Intensification of postconsolidation therapy in patients with high-risk neuroblastoma

Introduction. The results of treatment of high-risk neuroblastoma (NB) patients at the current stage remain unsatisfactory and overall survival does not exceed 50–60 %. Response to induction therapy, including response from distant metastases, is an important prognostic factor. Worse treatment outcomes are noted in patients who have not achieved complete resolution of metastatic foci. Intensification of postconsolidation therapy with the addition of cytostatic drugs not used at the induction treatment stage to 13-cis-retinoic acid (13-cis-RA) is a possible treatment option aimed at overcoming tumor cell resistance and improving both objective response and long-term prognosis in these patients.

Materials and methods. We conducted a multicenter prospective study of the use of 12 courses of temozolomide in combination with 9 courses of 13-cis-RA as part of postconsolidation therapy in high-risk NB patients who achieved an unsatisfactory response to induction therapy (persistence of metastatic foci) within the modified protocol of German Society for Pediatric Oncology and Hematology GPOH NB-2004, who received this therapy from January 2020 to January 2022. Temozolomide therapy was administered at a dosage of 150 mg/m²/day per os (intravenous administration was allowed) for 5 days and started on day 29 of the first cycle of 13-cis-RA. Another course of 13-cisRA was started on day 6 of temozolomide administration. During the 3-month break between the courses of 13-cis-RA (6 and 7 courses), temozolomide was continued for 5 days (the courses were repeated every 28 days).

Results. Fourteen high-risk NB patients with a median age at the time of diagnosis of 62 months (range – 9–173 months) were included in the study. Thirteen patients with newly diagnosed NB were verified with INSS stage 4 disease and INRGSS stage M; 1 patient with initial localized low-risk NB subsequently developed a combined relapse. 9/14 (64 %) patients received standard induction therapy and 5/14 (36 %) received intensified therapy due to an unfavorable response to the first six courses of induction chemotherapy. The response after completion of induction therapy was evaluated as partial response (PR) in 6/14 patients, mixed response (MR) in 6/14, and stable disease (SD) in 2/14. All patients received high-dose chemotherapy and autologous hematopoietic stem cell transplantation (auto-HSCT) during the consolidation phase. Postconsolidation therapy included a total of 134 cycles of temozolomide. Postconsolidation therapy including 12 cycles of temozolomide was completed by 10/14 (71 %) patients. 4/14 (28 %) patients did not complete therapy (2/4 – parental refusal of therapy and 2/4 – progression (PR)). 4/14 (29 %) patients included in the study fully completed the proposed regimen of post-consolidation therapy (13-cis-RA and temozolomide) without the addition of other therapeutic agents. 6/14 (43 %) patients received all 12 courses of temozolomide in combination with anti-GD2 targeted monoclonal antibodies (mAbs) immunotherapy and/or molecularly targeted therapy. In 3/14 (21 %) patients, manifestations of hematologic toxicity were observed, requiring reduction of temozolomide dosage and increasing the course interval. One out of 3 patients experienced thrombocytopenia on courses 2–5 and 2 out of 3 patients experienced grade II–III neutropenia on courses 5 and 2, 6, respectively. No unexpected serious toxicities, including deaths, were reported during all courses evaluated. Overall, 11/14 (79 %) patients completed first-line therapy (complete response (CR) – 2/11, PR – 7/11, SD – 1/11, PR – 1/11), 3/14 (21 %) did not complete due to disease progression. Currently, 11/14 (79 %) patients are alive (3/11 – after PR/relapse and 8/11 – alive without events). 2/14 (14 %) patients died from disease progression, 1/14 (7 %) – from non-tumor related causes. Median follow-up from diagnosis was 39.3 months for all patients (range – 12.5–62.5) and 42.5 months for survivors (range – 24.4–62.5).

Conclusions. For high-risk NB patients who have not achieved a complete metastatic response to the induction therapy phase, intensification of the postconsolidation phase of treatment may be suggested. The addition of temozolomide to the differentiation agent 13-cis-RA in our study demonstrated minimal toxicity, good tolerability, and improved response in a subset of patients. Further studies are needed to select the optimal regimen of postconsolidation therapy for patients with an unsatisfactory response to the induction phase.

1. Maris J.M. Recent advances in neuroblastoma. N Engl J Med. 2010;362(23):2202–11. doi: 10.1056/NEJMra0804577.

2. Goodman M.S., Gurney J.G., Smith M.A., Olshan A.F. Sympathetic nervous system tumors. In: Ries L.A.G., Smith M.A., Gurney J.G. (eds.). Cancer Incidence and Survival among Children and Adolescents: United States SEER Program 1975–1995, National Cancer Institute, SEER Program. NIH Pub. No. 99-4649. Bethesda, MD, 1999. Pp. 65–72.

3. Spix C., Pastore G., Sankila R., Stiller C.A., Steliarova-Foucher E. Neuroblastoma incidence and survival in European children (1978–1997): report from the Automated Childhood Cancer Information System project. Eur J Cancer. 2006;42(13):2081–91. doi: 10.1016/j.ejca.2006.05.008.

4. Pritchard J., Cotterill S.J., Germond S.M., Imeson J., de Kraker J., Jones D.R. High dose melphalan in the treatment of advanced neuroblastoma: results of a randomised trial (ENSG-1) by the European Neuroblastoma Study Group. Pediatr Blood Cancer. 2005;44(4):348–57. doi: 10.1002/pbc.20219.

5. Valteau-Couanet D., Le Deley M.C., Bergeron C., Ducassou S., Michon J., Rubie H., Le Teuff G., Coze C., Plantaz D., Sirvent N., Bouzy J., Chastagner P., Hartmann O. Long-term results of the combination of the N7 induction chemotherapy and the busulfanmelphalan high dose chemotherapy. Pediatr Blood Cancer. 2014;61(6):977–81. doi: 10.1002/pbc.24713.

6. Ladenstein R., Pötschger U., Valteau-Couanet D., Luksch R., Castel V., Yaniv I., Laureys G., Brock P., Michon J.M., Owens C., Trahair T., Chan G.C.F., Ruud E., Schroeder H., Beck Popovic M., Schreier G., Loibner H., Ambros P., Holmes K., Castellani MR., Gaze M.N., Garaventa A., Pearson A.D.J., Lode H.N. Interleukin 2 with anti-GD2 antibody ch14.18/CHO (dinutuximab beta) in patients with high-risk neuroblastoma (HR-NBL1/SIOPEN): a multicentre, randomised, phase 3 trial. Lancet Oncol. 2018;19(12):1617–29. doi: 10.1016/S1470-2045(18)30578-3.

7. 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-Couanet D., Pearson A.D., Cohn S.L. Advances in Risk Classification and Treatment Strategies for Neuroblastoma. J Clin Oncol. 2015;33(27):3008–17. doi: 10.1200/JCO.2014.59.4648.

8. Shamanskaya T.V., Kachanov D.Yu., Yadgarov M.Ya. The impact of response to induction chemotherapy on the event-free and overall survival in patients with high-risk neuroblastoma: a systematic review and meta-analysis. Voprosy gematologii/onkologii i immunopatologii v pediatrii = Pediatric Hematology/Oncology and Immunopathology. 2022;21(2):141‒56. (In Russ.). doi: 10.24287/1726-1708-2022-21-2-141-156.

9. Shamanskaya T.V., Varfolomeeva S.R., Kachanov D.Yu., Moiseenko R.A., Teleshova M.V., Konovalov D.M., Roshchin V.Yu., Kazakova A.N., Zemtsova L.V., Drui A.E., Yadgarov M.Ya., Tereshchenko G.V., Shcherbakov A.P., Likar Yu.N., Sukhov M.N., Grachev N.S., Akhaladze D.G., Maschan M.A., Nechesnyuk A.V., Pshonkin A.V., Kurnikova E.E., Skorobogatova E.V., Khachatryan L.A., Fomin D.K., Maschan A.A., Rumyantsev A.G., Novichkova G.A. The results of therapy in patients with high-risk neuroblastoma: the of Pediatric Hematology, Oncology and Immunology. Voprosy gematologii/onkologii i immunopatologii v pediatrii = Pediatric Hematology/Oncology and Immunopathology. 2023;22(2):65–91. (In Russ.). doi: 10.24287/1726-1708-2023-22-2-65-91.

10. Kazantsev I.V., Gevorgyan A.G., Yukhta T.V., Tolkunova P.S., Zvyagintseva D.A., Kozlov A.V., Golenkova M.S., Babenko E.V., Kuga P.S., Shvetsov A.N., Nikolaev I.Yu., Morozova E.V., Safonova S.A., Punanov Yu.A., Zubarovskaya L.S., Afanasyev B.V. The complex intensive therapy regimen as curative therapy in patients with primary-resistant and relapsed neuroblastoma: R.M. Gorbacheva Memorial Institute for Children Oncology, Hematology and Transplantation experience. Voprosy gematologii/ onkologii i immunopatologii v pediatrii = Pediatric Hematology/ Oncology and Immunopathology. 2020;19(2):129–40. (In Russ.). doi: 10.24287/1726-17082020-19-2-129-140.

11. Yu A.L., Gilman A.L., Ozkaynak M.F., London W.B., Kreissman S.G., Chen H.X., Smith M., Anderson B., Villablanca J.G., Matthay K.K., Shimada H., Grupp S.A., Seeger R., Reynolds C.P., Buxton A., Reisfeld R.A., Gillies S.D., Cohn S.L., Maris J.M., Sondel P.M.; Childrenʼs Oncology Group. Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N Engl J Med. 2010;363(14):1324–34. doi: 10.1056/NEJMoa0911123.

12. Yu A.L., Gilman A.L., Ozkaynak M.F., Naranjo A., Diccianni M.B., Gan J., Hank J.A., Batova A., London W.B., Tenney S.C., Smith M., Shulkin B.L., Parisi M., Matthay K.K., Cohn S.L., Maris J.M., Bagatell R., Park J.R., Sondel P.M. Long-Term Follow-up of a Phase III Study of ch14.18 (Dinutuximab) + Cytokine Immunotherapy in Children with High-Risk Neuroblastoma: COG Study ANBL0032. Clin Cancer Res. 2021;27(8):2179–89. doi: 10.1158/1078-0432.CCR-20-3909.

13. Simon T., Hero B., Schulte J.H., Deubzer H., Hundsdoerfer P., von Schweinitz D., Fuchs J., Schmidt M., Prasad V., Krug B., Timmermann B., Leuschner I., Fischer M., Langer T., Astrahantseff K., Berthold F., Lode H., Eggert A. 2017 GPOH Guidelines for Diagnosis and Treatment of Patients with Neuroblastic Tumors. Klin Padiatr. 2017;229(3):147–67. doi: 10.1055/s-0043-103086.

14. Morgenstern D.A., Barone G., Moreno L., Anderson J., Brock P., Elliott M., Gaze M., Gray J., Makin G., Squire R., Tweddle D., Ramanujachar R., Wheeler K., Pearson A.D.J. Options for the Treatment of Patients with Relapsed/Progressive High-Risk Neuroblastoma. Children’s cancer and leukaemia group (CCLG). Neuroblastoma special interest group, 2015. [Electronic resource]: https://www.cclg.org.uk/write/MediaUploads/Member%20area/Treatment%20guidelines/CCLG_Relapsed_Progressive_High_Risk_Neuroblastoma_Guidelines_March_2015_FINAL.pdf. (appeal date 01.07.2024).

15. Jaeckle K.A., Hess K.R., Yung W.K., Greenberg H., Fine H., Schiff D., Pollack I.F., Kuhn J., Fink K., Mehta M., Cloughesy T., Nicholas M.K., Chang S., Prados M.; North American Brain Tumor Consortium. Phase II evaluation of temozolomide and 13-cis-retinoic acid for the treatment of recurrent and progressive malignant glioma: a North American Brain Tumor Consortium study. J Clin Oncol. 2003;21(12):2305–11. doi: 10.1200/JCO.2003.12.097.

16. Butowski N., Prados M.D., Lamborn K.R., Larson D.A., Sneed P.K., Wara W.M., Malec M., Rabbitt J., Page M., Chang S.M. A phase II study of concurrent temozolomide and cis-retinoic acid with radiation for adult patients with newly diagnosed supratentorial glioblastoma. Int J Radiat Oncol Biol Phys. 2005;61(5):1454–9. doi: 10.1016/j.ijrobp.2004.08.023.

17. Berthold F., Faldum A., Ernst A., Boos J., Dilloo D., Eggert A., Fischer M., Frühwald M., Henze G., Klingebiel T., Kratz C., Kremens B., Krug B., Leuschner I., Schmidt M., Schmidt R., SchumacherKuckelkorn R., von Schweinitz D., Schilling F.H., Theissen J., Volland R., Hero B., Simon T. Extended induction chemotherapy does not improve the outcome for high-risk neuroblastoma patients: results of the randomized open-label GPOH trial NB2004-HR. Ann Oncol. 2020;31(3):422–9. doi: 10.1016/j.annonc.2019.11.011.

18. Brodeur G.M., Pritchard J., Berthold F., Carlsen N.L., Castel V., Castelberry R.P., De Bernardi B., Evans A.E., Favrot M., Hedborg F. Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment. J Clin Oncol. 1993;11(8):1466–77. doi: 10.1200/JCO.1993.11.8.1466.

19. Matthay K.K., Atkinson J.B., Stram D.O., Selch M., Reynolds C.P., Seeger R.C. Patterns of relapse after autologous purged bone marrow transplantation for neuroblastoma: a Childrens Cancer Group pilot study. J Clin Oncol. 1993;11(11):2226–33. doi: 10.1200/JCO.1993.11.11.2226.

20. Kachanov D.Yu. Results of risk-adapted therapy of neuroblastoma in children. Thesis abstract of … Dr. of Sci. (Med.). M., 2017. 62 p. (In Russ.).

21. 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 Childrenʼs Oncology Group study. J Clin Oncol. 2009;27(7):1007–13. doi: 10.1200/JCO.2007.13.8925. Erratum in: J Clin Oncol. 2014;32(17):1862–3.

22. Matthay K.K., Villablanca J.G., Seeger R.C., Stram D.O., Harris R.E., Ramsay N.K., Swift P., Shimada H., Black C.T., Brodeur G.M., Gerbing R.B., Reynolds C.P. Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. Childrenʼs Cancer Group. N Engl J Med. 1999;341(16):1165–73. doi: 10.1056/NEJM199910143411601.

23. Kohler J.A., Imeson J., Ellershaw C., Lie S.O. A randomized trial of 13-cis-retinoic acid in children with advanced neuroblastoma after high-dose therapy. Br J Cancer. 2000;83(9):1124–7. doi: 10.1054/bjoc.2000.1425.

24. NB2004 Trial Protocol for Risk Adapted Treatment of Children with Neuroblastoma. Berthold F. (principal investigator). [Electronic resource]: https://www.gpoh.de/kinderkrebsinfo/content/e1676/e9032/e68518/e206421/download38297/NB_2004_HR_3-Versandversion_ger.pdf. (appeal date 01.07.2024).

25. Nicholson H.S., Krailo M., Ames M.M., Seibel N.L., Reid J.M., LiuMares W., Vezina L.G., Ettinger A.G., Reaman G.H. Phase I study of temozolomide in children and adolescents with recurrent solid tumors: a report from the Childrenʼs Cancer Group. J Clin Oncol. 1998;16(9):3037–43. doi: 10.1200/JCO.1998.16.9.3037.

26. Estlin E.J., Lashford L., Ablett S., Price L., Gowing R., Gholkar A., Kohler J., Lewis I.J., Morland B., Pinkerton C.R., Stevens M.C., Mott M., Stevens R., Newell D.R., Walker D., Dicks-Mireaux C., McDowell H., Reidenberg P., Statkevich P., Marco A., Batra V., Dugan M., Pearson A.D. Phase I study of temozolomide in pediatric patients with advanced cancer. United Kingdom Childrenʼs Cancer Study Group. Br J Cancer. 1998;78(5):652–61. doi: 10.1038/bjc.1998.555.

27. Rubie H., Chisholm J., Defachelles A.S., Morland B., Munzer C., Valteau-Couanet D., Mosseri V., Bergeron C., Weston C., Coze C., Auvrignon A., Djafari L., Hobson R., Baunin C., Dickinson F., Brisse H., McHugh K., Biassoni L., Giammarile F., Vassal G; Société Françaisedes Cancers de l’Enfant; United Kingdom Children Cancer Study Group-New Agents Group Study. Phase II study of temozolomide in relapsed or refractory high-risk neuroblastoma: a joint Société Française des Cancers de l’Enfant and United Kingdom Children Cancer Study Group-New Agents Group Study. J Clin Oncol. 2006;24(33):5259–64. doi: 10.1200/JCO.2006.06.1572.

28. Bagatell R., London W.B., Wagner L.M., Voss S.D., Stewart C.F., Maris J.M., Kretschmar C., Cohn S.L. Phase II study of irinotecan and temozolomide in children with relapsed or refractory neuroblastoma: a Children’s Oncology Group study. J Clin Oncol. 2011;29(2):208–13. doi: 10.1200/JCO.2010.31.7107.

29. Di Giannatale A., Dias-Gastellier N., Devos A., Mc Hugh K., Boubaker A., Courbon F., Verschuur A., Ducassoul S., Malekzadeh K., Casanova M., Amoroso L., Chastagner P., Zwaan C.M., Munzer C., Aerts I., Landman-Parker J., Riccardi R., Le Deley M.C., Geoerger B., Rubie H. Phase II study of temozolomide in combination with topotecan (TOTEM) in relapsed or refractory neuroblastoma: a European Innovative Therapies for Children with Cancer-SIOPEuropean Neuroblastoma study. Eur J Cancer. 2014;50(1):170–7. doi: 10.1016/j.ejca.2013.08.012.

30. Desai A.V., Naranjo A., LaBarre B., Goldsmith K.C., Granger M.P., States L., Green S., Trunzo M., Fitzgerald W., DuBois S.G., Bagatell R., Park J.R., Marachelian A. A pilot study of postconsolidation chemoimmunotherapy for high-risk neuroblastoma (ANBL19P1): A report from the Children’s Oncology Group. Meeting Abstract: 2024 ASCO Annual Meeting Pediatric Oncology May 29, 2024. J Clin Oncol. 2024;42(16)suppl. doi: 10.1200/JCO.2024.42.16_suppl.10004.