 2004;62(9):1526–1532.
    1. Pranzatelli MR, Tate ED, McGee NR, Travelstead AL, Colliver JA, Ness JM, et al. BAFF/APRIL system in pediatric OMS: relation to severity, neuroinflammation, and immunotherapy. J Neuroinflammation. 2013;10:10.
    1. Bataller L, Rosenfeld MR, Graus F, Vilchez JJ, Cheung NK, Dalmau J. Autoantigen diversity in the opsoclonus-myoclonus syndrome. Ann Neurol. 2003;53(3):347–353.
    1. Raffaghello L, Conte M, De GE, Pistoia V. Immunological mechanisms in opsoclonus-myoclonus associated neuroblastoma. Eur J Paediatr Neurol. 2009;13(3):219–223.
    1. Pranzatelli MR, Tate ED, Travelstead AL, Barbosa J, Bergamini RA, Civitello L, et al. Rituximab (anti-CD20) adjunctive therapy for opsoclonus-myoclonus syndrome. J Pediatr Hematol Oncol. 2006;28(9):585–593.
    1. Pranzatelli MR, Tate ED, Shenoy S, Travelstead AL. Ofatumumab for a rituximab-allergic child with chronic-relapsing paraneoplastic opsoclonus-myoclonus. Pediatr Blood Cancer. 2012;58(6):988–991.
    1. Pinto NR, Applebaum MA, Volchenboum SL, Matthay KK, London WB, Ambros PF, et al. Advances in Risk Classification and Treatment Strategies for Neuroblastoma. J Clin Oncol. 2015;33(27):3008–3017.
    1. Baker DL, Schmidt ML, Cohn SL, Maris JM, London WB, Buxton A, et al. Outcome after reduced chemotherapy for intermediate-risk neuroblastoma. N Engl J Med. 2010;363(14):1313–1323.
    1. Kreissman SG, Rackoff W, Lee M, Breitfeld PP. High dose cyclophosphamide with carboplatin: a tolerable regimen suitable for dose intensification in children with solid tumors. J Pediatr Hematol Oncol. 1997;19(4):309–312.
    1. Strother DR, London WB, Schmidt ML, Brodeur GM, Shimada H, Thorner P, et al. Outcome after surgery alone or with restricted use of chemotherapy for patients with low-risk neuroblastoma: results of Children’s Oncology Group study P9641. J Clin Oncol. 2012;30(15):1842–1848.
    1. Cohn SL, Pearson AD, London WB, Monclair T, Ambros PF, Brodeur GM, et al. The International Neuroblastoma Risk Group (INRG) classification system: an INRG Task Force report. J Clin Oncol. 2009;27(2):289–297.
    1. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53:457–481.
    1. Peto R, Pike MC, Armitage P, Breslow NE, Cox DR, Howard SV, et al. Design and analysis of randomized clinical trials requiring prolonged observation of each patient. II. analysis and examples. Br J Cancer. 1977;35(1):1–39.
    1. Shimada H, Ambros IM, Dehner LP, Hata J, Joshi VV, Roald B. Terminology and morphologic criteria of neuroblastic tumors: recommendations by the International Neuroblastoma Pathology Committee. Cancer. 1999;86(2):349–363.
    1. Petruzzi MJ, de Alarcon PA. Neuroblastoma-associated opsoclonus-myoclonus treated with intravenously administered immune globulin G. J Pediatr. 1995;127(2):328–329.
    1. Borgna-Pignatti C, Balter R, Marradi P, Colamaria V. Treatment with intravenously administered immunoglobulins of the neuroblastoma-associated opsoclonus-myoclonus. J Pediatr. 1996;129(1):179–180.
    1. Davis S, Rogers MA, Pendergrass TW. The incidence and epidemiologic characteristics of neuroblastoma in the United States. Am J Epidemiol. 1987;126(6):1063–1074.
    1. Catsman-Berrevoets CE, Aarsen FK, van Hemsbergen ML, van Noesel MM, Hakvoort-Cammel FG, van den Heuvel-Eibrink MM. Improvement of neurological status and quality of life in children with opsoclonus myoclonus syndrome at long-term follow-up. Pediatr Blood Cancer. 2009;53(6):1048–1053.
    1. Hasegawa S, Matsushige T, Kajimoto M, Inoue H, Momonaka H, Oka M, et al. A nationwide survey of opsoclonus-myoclonus syndrome in Japanese children. Brain Dev. 2014
    1. Singhi P, Sahu JK, Sarkar J, Bansal D. Clinical profile and outcome of children with opsoclonus-myoclonus syndrome. J Child Neurol. 2014;29(1):58–61.
    1. Korfei M, Fuhlhuber V, Schmidt-Woll T, Kaps M, Preissner KT, Blaes F. Functional characterisation of autoantibodies from patients with pediatric opsoclonus-myoclonus-syndrome. J Neuroimmunol. 2005;170(1–2):150–157.
    1. Mitchell WG, Wooten AA, O’Neil SH, Rodriguez JG, Cruz RE, Wittern R. Effect of Increased Immunosuppression on Developmental Outcome of Opsoclonus Myoclonus Syndrome (OMS) J Child Neurol. 2014;30(8):976–982.

Source: PubMed

Sponsorzy i współpracownicy

Warunki medyczne

Interwencje lekowe

3
Subskrybuj