High-dose chemotherapy with autologous hematopoietic stem cell transplantation in high-risk neuroblastoma patients: Raisa Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation, First Pavlov State Medical University of St. Petersburg experience

Introduction. Neuroblastoma (NB) is the most common extracranial pediatric solid tumor. The high-risk group patients are characterized by adverse prognosis and require intensive complex therapy including high-dose chemotherapy (HDCT) with hematopoietic stem cell transplantation (auto-HSCT). The current study presents a single center experience of HSCT with auto-HSCT for high-risk NB performed in Raisa Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation, First Pavlov State Medical University of St. Petersburg, Ministry of Health of Russia.

Patients and methods. A cohort of 72 consecutive high-risk NB patients was included in the study. Among them 69 patients received Bu-Mel conditioning regimen (busulfan 16 mg/kg, melphalan 140 mg/m2 ), in 3 patients the 5D/5D regimen was used (carboplatin 1000 mg/m2 , irinotecan 150 mg/m2 , temozolomide 750 mg/m2 , etoposide 400 mg/m2 , cyclophosphamide 140 mg/kg). In most cases the autologous hematopoietic stem cells source was bone marrow (BM) (n = 59; 82 %), peripheral blood stem cells (PBSC) (n = 11; 15 %), or BM and PBSC (n = 2; 3 %). In 52/66 (79 %) patients with initial bone marrow involvement the potential transplant contamination was assessed by flow cytometry.

Results. The 2-year and 5-year overall (OS) and event-free (EFS) survival was 61 % and 48 %, 41 % and 35 % accordingly. The main adverse factors for OS and EFS were age of more than 18 months at diagnosis, combined bone marrow and bones involvement, MYCN amplification, initial neuron-specific enolase level of more than 100 ng/ml, primary resistance or relapse, and metaiodobenzylguanidinepositive lesions persistence prior to or after HSCT with auto-HSCT.

Conclusions. The results achieved are comparable to those described for similar cohorts. Some patient subgroups are unlikely to achieve response after HSCT with auto-HSCT. Therefore, additional stratification methods and treatment modalities are needed.

Conflict of interest. The authors declare no conflict of interest.

Funding. The study was performed without external funding.

1. Мень Т.Х., Поляков В.Г., Алиев М.Д. Эпидемиология злокачественных новообразований у детей в России. Онкопедиатрия 2014;1:7–13. [Men T.Kh., Polyakov V.G., Aliyev M.D. Epidemiology of malignant neoplasms in children in Russia. Onkopediatriya = Oncopediatrics 2014;1:7–13. (In Russ.)].

2. Maris J., Hogarty M., Bagatell R., Cohn S.L. Neuroblastoma. Lancet 2007;369(9579):2106–20. doi: 10.1016/S0140-6736(07)60983-0.

3. Smith M.A., Alterkruse S.F., Adamson P.C., Reaman G.H., Seibel N.L. Declining childhood and adolescent cancer mortality. Cancer 2014;120(16):2497–506. doi: 10.1002/cncr.28748.

4. Pinto N.R., Applebaum M.A., Volchenboum S.L., Matthay K.K., London W.B., Ambros P.F., Nakagawara A., Berthold F., Schleiermacher G., Park J.R., Valteau-Couaned D., Pearson A.D., Cohn S.L. Advances in Risk Classifi cation and Treatment Strategies for Neuroblastoma. J Clin Oncol 2015;33(27):3008–17. doi: 10.1200/JCO.2014.59.4648.

5. Maris J. Recent Advances in Neuroblastoma. N Engl J Med 2010;362(23):2202–11. doi: 10.1056/NEJMra0804577.

6. Matthay K.K., Shulkin B., Ladenstein R., Michon J., Giammarile F., Lewington V., Pearson A.D., Cohn S.L. Criteria for evaluation of disease extent by (123)I-metaiodobenzylguanidine scans in neuroblastoma: a report for the International Neuroblastoma Risk Group (INRG) Task Force. Br J Cancer 2010;102(9):1319–26. doi: 10.1038/sj.bjc.6605621.

7. Cohn S.L., Pearson A.D., London W.B., Monclair T., Ambros P.F., Brodeur G.M., Faldum A., Hero B., Iehara T., Machin D., Mosseri V., Simon T., Garaventa A., Castel V., Matthay K.K.; INRG Task Force. The International Neuroblastoma Risk Group (INRG) classifi cation system: an INRG Task Force report. J Clin Oncol 2009;27(2):289–97. doi: 10.1200/JCO.2008.16.6785.

8. Ward E., DeSantis C., Robbins A., Kohler B., Jemal A. Childhood and adolescent cancer statistics, 2014. CA Cancer J Clin 2014;64(2):83–103. doi: 10.3322/caac.21219.

9. Matthay K.K., Reynolds C.P., Seeger R.C., Shimada H., Adkins E.S., Haas-Kogan D., Gerbing R.B., London W.B., Villablanca J.G. Longterm results for children with high-risk neuroblastoma treated on a randomized trial of myeloablative therapy followed by 13-cisretinoic acid: a children’s oncology group study. J Clin Oncol 2009;27(7):1007–13. doi: 10.1200/JCO.2007.13.8925.

10. Berthold F., Ernst A., Hero B., Klingebiel T., Kremens B., Schilling F.H., Simon T. Long-term outcome of the GPOH NB97 trial for children with high-risk neuroblastoma comparing high-dose chemotherapy with autologous stem cell transplantation and oral chemotherapy as consolidation. Br J Cancer 2018;119(3):282–90. doi: 10.1038/s41416-018-0169-8.

11. Шаманская Т.В., Качанов Д.Ю., Андреев Е.С., Талыпов С.Р., Хисматуллина Р.Д., Шевцов Д.В., Скоробогатова Е.В., Киргизов К.И., Хачатрян Л.А., Рощин В.Ю., Ольшанская Ю.В., Осипова Е.Ю., Казакова А.Н., Терещенко Г.В., Щербаков А.П., Ликарь Ю.Н., Райкина Е.В., Феоктистова Е.В., Нечеснюк А.В., Грачёв Н.С., Фомин Д.К., Масчан М.А., Варфоломеева С.Р. Результаты терапии пациентов с нейробластомой группы высокого риска. Российский журнал детской гематологии и онкологии (специальный номер) 2018:88;тезис № 533. [Shamanskaya T.V., Kachanov D.Yu., Andreev E.S., Talypov S.R., Khismatullina R.D., Shevtsov D.V., Skorobogatova E.V., Kirgizov K.I., Khachatryan L.A., Roshchin V.Yu., Olshanskaya Yu.V., Osipova E.Yu., Kazakova A.N., Tereshchenko G.V., Shcherbakov A.P., Likar Yu.N., Raikina E.V. , Feoktistova E.V., Nechesnyuk A.V., Grachev N.S., Fomin D.K., Maschan M.A., Varfolomeeva S.R. Results of treatment of patients with high-risk neuroblastoma. Rossiyskiy zhurnal detskoy gematologii i onkologii = Russian Journal of Pediatric Hematology and Oncology (special number) 2018:88;abstr. 533. (In Russ.)].

12. Хижников А.В., Казанцев А.П. Лечение пациентов с нейробластомой группы высокого риска. Онкопедиатрия 2017;4(2):131–40. doi: 10.15690/onco.v4i2.1707. [Khizhnikov A.V., Kazantsev A.P. Treatment of patients with high-risk neuroblastoma. Onkopediatriya = Oncopediatrics 2017;4(2):131–40. (In Russ.)].

13. Скоробогатова Е.В., Балашов Д.Н., Трахтман П.Е., Масчан А.А., Румянцев А.Г., Киргизов К.И. Итоги двадцатилетнего опыта трансплантации гемопоэтических стволовых клеток у детей. Педиатрия 2011;90(4):12–6. [Skorobogatova E.V., Balashov D.N., Trakhtman P.E., Maschan A.A., Rumyantsev A.G., Kirgizov K.I. The results of twenty years of experience in hematopoietic stem cell transplantation in children. Pediatriya = Pediatrics 2011;90(4):12–6. (In Russ.)].

14. Corbacioglu S., Carreras E., Ansari M., Balduzzi A., Cesaro S., Dalle J.H., Dignan F., Gibson B., Guengoer T., Gruhn B., Lankester A., Locatelli F., Pagliuca A., Peters C., Richardson P.G., Schulz A.S., Sedlacek P., Stein J., Sykora K.W., Toporski J., Trigoso E., Vetteranta K., Wachowiak J., Wallhult E., Wynn R., Yaniv I., Yesilepek A., Mohty M., Bader P. Diagnosis and severity criteria for sinusoidal obstruction syndrome/veno-occlusive disease in pediatric patients: a new classifi cation from the European society for blood and marrow transplantation. Bone Marrow Transplant 2018;53(2):138–45. doi: 10.1038/bmt.2017.161.

15. Morgenstern D.A., Pötschger U., Moreno L., Papadakis V., Owens C., Ash S., Pasqualini C., Luksch R., Garaventa A., Canete A., Elliot M., Wieczorek A., Laureys G., Kogner P., Malis J., Ruud E., Beck-Popovic M., Schleiermacher G., Valteau-Couanet D., Ladenstein R. Risk stratifi cation of high-risk metastatic neuroblastoma: A report from the HR-NBL-1/SIOPEN study. Pediatr Blood Cancer 2018;65(11):e27363. doi: 10.1002/pbc.27363.

16. Georantzi K., Sköldenberg E.G., Stridsberg M., Kogner P., Jakobson Å., Janson E.T., Christoff erson R.H.B. Chromogranin A and neuronspecifi c enolase in neuroblastoma: Correlation to stage and prognostic factors. Pediatr Hematol Oncol 2018;35(2):156–65. doi: 10.1080/08880018.2018.1464087.

17. Cheung N.K., Zhang J., Parker M., Bahrami A., Tickoo S.K., Heguy A., Pappo A.S., Federico S., Dalton J., Cheung I.Y., Ding L., Fulton R., Wang J., Chen X., Becksfort J., Wu J., Billups C.A., Ellison D., Mardis E.R., Wilson R.K., Downing J.R., Dyer M.A.; St Jude Children’s Research Hospital – Washington University Pediatric Cancer Genome Project. Association of age at diagnosis and genetic mutations in patients with neuroblastoma. JAMA 2012;307(10):1062–71. doi: 10.1001/jama.2012.228.

18. Suzuki M., Kushner B.H., Kramer K., Basu E.M., Roberts S.S., Hammond W.J., LaQuaglia M.P., Wolden S.L., Cheung N.V., Modak S. Treatment and outcome of adult-onset neuroblastoma. Int J Cancer 2018;143(5):1249–58. doi: 10.1002/ijc.31399.

19. Berthold F., Hömberg M., Proleskovskaya I., Mazanek P., Belogurova M., Ernst A., Sterba J. Metronomic therapy has low toxicity and is as eff ective as current standard treatment for recurrent high-risk neuroblastoma. Pediatr Hematol Oncol 2017;37(5):308–19. doi: 10.1080/08880018.2017.1373314.

20. Kalra R., Zoger S., Kosovich M.S., Matthay K.K. Radiological case of the month. Miliary pulmonary neuroblastoma. Arch Pediatr Adolesc Med 1995;149(2):195–6.

21. Попов А.М., Шориков Е.В., Вержбицкая Т.Ю., Цаур Г.А., Друй А.Е., Солодовников А.Г., Савельев Л.И., Фечина Л.Г. Прогностическое значение определения поражения костного мозга у детей с нейробластомой методом проточной цитометрии. Вопросы онкологии 2014;60(4):470–6. [Popov A.M., Shorikov E.V., Verzhbitskaya T.Yu., Tsaur G.A., Druy A.E., Solodovnikov A.G., Saveliev L.I., Fechina L.G. The prognostic value of determining bone marrow damage in children with neuroblastoma by fl ow cytometry. Voprosy onkologii = Problems in Oncology 2014;60(4):470–6. (In Russ.)].

22. Попов А.М., Друй А.Е., Шориков Е.В., Цаур Г.А., Вержбицкая Т.Ю., Савельев Л.И., Фечина Л.Г. Сравнение результатов определения поражения костного мозга у детей с нейробластомой методами проточной цитометрии и полимеразной цепной реакции. Вопросы онкологии 2015;61(5):767–73. [Popov A.M., Druy A.E., Shorikov E.V., Tsaur G.A., Verzhbitskaya T.Yu., Saveliev L.I., Fechina L.G. Comparison of bone marrow lesion in children with neuroblastoma using fl ow cytometry and polymerase chain reaction. Voprosy onkologii = Problems in Oncology 2015;61(5):767–73. (In Russ.)].

23. Druy A.E., Shorikov E.V., Tsaur G.A., Popov A.M., Zaychikov A.N., Tuponogov S.N., Saveliev L.I., Tytgat G.A.M., Fechina L.G. Prospective investigation of applicability and the prognostic signifi cance of bone marrow involvement in patients with neuroblastoma detected by quantitative reverse transcription PCR. Pediatr Blood Cancer 2018;65(11):e27354. doi: 10.1002/pbc.27354.

24. Schechter T., Perez-Albuerne E., Lin T.F., Irwin M.S., Essa M., Desari A.V., Frangoul H., Yanik G., Dupuis L.L., Jacobsohn D., Kletzel M., Ranalli M., Soni S., Seif A.E., Grupp S., Dvorak C.C. Veno-occlusive disease after high-dose busulfan-melphalan in neuroblastoma. Bone Marrow Transplant 2018. doi: 10.1038/s41409-018-0298-y. [Epub ahead of print].

25. Abate M.E., Paoili A., Cammeli S., Cesari M., Longhi A., Palmerini E., Ferrari S., Carreta E., Picci P., Piscaglia F. Sinusoidal obstruction syndrome/venoocclusive disease after high-dose intravenous busulfan/melphalan conditioning therapy in high-risk Ewing sarcoma. Bone Marrow Transplant 2018;53(5):591–9. doi: 10.1038/s41409-017-0066-4.

26. Applebaum M.A., Vaksman Z., Lee S.M., Hungate E.A., Henderson T.O., London W.B., Pinto N., Volchenboum S.L., Park J.R., Naranjo A., Hero B., Pearson A.D., Stranger B.E., Cohn S.L., Diskin S.J. Neuroblastoma survivors are at increased risk for second malignancies: A report from the International Neuroblastoma Risk Group Project. Eur J Cancer 2017;72:177–85. doi: 10.1016/j.ejca.2016.11.022.

27. Ladenstein R., Pötschger U., Pearson A.D.J., Brock P., Luksch R., Castel V., Yaniv I., Papadakis V., Laureys G., Malis J., Balwierz W., Ruud E., Kogner P., Schroeder H., de Lacerda A.F., Beck-Popovic M., Bician P., Garami M., Trahair T., Canete A., Ambros P.F., Holmes K., Gaze M., Schreier G., Garaventa A., Vassal G., Michon J., ValteauCouanet D.; SIOP Europe Neuroblastoma Group (SIOPEN). Busulfan and melphalan versus carboplatin, etoposide, and melphalan as highdose chemotherapy for high-risk neuroblastoma (YR-NBL1/SIOPEN): an international, randomized, multi-arm, open-label, phase 3 trial. Lancet Oncol 2017;18(4):500–14. doi: 10.1016/S1470-2045(17)30070-0.

28. Kushner B.H., Modak S., Kramer K., Basu E.M., Roberts S.S., Cheung N.K. 5-day/5-drug myeloablative outpatient regimen for resistant neuroblastoma. Bone Marrow Transplant 2013;48(5):642–5. doi: 10.1038/bmt.2012.202.

29. Yanik G.A., Villablanca J.G., Maris J.M., Weiss B., Groshen S., Marachelian A., Park J.R., Tsao-Wei D., Hawkins R., Shulkin B.L., Jackson H., Goodarzian F., Shimada H., Courtier J., Hutchinson R., Haas-Koga D., Hasenauer C.B., Czarnecki S., Katzenstein H.M., Matthay K.K. 131I-Metaiodobenzylguanidine with Intensive Chemotherapy and Autologous Stem Cell Transplantation for HighRisk Neuroblastoma. A New Approaches to Neuroblastoma Therapy (NANT) Phase II Study. Biol Blood Marrow Transplant 2015;21(4):673-81. doi: 10.1016/j.bbmt.2014.12.008.

30. Ladenstein R., Pötschger U., Valteau-Couanet D., Gray J., Luksch R., Castel V., Shifra A., Laureys G., Owens C., Trahair T., Chi Fung Chan G., Ruud E., Schroeder H., Popovic M.B., Loibner H., Schreier G., Ambros P.F., Sarnacki S., Boterberg T., Lode H.N. Immunotherapy with anti-GD2 antibody ch4.18/CHO ± IL2 within the HR-NBL1/ SIOPEN trial to improve outcome of high-risk neuroblastoma patients compared to historical controls. J Clin Oncol 2018;36(15s):1059. doi: 10.1200/JCO.2018.36.15_suppl.10539.