Rhabdoid Tumors (AT/RT): a Report from the European Rhabdoid Registry (EU-RHAB)

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ORIGINAL ARTICLE High-dose chemotherapy (HDCT) with auto-SCT in children with atypical teratoid/rhabdoid tumors (AT/RT): a report from the European Rhabdoid Registry (EU-RHAB)

M Benesch1, K Bartelheim2, G Fleischhack3, B Gruhn4, PG Schlegel5, O Witt6, KD Stachel7, H Hauch8, C Urban1, F Quehenberger9, M Massimino10, T Pietsch11, M Hasselblatt12, F Giangaspero13,14, U Kordes15, R Schneppenheim15, P Hauser16, T Klingebiel17 and MC Fru¨ hwald2,18

A retrospective analysis of data from the European Rhabdoid Registry (EU-RHAB) was performed to describe the outcome of children with atypical teratoid/rhabdoid tumors (AT/RT) who underwent high-dose chemotherapy (HDCT) with auto-SCT. Nineteen patients (male, n ¼ 15; median age at diagnosis 21 months) were identified. Nine patients presented with metastatic disease at diagnosis. A partial or subtotal resection was achieved in 11, a total resection in five and a biopsy in three patients. Patients received a median of six chemotherapy cycles prior to HDCT. Additional radiotherapy was performed in 14 patients (first-line, n ¼ 9; following progression, n ¼ 5). Six patients underwent tandem auto-SCT. Disease status before HDCT was CR in six, PR in eight, stable disease in two and progressive disease (PD) in two patients (data missing, n ¼ 1). With a median follow-up of 16 months, 14 patients progressed. Estimated progression-free and OS at 2 years were 29% (±11%) and 50% (±12%), respectively. At last follow-up, eight patients were alive (first CR, n ¼ 4; second CR, n ¼ 2; PR, n ¼ 1; PD, n ¼ 1). Eleven patients died of PD. Median time-to-progression was 14 months. Selected patients with AT/RT might benefit from HDCT with radiotherapy. The definitive impact of this treatment modality has to be evaluated prospectively in a randomized trial.

Bone Marrow Transplantation (2014) 49, 370–375; doi:10.1038/bmt.2013.208; published online 13 January 2014 Keywords: atypical teratoid/rhabdoid tumors; auto-SCT; children

INTRODUCTION outcome.4,5–7,9 In terms of treatment, a gross total resection2,4,5,8 5,6,9 Atypical teratoid/rhabdoid tumors (AT/RT) are highly malignant and radiotherapy seem to contribute to a prolongation of tumors of the central nervous system (CNS).1 Among children survival. below the age of 3 years, AT/RT constitute the most common The impact of high-dose chemotherapy (HDCT) with auto-SCT malignant CNS tumors (17.3%), followed by medulloblastomas on prognosis is unclear. The aim of the present retrospective (16%) and primitive neuroectodermal tumors of the CNS (13.3%).2 analysis was thus to report the clinical characteristics and outcome In a population-based study, the age-standardized incidence rate of 19 children with AT/RT who underwent HDCT within the of AT/RT was calculated at 1.38 per 1 000 000 person–years.2 The European Rhabdoid Registry (EU-RHAB) and the previous registry median age at diagnosis is between 14 and 24 months, with boys Rhabdoid 2007. more commonly affected than girls.1–9 Infratentorial location has been reported in 38–65% of AT/RT and up to 1/3 of patients with AT/RT present with metastatic disease at diagnosis.1–9 PATIENTS AND METHODS Prognosis of patients with AT/RT is generally poor. The vast Aims of EU-RHAB and rhabdoid 2007 majority of patients develop early local progression or recurren- 1–8 The primary goal of the EU-RHAB registry is to optimize the management ce±distant metastases within 1 year following diagnosis. of patients with rhabdoid tumors of all anatomical sites. Thus EU-RHAB Among various clinical parameters, younger age and presence serves as a platform for the standardized registration of epidemiologic-, of metastases were most consistently associated with a worse molecular-, clinical- and treatment-related data. EU-RHAB contains

1Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria; 2Swabian Children’s Cancer Center, Children’s Hospital Augsburg, Augsburg, Germany; 3Pediatrics III, University Hospital of Essen, Essen, Germany; 4Department of Pediatrics, Jena University Hospital, Jena, Germany; 5Department of Pediatric Hematology, Oncology and Neurooncology, University Children’s Hospital Wu¨rzburg, Wu¨rzburg, Germany; 6Department of Pediatric Oncology, Hematology, Immunology and Pneumonology, Children’s Hospital, University of Heidelberg, Heidelberg, Germany; 7Children’s University Hospital, Friedrich-Alexander University Erlangen-Nu¨rnberg, Erlangen, Germany; 8Department of Pediatric Hematology and Oncology, Justus Liebig University Gieen, Gieen, Germany; 9Institute for Medical Statistics, Medical University of Graz, Graz, Austria; 10Department of Pediatrics, Fondazione IRCCS, Istituto Nazionale Tumori, Milan, Italy; 11Institute of Neuropathology, University of Bonn, Bonn, Germany; 12Institute of Neuropathology, University Hospital Mu¨nster, Mu¨ nster, Germany; 13Department of Radiological, Oncological and Anatomo-pathological Sciences, University La Sapienza, Rome, Italy; 14IRCCS Neuromed, Pozzilli, Italy; 15Department of Pediatric Hematology and Oncology, University Medical Center Hamburg- Eppendorf, Hamburg, Germany; 16Department of Pediatrics, Semmelweis University, Budapest, Hungary; 17Division of Pediatric Hematology and Oncology, Department of Pediatrics, J. W. Goethe University Children’s Hospital of Frankfurt, Frankfurt, Germany and 18Department of Pediatric Hematology and Oncology, University Children’s Hospital Mu¨nster, Mu¨ nster, Germany. Correspondence: Dr M Benesch, Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Auenbruggerplatz 38, A-8036 Graz, Austria or Dr MC Fru¨hwald, Swabian Children’s Cancer Center, Children’s Hospital Augsburg, Stenglinstrae 2, D-86156 Augsburg, Germany. E-mail: [email protected] or [email protected] Received 9 July 2013; revised 12 November 2013; accepted 12 November 2013; published online 13 January 2014 Auto-SCT in children with AT/RT M Benesch et al 371 treatment recommendations based on the best available evidence treatment. In addition, patients who did not receive chemotherapy at full including published data sets, the investigators’ own experiences and doses were candidates for maintenance therapy. data from the German, Austrian and Swiss Society of Pediatric Oncology ´ ´ ´ and Hematology and the Societe International d’Oncologie Pediatrique. Radiotherapy These recommendations represent a non-investigational consensus standard of care derived from currently available data. The previous In children X18 months or older, radiotherapy had to be started as soon as Rhabdoid 2007 registry had the same objectives; however, treatment possible. Children o18 months were irradiated only under exceptional recommendations were less detailed compared with those of the EU-RHAB. circumstances. In the case of primary metastatic disease, RT might be Also, it did not reach an uniform European consensus, as it did not include delayed until the end of intensive chemotherapy (following cycle 9). actinomycin D and contained VCR in each element of chemotherapy. Postponing radiotherapy was recommended in children p18 months until Between October 2005 and August 2011, six patients were enrolled in the age permitted its use or following cycle 9. In children X18 months with Rhabdoid 2007 and 13 in the subsequent EU-RHAB registry. It was localized AT/RT, the extended tumor region was irradiated with 54.0 Gy prospectively anticipated to officially initiate the Rhabdoid registry in 2007. (1.8 Gy/day, 5 fractions/week). Patients with metastatic disease (Chang M1– However, data collection started earlier in 2005 explaining the fact that M3, age 418 months to 3 years) were scheduled to receive craniospinal four patients were treated before the formal initiation of the Rhabdoid radiotherapy with 24.0 Gy (1.6 Gy/day). Boosts were delivered to the 2007 registry. EU-RHAB has been approved by the ethics committee of the primary tumor site (54 Gy, 1.8 Gy/day) and circumscribed solid spinal and University of Mu¨nster, Germany. Informed consent was obtained from all intracranial metastases (49.2 Gy, 1.8 Gy/day). In children older than 3 years patients by parents or guardians prior to the initiation of therapy. with metastatic disease (Chang M1–M3), the craniospinal axis dose was 35.2 Gy. Diagnostic evaluation High-dose chemotherapy Complete CNS staging including contrast-enhanced magnetic resonance imaging (MRI) of the entire neuraxis and cytological analysis of Within the Rhabdoid 2007/EU-RHAB registries, the use of HDCT was at the cerebrospinal fluid (CSF) was strongly recommended for all patients at discretion of the treating physician (Supplementary Figures 2 and 3). As diagnosis. Extraneural metastases were excluded by clinical examination individual centers and some countries prefer to employ HDCT in patients and imaging studies. Follow-up MRI was recommended following cycles 2, with AT/RT, the protocol aimed to harmonize transplant strategies. The HDCT protocol recommended a conditioning regimen based on carbo- 4, 6 and 9 of intensive chemotherapy. However, the clinical course often 2 2 necessitated MRI at shorter intervals. Complete neuraxis staging was platin (500 mg/m /day; days À 6to À 4) and thiotepa (300 mg/m /day; performed in 16/19 patients (84%). Central pathological review was days À 6to À 4). Stem cell harvest had to be performed after the first ICE performed at the time of diagnosis in 18 patients (95%) either at the cycle. If indicated, stem cell collection might be repeated after the second ICE cycle. Stem cell mobilization and processing were performed according Neuropathology Reference Centre of the HIT network (Institute of 6 Neuropathology, University of Bonn, Germany, n ¼ 12), the Institute of to standard procedures. A minimum of 3 Â 10 CD34 þ stem cells per kg body weight was required for transplantation. Other conditioning Neuropathology, University Hospital Mu¨nster, Germany (n ¼ 4), or at the 2 Department of Pathology, University La Sapienza, Rome, Italy (n ¼ 2). In regimens (Table 2) used were carboplatin (500 mg/m /day on days À 8 to À 5) and etoposide (250 mg/m2/day on days À 8to À 5) for the first one patient, diagnosis was established only by cytology of CSF cells 2 2 followed by FISH for SMARCB1 deletion as the patient was deemed and thiotepa (300 mg/m /day on days À 4to À 2) and CY (1500 mg/m / inoperable. Genetic testing for germline mutations of SMARCB1 was day on days À 4to À 2) for the second transplantation in five patients 10 who underwent tandem auto-SCT. In one patient who received tandem performed in 13 patients (68%) as previously described; in four of them 2 (patients 5, 6, 13 and 15) a germline mutation was identified. auto-SCT conditioning consisted of thiotepa (150 mg/m /day on days À 5 to À 4) and melphalan (40 mg/m2/day on days À 5to À 3 and 20 mg/m2/ day on day À 2 (total melphalan dose 140 mg/m2)) for the first and second Chemotherapy (Rhabdoid 2007) transplant. Three patients received conditioning with carboplatin and Postoperative chemotherapy contained a total of nine cycles of alternating etoposide (doses as above). VCD and ICE (see below) with concomitant age-adjusted intraventricular MTX via the Ommaya or Rickham reservoir (Supplementary Figure 1). The Data extraction and statistical analysis registry documents of Rhabdoid 2007 and EU-RHAB provided also detailed All data were extracted without direct personal identification. Treatment guidelines on the administration of intraventricular MTX in the presence of centers were contacted by the EU-RHAB study center in order to obtain the a ventriculoperitoneal (VP) shunt. In our series two patients had a VP shunt most recent follow-up information. Events other than relapse or with a pressure regulating valve and 2 subduroperitoneal shunts. In all progression did not occur. The influence of risk factors (age, gender, cases the guidelines were strictly followed. metastases at diagnosis, extent of resection, achievement of CR prior to VCD consisted of VCR (1.5 mg/m2/day; days 1, 8 and 15), CY (1800 mg/ HDCT, radiotherapy and presence of SMARCB1 germline mutations) in m2/day; day 1) and doxorubicin (37.5 mg/m2/day; days 1 and 2). ICE disease progression was tested using the log-rank test. R 2.15.2 (www. consisted of ifosfamide (2 g/m2/day; days 1–3), carboplatin (600 mg/m2/ r-project.org) and package survival version 2.36–5 were used for calculations. day; day 1) and etoposide (100 mg/m2/day; days 1–3). Drug doses were Asymptotic 95% confidence limits were calculated on the log–log of the calculated in kg body weight in children under the age of 12 months (VCR survival function. Results were updated as of 31 January 2013. o36 months).

Chemotherapy (EU-RHAB) RESULTS Chemotherapy also included nine cycles of doxorubicin, ICE and VCA with Clinical characteristics concomitant age-adjusted intraventricular MTX (o2 years: 0.5 mg, 2–3 Basic clinical characteristics of study patients are shown in Table 1. years: 1 mg, 3 years: 2 mg; 4 doses during doxorubicin, 3 doses during VCA The median age at diagnosis was 21 months (range, 0–64) with a and 4 doses during ICE cycles) (Supplementary Figures 2 and 3). Doxorubicin was given as a single agent at 37.5 mg/m2/day on days 1 strong male predominance of 3.75:1. Nine patients (47%) had and 2. ICE chemotherapy was identical to that used in Rhabdoid 2007 metastatic disease at diagnosis (positive CSF, n ¼ 4; solid CNS except for a slight dose reduction of carboplatin (500 mg/m2/day). VCA metastases, n ¼ 2; positive CSF and solid CNS metastases, n ¼ 3). consisted of VCR (1.5 mg/m2/day; days 1 and 8), CY (1500 mg/m2/day; Tumor location was supratentorial in 11 and infratentorial in eight day 1) and actinomycin D (25 mg/m2/day; days 1 and 2). For infants o6 patients. Two of the patients with SMARCB1 germline mutations months or o10 kg, doses were further reduced to 2/3 or 1/2 in initial cycles presented with synchronous peripheral malignant rhabdoid and were adjusted according to tolerance. tumors (Table 1). One patient (patient 13) has been reported previously.11 Brieﬂy, a 2-year-old boy with mosaic Klinefelter Maintenance chemotherapy syndrome was primarily found to have metastatic medullo- Maintenance therapy with trofosfamide, idarubicine, etoposide and blastoma and was treated according to the Italian protocol for temozolomide was recommended in patients with germline mutations, high-risk medulloblastoma. He was in CR until the age of 7½ years residual disease after termination of intensive therapy or slow response to when he developed an isolated spinal lesion, which was subtotally

& 2014 Macmillan Publishers Limited Bone Marrow Transplantation (2014) 370 – 375 Auto-SCT in children with AT/RT M Benesch et al 372 Table 1. Basic clinical characteristics of study patients

Patient Gender Age at Tumor location Dissemination Initial surgery diagnosis (mos) at diagnosis

1 Male 31 Supratentorial Noa Partial resection 2 Male 22 Supratentorial Yes (CSF) Subtotal resection 3 Male 11 Infratentorial No Partial resection 4 Female 11 Infratentorial No Total resection 5 Female 0 Supratentorial, synchronous No Total resection temporo-/ periorbital MRT 6 Male 4 Infratentorial/ central midline, Yes (CSF þ solid) Total resection synchronous cervical MRT 7 Female 42 Supratentorial Yes (CSF þ solid) Biopsy 8 Male 10 Infratentorial Nob Subtotal resection 9 Male 64 Infratentorial No Partial resection 10 Male 1 Infratentorial No Biopsy 11 Male 35 Supratentorial Yes (CSF) Partial resection 12 Male 6 Supratentorial Yes (solid) Subtotal resection 13c Male 24 Infratentorial Yes (CSF þ solid) Partial resection 14 Male 52 Supratentorial No Partial resection 15 Male 29 Supratentorial Yes (CSF)b Total resection 16 Male 29 Supratentorial Yes (solid) Biopsy 17 Male 21 Supratentorial Yes (CSF) Partial resection 18 Female 10 Supratentorial No Total resection 19 Male 13 Infratentorial No Partial resection

Abbreviations: Mos ¼ months; MRT ¼malignant rhabdoid tumor. aNo cytological analysis of CSF. bNo spinal MRI. cSpinal relapse of an infratentorial tumor originally considered to be medulloblastoma was treated according to the EU-RHAB.

Table 2. Treatment characteristics of study patients

Patient Number of Response to Radiotherapy Conditioning Disease Clinical course and chemotherapy induction status follow-up (mos) cycles prior chemotherapy after to HDCT HDCT

1 6 SD No CBCDA/ETO PD DOD (8) 2 6 n.a. No First auto-SCT: CBCDA/ETO CR PD-DOD (11) second auto-SCT: CPM/TTP 3 8 CR Yes (50 Gy, following CBCDA/ETO PD PD-DOD (14) progression þ SL surgery) 4 9 PR Yes (54 Gy, following progression) CBCDA/TTP CR PD-CR2/NED (48) 5 8 CR No First auto-SCT: CBCDA/ETO CR NED (49) second auto-SCT: CPM/TTP 6 6 PR Yes (54 Gy, following progression) CBCDA/TTP PR PD-DOD (27) 7 6 PD Yes (30 Gy, CSI (early CBCDA/TTP SD PD-DOD (11) discontinuation), following progression) 8 6 CR Yes (54 Gy, prior to progression) CBCDA/TTP CR PD-AWD (34) 9 6 CR Yes (54 Gy, prior to progression) CBCDA/TTP PD PD-DOD (15) 10 5 PR No First auto-SCT: CBCDA/ETO SD PD-DOD (12) second auto-SCT: CPM/TTP 11 7 SD Yes (50 Gy, prior to progression) CBCDA/TTP PD PD-DOD (16) 12 2 PD Yes (20 Gy, area of recurrence First/second auto-SCT: SD PD-DOD (10) only) TTP/MEL 13a 6 PR Yes (40 Gy) CBCDA/TTP PR PD-CR2 (91) 14 6 CR Yes (54 Gy, prior to progression) CBCDA/TTP CR PD-DOD (22) 15 3 PR No CBCDA/ETO CR PD-DOD (18) 16 6 PR Yes (55 Gy, CSI (35.2 Gy)) CBCDA/TTP PR PR-AWD (16) 17 8 PR Yes (60 Gy) CBCDA/TTP PR CR-NED (15) 18 4 CR Yes (54 Gy) First auto-SCT: CBCDA/ETO CR CR-NED (83) second auto-SCT: CPM/TTP 19 6 PR Yes (54 Gy, 6 Gy boost) First auto-SCT: CBCDA/ETO PR CR-NED (43) second auto-SCT: CPM/TTP

Abbreviations: AWD ¼ alive with disease; CBCDA ¼ carboplatin; CPM ¼ CY; CSI ¼ craniospinal irradiation; DOD ¼ dead of disease; ETO ¼ etoposide; MEL ¼ melphalan; n.a. ¼ not available; NED ¼ no evidence of disease; PD ¼ progressive disease; SD ¼ stable disease; SL ¼ second look; TTP ¼ thiotepa. aSpinal relapse of an infratentorial tumor originally considered to be medulloblastoma was treated according to the EU-RHAB.

Bone Marrow Transplantation (2014) 370 – 375 & 2014 Macmillan Publishers Limited Auto-SCT in children with AT/RT M Benesch et al 373 removed. Histopathological (re-) evaluation of both the spinal a Patients and previous cerebellar lesion revealed AT/RT. Genetic testing for rhabdoid tumor predisposition syndrome was positive. 1.0 Subsequent treatment was performed according to the EU-RHAB recommendations. 0.8

Treatment prior to high-dose chemotherapy 0.6 Treatment-related data of study patients are summarized in Tables 1 and 2. All patients underwent initial surgery (total 0.4 resection, n ¼ 5; partial or subtotal resection, n ¼ 11; biopsy, n ¼ 3) and conventional induction chemotherapy prior to HDCT. The median number of pretransplant chemotherapy cycles was 6 0.2 (range, 2–9). As the Rhabdoid 2007 registry did not contain any Progression-free survival speciﬁc recommendation concerning HDCT, it was at the 0.0 discretion of the treating physician when to proceed with HDCT. 0 122436486072 Ten of the 13 patients included in the EU-RHAB completed the six planned chemotherapy courses prior to HDCT as per protocol. Months Two patients received one and two additional courses at the b discretion of the treating physicians, respectively. The remaining 1.0 patient progressed under chemotherapy and received only 5 cycles. Radiotherapy was performed in 14 patients (ﬁrst-line, n ¼ 9; 0.8 following progression, n ¼ 5); 12 of these patients received local and two received craniospinal radiotherapy. 0.6

High-dose chemotherapy 0.4 The median age at the time of transplantation was 29 months

(range, 6–98). HDCT was used as part of the first-line treatment in Overall survival 12 study patients. In seven patients, HDCT was performed as 0.2 salvage treatment following first relapse or progression. Six study patients underwent tandem auto-SCT. Carboplatin/thiotepa 0.0 (n ¼ 10) was the most commonly employed regimen, followed by carboplatin/etoposide (n ¼ 8), CY/thiotepa (n ¼ 5) and thiotepa/ 0 122436486072 melphalan regimens (n ¼ 2) (Table 2). In the vast majority of Months patients, conditioning was based on carboplatin (n ¼ 18) and/or Figure 1. (a) Kaplan–Meier plots of the estimated PFS rate for all 19 thiotepa (n ¼ 17). Disease status before HDCT was CR in six, PR in study patients. (b) Kaplan–Meier plots of the estimated OS rate for eight, stable disease in two and progressive disease (PD) in two all 19 study patients. patients (data missing, n ¼ 1). In two patients, remission status (CR/PR) was achieved by second look surgery following relapse. A median of 9.4 Â 106 CD34 þ cells per kg body weight (range, 1.2– Of note, two patients with germline SMARCB1 mutations are in 37.4) was infused. All patients engrafted. TRM was 0%. first (patient 5) or second (patient 13) CR. The two other patients with germline SMARCB1 mutations died of PD 26 and 18 months after diagnosis. Clinical course and status of remission With a median follow-up of 16 months (range, 8–83), 14 patients Late effects in long-term survivors (74%) progressed. Estimated PFS and OS at 2 years were 29% ± ± The late effects of the previously reported patient are described in ( 11%) and 50% ( 12%), respectively (Figures 1a and b). At last 11 follow-up, eight patients were alive (first CR, n ¼ 4; second CR, detail elsewhere. Of the remaining four long-term survivors n ¼ 2; PR, n ¼ 1; PD, n ¼ 1). Eleven patients died of PD. The median (X24 months follow-up from diagnosis), one (patient 19) suffers estimated time-to-progression was 14 months. The first recurrence from eye movement dysfunction (strabismus), mild ataxia and was a local progression in five, a locoregional relapse in four and a mild dyslalia. One patient (patient 18) has tumor-associated left- distant relapse in four patients. One patient had a combined local sided hemiparesis and facial nerve paresis already present at the and distant progression. time of diagnosis. Both patients developed bilateral sensorineural None of the parameters tested had an impact on PFS or OS. Of hearing loss requiring a hearing aid in one of them and seven patients who underwent HDCT following progression or (currently unsubstituted) growth hormone deficiency. They also relapse, two (patients 4 and 13) were alive at last follow-up in demonstrate delay of language development; hence they attend a second CR 32 and 24 months after relapse (28 and 17 months special preschool class and receive additional speech and after HDCT). Both patients had received additional local radio- educational training. A developmental delay, ataxia of the trunk, therapy following relapse. amblyopia and strabism were observed in patient 4, whereas in Of 12 patients who were transplanted as part of their first-line patient 5, who attends a normal kindergarten, no late sequelae are treatment, four (patients 5, 17, 18 and 19) were in first continuous documented. CR 49, 15, 83 and 43 months after diagnosis. Ages at diagnosis of these patients were 0, 21, 20 and 13 months. Three had a supratentorial and one an infratentorial AT/RT. One patient DISCUSSION (patient 17) had positive CSF cytology at the time of diagnosis; Although intensive multimodality treatment12,13 has been shown none had solid metastases. Local radiotherapy at 54–60 Gy to improve survival in a proportion of patients with AT/RT, data was delivered in three patients (prior to HDCT, n ¼ 1; following concerning the use of HDCT are still conflicting and limited to case HDCT, n ¼ 2). reports and few retrospective case series.5,8,14–21 These reports are

& 2014 Macmillan Publishers Limited Bone Marrow Transplantation (2014) 370 – 375 Auto-SCT in children with AT/RT M Benesch et al 374 Table 3. Reports on HDCT and auto-SCT in children with AT/RT

Reference Number of Median Surgery Radiotherapy Status Conditioning Outcome (survival (mos)) patients age (mos) prior to HDCT (M status)

5 n ¼ 13 (n.r.) 31 GTR, n ¼ 7 n ¼ 5 NED, n ¼ 9 CBCDA/TTP, n ¼ 7 NED, n ¼ 6 (9.5–90) STR, n ¼ 6 (CSI, n ¼ 2) MD, n ¼ 4 Other regimens, n ¼ 6 DOD, n ¼ 6, DOC, n ¼ 1 8a,b n ¼ 9(Mþ , n ¼ 3) 19.8 GTR, n ¼ 5 n ¼ 3 n.r. CBCDA/TTP/ETO, n ¼ 1 NED, n ¼ 8 (29.2–96) oGTR, n ¼ 4 (CSI, n ¼ 1) CBCDA/TTP ( Â 3), n ¼ 8 AWD, n ¼ 1 14 n ¼ 1(M0) 4 oGTR — MD CBCDA/TTP/ETO (First HDCT) NED (32) BU/MEL/TTP (second HDCT) 15 n ¼ 3 (M0) 29, 42, 91 GTR, n ¼ 2 n ¼ 3 NED, n ¼ 3 ETO/TTP/CPM NED, n ¼ 2(101þ /105 þ ) oGTR, n ¼ 1 AWD, n ¼ 1 16 n ¼ 6(Mþ , n ¼ 2) 24 GTR, n ¼ 5 n ¼ 1 NED, n ¼ 6 Various regimens NED, n ¼ 2 (78/98) oGTR, n ¼ 1 DOD, n ¼ 3 AWD, n ¼ 1 17b n ¼ 6(Mþ , n ¼ 3) 35 GTR, n ¼ 2 n ¼ 2 n.r. CBCDA/TTP (x3) NED, n ¼ 4 (23–64) STR, n ¼ 4 DOD, n ¼ 2 18c n ¼ 6(Mþ , n ¼ 4) 11.5 GTR, n ¼ 4 n ¼ 5 NED, n ¼ 2 CBCDA/TTP/ETO NED, n ¼ 4 (16–70) oGTR, n ¼ 2 MD, n ¼ 4 (First HDCT) AWD, n ¼ 1 CPM/MEL DOD, n ¼ 1 (second HDCT) 19c n ¼ 5(Mþ , n ¼ 5) 14.5 GTR, n ¼ 3 n ¼ 2MD,n ¼ 5 CBCDA/TTP/ETO PD, n ¼ 5 oGTR, n ¼ 2 (First HDCT) CPM/MEL (second HDCT) 20d n ¼ 13 35 GTR, n ¼ 7 n ¼ 4 NED, n ¼ 6 CBCDA/TTP/ETO NED, n ¼ 3 oGTR, n ¼ 6 (CSI, n ¼ 2) MD, n ¼ 5 (42 þ ,54þ ,67þ ) n.r., n ¼ 2 DOD, n ¼ 8 DOC, n ¼ 2 21d n ¼ 32 HSI: 36 GTR/near GTR — n.r. CBCDA/TTP/ETO 2-year EFS (HSI): n.r. HSII: 28 HSI: 33% 2-year EFS (HSII): 43% HSIII: 13.6 HSII: 72% 2-year EFS (HSIII): 28% HSIII: 73%

Abbreviations: AT/RT ¼atypical teratoid/rhabdoid tumors; AWD ¼ alive with disease; CSI ¼ craniospinal irradiation; DOC ¼ dead of other causes; DOD ¼ dead of disease; GTR ¼ gross total resection; oGTR ¼ less than gross total resection; HDCT ¼ high-dose chemotherapy; HS ¼ Head Start; M0 ¼ no metastases at the time of diagnosis; M þ¼evidence of metastases at the time of diagnosis; MD ¼ measurable disease; n.r. ¼ not reported; NED ¼ no evidence of disease; PD ¼ progressive disease; STR ¼ subtotal resection. aA total of 19 patients underwent HDCT with auto-SCT. Detailed data of the nine survivors were provided in the paper. b,c,dOverlapping study populations.

summarized in Table 3. The number of patients included in these So far, HDCT has generally been well tolerated with low TRM. studies ranges from 3 to 32.5,8,14–21 In the larger series, a 2-year One out of 13 patients died from toxic death in the study by (event-free or overall) survival of up to 50% has been reported.8,21 Hilden et al.5 Among patients (n ¼ 7) treated according to the Recently, a retrospective, non-randomized Canadian study has Head Start II protocol, one patient died from meningitis and demonstrated a statistically significant survival benefit in patients another from secondary leukemia.20 In other studies, no who had undergone HDCT.8 treatment-related deaths were explicitly reported.8,15–18 A descriptive analysis of 26 long-term survivors after HDCT— In contrast, the best treatment results in patients with AT/RT arbitrarily defined as surviving without evidence of disease X24 reported to date were achieved by an intensive multimodality months from diagnosis—included in the present and previous treatment based on systemic and intrathecal chemotherapy and series5,8,14–18,20 revealed a median age at diagnosis of 18 months radiotherapy. PFS and OS at 2 years were 53% and 70%, (range, 0–49). Supra- and infratentorial AT/RT were almost equally respectively. Craniospinal and primary site doses in the Rhabdoid represented (12:14). In the vast majority of patients (n ¼ 19), the 2007 and EU-RHAB registries were identical to those used in the tumor was localized at diagnosis; only three patients had study by Chi et al.12 which enrolled 20 patients with AT/RT. Eleven metastatic disease (data on the disease stage not available, of them received conformal RT and two of them relapsed. Among n ¼ 4). A complete resection was achieved in 17 patients. the four patients who received craniospinal irradiation, three have Radiotherapy was administered in seven patients as part of initial experienced relapse. treatment and in five patients at relapse. Fourteen patients (53%) Age was a significant prognostic parameter in some,4,5,7,9 but did not receive any radiotherapy. Of note, a small number of not all studies.6,8,12 As the median age at diagnosis of patients patients (n ¼ 6) in these studies were in remission but had shorter who receive radiotherapy is higher than in non-irradiated (o24 months) follow-up. The high proportion of non-irradiated patients,4,5 the better outcome of older patients most probably patients indicates that HDCT is used in a considerable number of reflects the fact that these patients are more likely to be subjected patients to avoid radiotherapy and, in fact, this approach might to radiotherapy. However, none of the studies is presently able to occasionally be successful. Another goal of HDCT is to rescue answer the question whether or not older age is per se a good patients who had experienced disease progression. Five of the 26 prognostic factor. patients who survived 42 years were transplanted following PD The present multi-institutional series is one of the largest and achieved a second remission. All five patients underwent studies on HDCT in children with centrally reviewed AT/RT. irradiation at the time of relapse; in three of them second surgery Striking clinical characteristics were the strong male predomi- was performed. Thus, radiotherapy seems to be critically nance (3.75:1) and more importantly the high proportion of important in achieving a second remission following PD. Three patients with metastatic disease (47%). Despite this negative of the 26 patients had metastases at diagnosis, indicating that selection, 2-year PFS (29±11%) and OS (50±12%) in our study only a small minority of patients with disseminated disease will are comparable to those reported by others. Radiotherapy appears ultimately reach long-term survival. to have contributed to the positive outcome in our long-term

Bone Marrow Transplantation (2014) 370 – 375 & 2014 Macmillan Publishers Limited Auto-SCT in children with AT/RT M Benesch et al 375 survivors. Complete CNS staging and central pathological 6 Buscariollo DL, Park HS, Roberts KB, Yu JB. Survival outcomes in atypical teratoid review could be obtained in 84 and 95% of study patients. With rhabdoid tumor for patients undergoing radiotherapy in a Surveillance, Epide- 13 of 19 patients analyzed, this study also includes the most miology, and End Results analysis. Cancer 2012; 118: 4212–4219. comprehensive data for SMARCB1 germline mutations in AT/RT 7 Dufour C, Beaugrand A, Le Deley MC, Bourdeaut F, Andre´ N, Leblond P et al. patients treated with HDCT. Mutations were detected in 4/13 Clinicopathologic prognostic factors in childhood atypical teratoid and rhabdoid analyzed patients, which is an expected frequency;22 interestingly, tumor of the central nervous system: a multicenter study. Cancer 2012; 118: two of these patients are long-term survivors. Treatment 3812–3821. recommendations were less consistently followed (for example, 8 Lafay-Cousin L, Hawkins C, Carret AS, Johnston D, Zelcer S, Wilson B et al. Central nervous system atypical teratoid rhabdoid tumours: the Canadian Paediatric Brain carboplatin/thiotepa was used as conditioning in 10/19 patients) Tumour Consortium experience. Eur J Cancer 2012; 48: 353–359. reflecting the lack of evidence concerning optimal treatment of 9 Tekautz TM, Fuller CE, Blaney S, Fouladi M, Broniscer A, Merchant TE et al. Atypical AT/RT. However, with increasing acceptance and recruitment teratoid/rhabdoid tumors: improved survival in children 3 years of age and older numbers a stricter adherence to protocol guidelines is expected. with radiation therapy and high-dose alkylator-based chemotherapy. J Clin Oncol 2005; 23: 1491–1499. 10 Kordes U, Gesk S, Fru¨hwald MC, Graf N, Leuschner I, Hasselblatt M et al. CONCLUSION Clinical and molecular features in patients with atypical teratoid rhabdoid Although current evidence suggests that approximately one-third tumor or malignant rhabdoid tumor. Genes Chromosomes Cancer 2010; 49: 176–181. of patients with AT/RT can achieve sustained remissions after 11 Modena P, Sardi I, Brenca M, Giunti L, Buccoliero AM, Pollo B et al. Case report: HDCT, the question which patient might eventually benefit from long-term survival of an infant syndromic patient affected by atypical teratoid- this approach cannot be answered based on available data. The rhabdoid tumor. BMC Cancer 2013; 13: 100. present series are limited by small patient numbers, heteroge- 12 Chi SN, Zimmerman MA, Yao X, Cohen KJ, Burger P, Biegel JA et al. Intensive neous study populations and a non-randomized and retrospective multimodality treatment for children with newly diagnosed CNS atypical teratoid study design. HDCT might be useful in patients with localized rhabdoid tumor. J Clin Oncol 2009; 20: 385–389. disease, good response to induction chemotherapy and no or 13 Zimmerman MA, Goumnerova LC, Proctor M, Scott RM, Marcus K, small residual tumor following conventional therapy. In addition, Pomeroy SL et al. Continuous remission of newly diagnosed and relapsed the impact of each treatment modality on long-term survival central nervous system atypical teratoid/rhabdoid tumor. J Neurooncol 2005; 72: 77–84. remains to be elucidated. A meta-analysis of all available patients’ 14 Gidwani P, Levy A, Goodrich J, Weidenheim K, Kolb EA. Successful outcome with data might help to better define prognostic factors. The definitive tandem myeloablative chemotherapy and autologous peripheral blood stem cell role of HDCT, however, has to be evaluated in a randomized study. transplants in a patient with atypical teratoid/rhabdoid tumor of the central nervous system. J Neurooncol 2008; 88: 211–215. 15 Fidani P, De Ioris MA, Serra A, De Sio L, Ilari I, Cozza R et al. A multimodal strategy CONFLICT OF INTEREST based on surgery, radiotherapy, ICE regimen and high dose chemotherapy in The authors declare no conflict of interest. atypical teratoid/rhabdoid tumours: a single institution experience. J Neurooncol 2009; 92: 177–183. 16 Nicolaides T, Tihan T, Horn B, Biegel J, Prados M, Banerjee A. High-dose che- ACKNOWLEDGEMENTS motherapy and autologous stem cell rescue for atypical teratoid/rhabdoid tumor of the central nervous system. J Neurooncol 2010; 98: 117–123. We thank Petra Neumayer (EU-RHAB trial center Augsburg, Germany) for excellent 17 Finkelstein-Shechter T, Gassas A, Mabbott D, Huang A, Bartels U, Tabori U et al. data management and administrative support. EU-RHAB is supported by the Atypical teratoid or rhabdoid tumors: improved outcome with high-dose che- Deutsche Kinderkrebsstiftung (German Childhood Cancer Foundation). motherapy. J Pediatr Hematol Oncol 2010; 32: e182–e186. 18 Park ES, Sung KW, Baek HJ, Park KD, Park HJ, Won SC et al. 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