Venetoclax Plus Cyclophosphamide and Topotecan in Heavily Pre-treated Relapsed Metastatic Neuroblastoma: a Single Center Case Series

Overview

Journal Sci Rep

Specialty Science

Date 2023 Nov 7

PMID 37935707

Authors

Maria Antonietta De Ioris

Francesco Fabozzi

Francesca Del Bufalo

Giada Del Baldo

Maria Felicia Villani

Maria Giuseppina Cefalo

Maria Carmen Garganese

Alessandra Stracuzzi

Federica Tangari

Arturo Maria Greco

Isabella Giovannoni

Roberto Carta

Maria Luisa DAndrea

Angela Mastronuzzi

Franco Locatelli

Affiliations

Soon will be listed here.

Abstract

The prognosis of relapsed/refractory (R/R) neuroblastoma (NB) is dismal, calling for new therapeutic strategies. Venetoclax (VEN) is a highly selective, potent, orally bioavailable, BCL-2 inhibitor small-molecule that showed a synergistic effect with cyclophosphamide and topotecan (Cy-Topo) in murine NB models. Our aim was to evaluate the feasibility of VEN plus Cy-Topo in children with R/R NB. Four patients, who had previously failed > 3 lines of treatment, were treated with VEN plus Cy-Topo based on a 28-day schedule in an outpatient setting. BCL-2 expression in immunochemistry on tumor samples at relapse and the BCL2 gene status was evaluated in all patients. The main toxicity was hematological, with grade 4 neutropenia and thrombocytopenia occurring in all courses and leading to transient VEN discontinuation. Grade 3 oral mucositis was observed in 1/8 courses. No other grade 2-4 toxicities were observed. BCL-2 was expressed in all tumors, while no molecular abnormalities in the BCL-2 genes were detected. A stable disease was observed in all patients, without any progression during the study period. VEN plus Cy-Topo is well tolerated, with encouraging results that may be improved by testing the schedule in less advanced patients.

Citing Articles

Neuropathiazol induces neuronal-like differentiation in neuroblastoma cells via upregulation of PEG5.

Xu H, Zhang F, Xu Y, Chen T, Yuan F, Nie Q Pediatr Res. 2025; .

PMID: 39972157 DOI: 10.1038/s41390-025-03925-1.

References

Park J, Bagatell R, Cohn S, Pearson A, Villablanca J, Berthold F . Revisions to the International Neuroblastoma Response Criteria: A Consensus Statement From the National Cancer Institute Clinical Trials Planning Meeting. J Clin Oncol. 2017; 35(22):2580-2587. PMC: 5676955. DOI: 10.1200/JCO.2016.72.0177. View

Souers A, Leverson J, Boghaert E, Ackler S, Catron N, Chen J . ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med. 2013; 19(2):202-8. DOI: 10.1038/nm.3048. View

Del Bufalo F, De Angelis B, Caruana I, Del Baldo G, De Ioris M, Serra A . GD2-CART01 for Relapsed or Refractory High-Risk Neuroblastoma. N Engl J Med. 2023; 388(14):1284-1295. DOI: 10.1056/NEJMoa2210859. View

Pearson A, Barry E, Mosse Y, Ligas F, Bird N, de Rojas T . Second Paediatric Strategy Forum for anaplastic lymphoma kinase (ALK) inhibition in paediatric malignancies: ACCELERATE in collaboration with the European Medicines Agency with the participation of the Food and Drug Administration. Eur J Cancer. 2021; 157:198-213. DOI: 10.1016/j.ejca.2021.08.022. View

Davids M, Letai A . Targeting the B-cell lymphoma/leukemia 2 family in cancer. J Clin Oncol. 2012; 30(25):3127-35. PMC: 4979238. DOI: 10.1200/JCO.2011.37.0981. View

Chung C, Boterberg T, Lucas J, Panoff J, Valteau-Couanet D, Hero B . Neuroblastoma. Pediatr Blood Cancer. 2021; 68 Suppl 2:e28473. PMC: 8785544. DOI: 10.1002/pbc.28473. View

Flaadt T, Ladenstein R, Ebinger M, Lode H, Arnardottir H, Poetschger U . Anti-GD2 Antibody Dinutuximab Beta and Low-Dose Interleukin 2 After Haploidentical Stem-Cell Transplantation in Patients With Relapsed Neuroblastoma: A Multicenter, Phase I/II Trial. J Clin Oncol. 2023; 41(17):3135-3148. PMC: 10256422. DOI: 10.1200/JCO.22.01630. View

Gibson A, Trabal A, McCall D, Khazal S, Toepfer L, Bell D . Venetoclax for Children and Adolescents with Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma. Cancers (Basel). 2022; 14(1). PMC: 8750927. DOI: 10.3390/cancers14010150. View

Mody R, Yu A, Naranjo A, Zhang F, London W, Shulkin B . Irinotecan, Temozolomide, and Dinutuximab With GM-CSF in Children With Refractory or Relapsed Neuroblastoma: A Report From the Children's Oncology Group. J Clin Oncol. 2020; 38(19):2160-2169. PMC: 7325366. DOI: 10.1200/JCO.20.00203. View

10.

Castle V, Heidelberger K, Bromberg J, Ou X, Dole M, Nunez G . Expression of the apoptosis-suppressing protein bcl-2, in neuroblastoma is associated with unfavorable histology and N-myc amplification. Am J Pathol. 1993; 143(6):1543-50. PMC: 1887263. View

11.

London W, Frantz C, Campbell L, Seeger R, Brumback B, Cohn S . Phase II randomized comparison of topotecan plus cyclophosphamide versus topotecan alone in children with recurrent or refractory neuroblastoma: a Children's Oncology Group study. J Clin Oncol. 2010; 28(24):3808-15. PMC: 2940398. DOI: 10.1200/JCO.2009.27.5016. View

12.

Lerman B, Li Y, Carlowicz C, Granger M, Cash T, Sadanand A . Progression-Free Survival and Patterns of Response in Patients With Relapsed High-Risk Neuroblastoma Treated With Irinotecan/Temozolomide/Dinutuximab/Granulocyte-Macrophage Colony-Stimulating Factor. J Clin Oncol. 2022; 41(3):508-516. DOI: 10.1200/JCO.22.01273. View

13.

Krajewski S, CHATTEN J, Hanada M, Reed J . Immunohistochemical analysis of the Bcl-2 oncoprotein in human neuroblastomas. Comparisons with tumor cell differentiation and N-Myc protein. Lab Invest. 1995; 72(1):42-54. View

14.

Qiu B, Matthay K . Advancing therapy for neuroblastoma. Nat Rev Clin Oncol. 2022; 19(8):515-533. DOI: 10.1038/s41571-022-00643-z. View

15.

Lewington V, Lambert B, Poetschger U, Sever Z, Giammarile F, McEwan A . I-mIBG scintigraphy in neuroblastoma: development of a SIOPEN semi-quantitative reporting ,method by an international panel. Eur J Nucl Med Mol Imaging. 2016; 44(2):234-241. PMC: 5214990. DOI: 10.1007/s00259-016-3516-0. View

16.

Bate-Eya L, den Hartog I, van der Ploeg I, Schild L, Koster J, Santo E . High efficacy of the BCL-2 inhibitor ABT199 (venetoclax) in BCL-2 high-expressing neuroblastoma cell lines and xenografts and rational for combination with MCL-1 inhibition. Oncotarget. 2016; 7(19):27946-58. PMC: 5053701. DOI: 10.18632/oncotarget.8547. View

17.

Tanos R, Karmali D, Nalluri S, Goldsmith K . Select Bcl-2 antagonism restores chemotherapy sensitivity in high-risk neuroblastoma. BMC Cancer. 2016; 16:97. PMC: 4752777. DOI: 10.1186/s12885-016-2129-0. View

18.

Karol S, Alexander T, Budhraja A, Pounds S, Canavera K, Wang L . Venetoclax in combination with cytarabine with or without idarubicin in children with relapsed or refractory acute myeloid leukaemia: a phase 1, dose-escalation study. Lancet Oncol. 2020; 21(4):551-560. PMC: 7153631. DOI: 10.1016/S1470-2045(20)30060-7. View

19.

Place A, Goldsmith K, Bourquin J, Loh M, Gore L, Morgenstern D . Accelerating drug development in pediatric cancer: a novel Phase I study design of venetoclax in relapsed/refractory malignancies. Future Oncol. 2018; 14(21):2115-2129. DOI: 10.2217/fon-2018-0121. View

20.

Di Giannatale A, Dias-Gastellier N, Devos A, Mc Hugh K, Boubaker A, Courbon F . Phase II study of temozolomide in combination with topotecan (TOTEM) in relapsed or refractory neuroblastoma: a European Innovative Therapies for Children with Cancer-SIOP-European Neuroblastoma study. Eur J Cancer. 2013; 50(1):170-7. DOI: 10.1016/j.ejca.2013.08.012. View