Elsevier

European Journal of Cancer

Volume 81, August 2017, Pages 1-8
European Journal of Cancer

Original Research
Haematological malignancies following temozolomide treatment for paediatric high-grade glioma

https://doi.org/10.1016/j.ejca.2017.04.023Get rights and content

Highlights

  • •

    The 10-year incidence of secondary haematological malignancies (SHMs) following paediatric high-grade glioma is estimated 7.7 ± 3.2%.

  • •

    First-line temozolomide seems not to increase the risk of SHMs compared with multiagent chemotherapy.

  • •

    Second-line temozolomide may disproportionately increase the risk of SHMs.

Abstract

Background

Temozolomide (TMZ) is widely used in high-grade glioma (HGG). There is a major concern of treatment-induced secondary haematological malignancies (SHMs). Due to the poor overall survival of HGG patients, the true incidence is yet elusive. Thus, the aim of this study was to determine the risk of SHMs following TMZ in paediatric HGG.

Methods

We analysed 487 patients from the HIT-HGG database of the German-speaking Society of Pediatric Oncology and Hematology with follow up beyond 1 year.

Results

The incidence of SHM was 7.7 ± 3.2% at 10 years. No SHM occurred in 194 patients after first-line TMZ therapy, but four out of 131 patients treated with TMZ for relapse following first-line multiagent chemotherapy experienced SHM (20% at 10 years; p = 0.041). SHMs occurred in two out of 162 patients who underwent multiagent chemotherapy without TMZ (4.1% at 10 years). Gender, patient age and acute haematological toxicity during treatment did not affect the incidence of SHMs.

Conclusion

Data of our cohort do not indicate an increased risk of SHM following TMZ treatment when compared to previous chemotherapy regimen. However, if TMZ is administered as a second-line treatment following conventional chemotherapy regimen, the risk might be disproportionately increasing.

Introduction

Temozolomide (TMZ) has widely changed the treatment of high-grade glioma (HGG) in adults and in the paediatric population. Following tumour resection, current paediatric protocols usually recommend TMZ concomitantly to radiotherapy, followed by adjuvant TMZ [1]. The possibility of a largely outpatient treatment due to the oral application and a favourable toxicity profile has contributed to an improved quality of life for these patients whose prognosis remains poor [2], [3].

However, similar to other alkylating agents, TMZ induces single- and/or double-strand DNA breaks and may therefore lead to secondary neoplasms [3]. Most reports of both children and adult patients associate TMZ with secondary haematological malignancies (SHMs). Adults predominantly experience treatment-related acute lymphoblastic leukaemia, acute myeloid leukaemia, and myelodysplasia [4], [5], [6], [7], [8], [9], [10], [11], [12]. This may be explained by a particularly low intrinsic O6-methylguanine-DNA methyltransferase activity in haematopoetic cells and lymphoid tissue [13]. Due to the poor survival of HGG and the relatively recent introduction of TMZ into treatment compared with conventional chemotherapy agents, the true incidence of SHM following TMZ is yet to be clarified. However, a disproportionately increased risk of SHMs in adults seems to be associated with TMZ as a second-line treatment following preceding mutagenic agents including nimustine (ACNU) or etoposide [14].

To date, no larger series have been published with regards to incidence and risk factors of SHM following TMZ for paediatric HGG. We present the HIT-HGG experience on these fatal events. We analysed the risk of SHM following TMZ treatment in comparison to conventional multiagent chemotherapy regimens. Since treatment-induced SHM are unlikely to occur within the first year of treatment [3], survival and follow up for all 487 paediatric patients in the present study exceeded 1 year.

Section snippets

Patients' characteristics and inclusion/exclusion criteria

Patient data were obtained from the HIT-HGG database of the Society of Pediatric Oncology and Hematology (Gesellschaft für Pädiatrische Onkologie und Hämatologie, GPOH) in Germany, Austria and Switzerland. This registry contains prospective clinical data of all patients enrolled in the subsequent HGG trials (HIT-GBM A-D) [15], [16], [17], [18] as well as the ongoing HIT-HGG 2007 trial (Eudra-CT 2007-010128-42, ISRCTN19852453). In addition, the registry includes patients aged <3 years at

Results

The HIT-HGG database included 487 paediatric HGG and diffuse intrinsic pontine glioma patients with a minimum follow up of 1 year after the start of treatment. All patients had been registered to the consecutive trials HIT-GBM-A, -B, -C, -D and HIT-HGG 2007. In addition, we included observational patients <3 years of age treated according to the HIT-SKK regimen (Table 1). Median overall survival was 2.1 years (1–14.8), and median follow up of the surviving patients was 4.1 years (1–14.8),

Discussion

The incidence of SHM in our cohort was 7.7 ± 3.2% at 10 years. No SHM occurred in 194 patients after first-line TMZ therapy. In contrast, four patients out of 131 treated with TMZ as second-line treatment following first-line multiagent chemotherapy experienced SHM (20% at 10 years of follow up; p = 0.041). SHMs occurred in two out of 162 patients who underwent multiagent chemotherapy without TMZ (4.1% at 10 years). There was no significant impact of gender, patient age and acute haematological

Funding

The present research is based on the clinical data from the HIT-GBM/HIT-HGG trials which were all funded by the Deutsche Kinderkrebsstiftung, Bonn, Germany.

Conflict of interest statement

None declared.

Acknowledgement

The ongoing support of the Deutsche Kinderkrebsstiftung, Bonn, Germany, is greatly acknowledged. Without this support, performance of clinical trials as well as quality control measures like central neuropathological and neuroradiological review and a central review of radiotherapy planning would not be possible within the GPOH Pediatric Brain Tumor Network (HIT-Netzwerk). The authors thank all colleagues who contributed patients and their data to the HIT-GBM/HIT-HGG studies. The excellent work

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    Authors contributed equally to the manuscript.

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