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. 2024 Nov 4;26(11):2125-2139.
doi: 10.1093/neuonc/noae111.

Medulloblastoma in children with Fanconi anemia: Association with FA-D1/FA-N, SHH type and poor survival independent of treatment strategies

Marthe Sönksen  1 , Denise Obrecht-Sturm  1 , Pablo Hernáiz Driever  2 , Axel Sauerbrey  3 , Norbert Graf  4 , Udo Kontny  5 , Christian Reimann  6 , Mina Langhein  1 , Uwe R Kordes  1 , Rudolf Schwarz  7 , Tobias Obser  8 , Felix Boschann  9   10 , Ulrich Schüller  11   12   1 , Lea Altendorf  12   1 , Tobias Goschzik  13 , Torsten Pietsch  13 , Martin Mynarek  14   1 , Stefan Rutkowski  1
Affiliations

Medulloblastoma in children with Fanconi anemia: Association with FA-D1/FA-N, SHH type and poor survival independent of treatment strategies

Marthe Sönksen et al. Neuro Oncol. .

Abstract

Background: The outcome of children with medulloblastoma (MB) and Fanconi Anemia (FA), an inherited DNA repair deficiency, has not been described systematically. Treatment is complicated by high vulnerability to treatment-associated side effects, yet structured data are lacking. This study aims to give a comprehensive overview of clinical and molecular characteristics of pediatric FA MB patients.

Methods: Clinical data including detailed information on the treatment and toxicities of 6 previously unreported FA MB patients were supplemented with data of 16 published cases.

Results: We identified 22 cases of children with FA and MB with clinical data available. All MBs with subgroup reporting were SHH-activated (n = 9), confirmed by methylation profiling in 5 patients. FA MB patients exclusively belonged to complementation groups FA-D1 (n = 16) or FA-N (n = 3). Patients were treated with postoperative chemotherapy only (50%) or radiotherapy (RT) ± chemotherapy (27%). Of 23% did not receive adjuvant therapy. Excessive treatment-related toxicities were frequent. Severe hematological toxicity occurred in 91% of patients treated with alkylating chemotherapy, while non-alkylating agents and RT were less toxic. Median overall survival (OS) was 1 year (95%CI: 0.3-1.8). 1-year-progression-free-survival (PFS) was 26.3% ± 10.1% and 1-year-OS was 42.1% ± 11.3%. Adjuvant therapy prolonged survival (1y-OS/1y-PFS 0%/0% without adjuvant therapy vs. 53.3% ± 12.9%/33.3 ± 12.2% with adjuvant therapy, P = .006/P = .086).

Conclusions: MB in FA patients is strongly associated with SHH activation and FA-D1/FA-N. Despite the dismal prognosis, adjuvant therapy may prolong survival. Non-alkylating chemotherapy and RT are feasible in selected patients with careful monitoring of toxicities and dose adjustments. Curative therapy for FA MB-SHH remains an unmet medical need.

Keywords: FA-D1; FA-N; Fanconi anemia; medulloblastoma; tumor predisposition.

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Conflict of interest statement

PHD is the international coordinating investigator of the Sprinkle study and advisory board member for Alexion. URK is part of a data safety monitoring board or advisory board for Astra Zeneca and Merck and received support for attending meetings and/or travel from Astra Zeneca. RS receives funds from the German Childhood Cancer Foundation for quality assurance of radiotherapy in pediatric brain tumors in Germany and is part of a data safety monitoring board or advisory board for the Oscar 1 Trial (Osteosarcoma) of University Hospital Heidelberg, Germany, and for proton therapy trials of University Hospital Dresden, Germany. TP receives funds for the Brain Tumor Reference Center for reference neuropathological assessments in the HIT network by the German Childhood Cancer Foundation. SR received fees for advisory board roles from Bayer, Novartis, BMS, and Roche; for DMSC from Celegne; for assessment from the German Childhood Cancer Foundation; and from MyChildsCancer for consulting. The other authors have no competing interests to declare that are relevant to the content of this article.

Figures

Graphical Abstract
Graphical Abstract
Figure 1.
Figure 1.
Clinical courses and molecular information of the study cohort. (A) Overview of cohort assembly, clinical courses, and outcomes. (B) Explorative t-SNE plot of unpublished cases with methylation data available, all MB reference cases from Capper et al., 2018 (23) and Cavalli et al., 2017 (24). (C) Explorative t-SNE plot of unpublished cases with methylation data available, only SHH-MB reference cases from Capper et al., 2018 (23) and Cavalli et al., 2017 (24).
Figure 2.
Figure 2.
Visualization of the frequency of treatment-associated toxicities in children with MB and FA. Treatment-associated toxicities are depicted according to the type of treatment administered. Type of toxicities are described on the x-axis while the fraction of patients experiencing those toxicities upon administration of the respective type of treatment is given on the y-axis. Organ-specific damages were: mucositis/dermatitis (n = 3 after i.v. chemotherapy with alkylating agents/anthracyclines, n = 2 after i.v. chemotherapy w/o alkylating agents/anthracyclines, n = 1 after radiotherapy), cholangitis (n = 1 after i.v. chemotherapy with alkylating agents/anthracyclines), hepatobiliary toxicity (n = 1 after i.v. chemotherapy w/o alkylating agents/anthracyclines), impairment of renal function (n = 1 after i.v. chemotherapy with alkylating agents/anthracyclines), and leukoencephalopathy (n = 1 after i.v. chemotherapy w/o alkylating agents/anthracyclines).
Figure 3.
Figure 3.
Survival of the whole cohort (A, n = 19) and according to treatment (B and C, n = 17) depicted by Kaplan–Meier plot.
See this image and copyright information in PMC

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