Girish Dhall

Medulloblastoma is the most common brain tumor in early childhood. Molecular profiling of medulloblastomas has resulted in a classification system including at least 4 major subtypes of disease, defining prognosis in patients treated largely on traditional chemotherapy and irradiation-based protocols. The Head Start Consortium has developed treatment protocols designed to avoid irradiation and its debilitating long-term side effects. The first three Head Start trials showed promising results; however, prospective genetic data are still lacking to evaluate whether molecular alterations can predict patient response to irradiation-avoiding treatment strategies. The Head Start 4 Protocol is a multi-national trial that incorporates non-mandatory, prospective tumor and blood collection for analysis in an attempt to address this question. Currently, 100% of patients enrolled to date have submitted samples for WES. Paired blood and tumor samples (FFPE) from the first 10 medulloblastoma patients had WES (SureSelect Human All Exon V6+COSMIC) performed utilizing an Illumina Hiseq 4000. Data were processed using varscan v2.4.1 somatic command on tumor/normal pairs and annotated using Variant Effect Predictor from ensembl. Results were filtered at a threshold of 20 read depth or 40% variant allele frequency. Low-impact mutations were removed. Mutation profiles were compared with pediatric medulloblastoma gene mutation data from the PedcBioPortal and PeCan databases. A total of 903 mutation events were identified across 10 patients with each patient demonstrating mutations in one or more genes previously reported to be mutated in medulloblastoma. Two samples harbored SUFU mutations similar to those reported previously. CONCLUSIONS: These data show the feasibility of prospective high-dimensional mutational analysis using non-mandatory tissue submissions for pediatric medulloblastoma patients enrolled on the Head Start 4 Protocol. Copy-number and methylation analysis is ongoing. FUNDING: Thrasher Research Fund (JF, AC). R01CA108633, R01CA169368, RC2CA148190, U10CA180850-01 (NCI), Brain Tumor Funders Collaborative Grant, and OSUCCC (AC).

Pineoblastoma is a rare malignant pineal region tumor, the optimal management of which in young children remains unclear. We report the outcomes of 23 children with pineoblastoma prospectively enrolled on three sequential Head Start (HS) trials between 1990 and 2009. The HS treatment strategy included maximal surgical resection followed by five cycles of intensive induction chemotherapy and consolidation with marrow-ablative chemotherapy and autologous hematopoietic cell rescue (HDCx/AuHCR). Irradiation following recovery from consolidation was reserved for children over six years old or with residual tumor. Data on 23 children with pineoblastoma including two with trilateral retinoblastoma aged 0.44–5.72 (median 3.12) years were analyzed. Median overall survival (OS) was 12 months (95% CI: 7.6–29.7 months). The 3-year progression-free survival (PFS) and OS were 14.5% (95% CI: 5.1–41.2%) and 17.4% (95% CI: 7.1–42.4%), respectively. Three patients were long-term survivors beyond 5 years. Eight patients experienced progressive disease (PD) during induction chemotherapy, six following the fourth and fifth cycles. Ten patients proceeded to consolidation with HDCx/AuHCR; eight experienced PD post-consolidation. Seven patients received craniospinal irradiation with boost(s) (median dose 20.7 (18–36) Gy), three patients as adjuvant therapy and four upon progression/recurrence. Favorable prognostic factors were administration of radiotherapy (hazard ratio (HR) for OS=0.30 (0.11–0.86), p<0.025), and undergoing HDCx/AuHCR (HR for OS=0.40 (0.16–0.99), p<0.047). There were no statistically significant associations between age, metastasis and extent of surgical resection and OS. CONCLUSIONS: Radiotherapy and HDCx/AuHCR were the sole driving factors for positive impact on survival. No benefit of high-dose methotrexate during induction was demonstrable. The high PD rate during later induction cycles as well as following consolidation chemotherapy warrant consideration of (1) fewer induction cycles prior to consolidation, (b) intensification of consolidation with multiple cycles of marrow-ablative chemotherapy and (c) judicious post-consolidation irradiation, in order to improve outcomes.

IGTS is a rare phenomenon of paradoxical germ cell tumor (GCT) growth during or following treatment despite normalization of tumor markers. We sought to evaluate the frequency, clinical characteristics and outcome of IGTS in patients in 21 North-American and Australian institutions. Patients with IGTS diagnosed from 2000-2017 were retrospectively evaluated. Out of 739 GCT diagnoses, IGTS was identified in 33 patients (4.5%). IGTS occurred in 9/191 (4.7%) mixed-malignant GCTs, 4/22 (18.2%) immature teratomas (ITs), 3/472 (0.6%) germinomas/germinomas with mature teratoma, and in 17 secreting non-biopsied tumours. Median age at GCT diagnosis was 10.9 years (range 1.8-19.4). Male gender (84%) and pineal location (88%) predominated. Of 27 patients with elevated markers, median serum AFP and ßHCG were 70 ng/mL (range 9.2-932) and 44 IU/L (range 4.2-493), respectively. IGTS occurred at a median time of 2 months (range 0.5-32) from diagnosis, during chemotherapy in 85%, radiation in 3%, and after treatment completion in 12%. Surgical resection was attempted in all, leading to gross total resection in 76%. Most patients (79%) resumed GCT chemotherapy/radiation after surgery. At a median follow-up of 5.3 years (range 0.3-12), all but 2 patients are alive (1 succumbed to progressive disease, 1 to malignant transformation of GCT). IGTS occurred in less than 5% of patients with GCT and most commonly after initiation of chemotherapy. IGTS was more common in patients with IT-only on biopsy than with mixed-malignant GCT. Surgical resection is a principal treatment modality. Survival outcomes for patients who developed IGTS are favourable.

Intracranial germ cell tumors represent 3-5% of pediatric CNS tumors. Non-germinomatous germ cell tumors (NGGCT) have worse outcomes compared to germinomas, however, improved survivals were achieved on COG ACNS0122 utilizing a combination of chemotherapy and craniospinal irradiation (CSI). Since CSI is associated with significant late effects, a Phase 2 study was undertaken to determine whether irradiation could be reduced without impacting survival in a subgroup of NGGCT patients. Patients with localized disease who achieved a complete (CR) or partial response (PR) to chemotherapy were eligible for reduced irradiation to 30.6Gy whole ventricular field (WVI) and 54Gy tumor-bed boost as compared to 36Gy CSI plus tumor-bed boost as used on ACNS0122. Between 5/2012 and 11/2016, 107 eligible patients were accrued. Median age was 11 years (range: 4-22) and 75% were male. Tumor location was pineal in 58, suprasellar in 37, ventricular in 6 and bifocal in 6 patients. Sixty-six patients achieved CR/PR post-induction and received reduced irradiation. The 2-year progression-free survival (PFS) was 89% (95% CI: 81%-97%) and overall survival was 92% (95% CI: 86%- 99%). Eight patients progressed; seven had a distant relapse (outside the irradiation field) and one patient had a local plus distant relapse. Alpha-fetoprotein and beta-human chorionic gonadotropin levels were not associated with PFS. There were no unexpected treatment-related adverse events or deaths. Although these survival data are encouraging, distant relapses noted in all of the patients who progressed are concerning. Longer follow-up of the ACNS1123 cohort may better inform our recommendations in the future.

Prognosis for central nervous system (CNS) non-germinomatous germ cell tumor (NGGCT) patients that relapse during induction is poor. We present our experience for these patients. Medical records of CNS NGGCT patients at Children’s Hospital Los Angeles between 2008 and 2014 were reviewed for clinical characteristics, treatment, and outcome. Eight (27.6%) of 29 patients relapsed or were refractory during induction chemotherapy, an average of 6.3 months from diagnosis. Five patients had pineal primaries and three patients had synchronous pineal and suprasellar tumors. All patients had tumor marker (TM) elevation in serum and/or CSF; four patients underwent biopsy. Three patients had local relapse, two local and ventricular, and three had TM-only relapse. All received re-induction chemotherapy with gemcitabine 800mg/m2, paclitaxel 170mg/m2, and oxaliplatin 100mg/m2 (GemPOx). After re-induction, the three TM-only relapses continued to have no evidence of disease (NED) radiographically, three patients showed a partial response (PR), and two patients had stable disease (SD). Seven patients received high-dose chemotherapy with a thiotepa-based regimen followed by autologous stem cell rescue (ASCR). After ASCR, radiographically, three TM positive cases continued to be NED, three had a PR, and one patient had SD. Six received additional irradiation post-transplant, of which five are alive. Six of eight relapsed/refractory patients are alive at 41, 42, 66, 71, 78, 79 months from initial diagnosis. Relapsed/refractory CNS NGGCT patients can be successfully salvaged by re-induction chemotherapy followed by consolidation with a thiotepa-based myeloablative regimen and re- irradiation.

Radiation therapy, while a mainstay of medulloblastoma treatment, is associated with significant age-dependent neurocognitive morbidity in children. Relatively little is known about the subgroup-specific outcome of infants and young children with medulloblastoma treated with irradiation-sparing regimens. Infants and young children <10 years of age with medulloblastoma treated with irradiation-sparing regimens (Head Start, COG-99703, or others) at Children’s Hospital Los Angeles since 1980 were identified. Molecular subgroup was determined using a 31-gene TaqMan Low Density Array signature. Survival analyses were conducted based on 4 molecular subgroups (WNT, SHH, Group 3, and Group 4). Seventy-six patients with medulloblastoma were identified, with five excluded from survival analysis secondary to non-cancer related deaths. Of these 71 patients, 30 did not receive irradiation as part of their upfront therapy. These patients were divided into SHH (n=17), Group 3 (n=3) and Group 4 subgroups (n=10), with no WNT subgroup identified. Median age at diagnosis was 2.16 (range:0.24-9.80) years. 5-year progression-free survival rates for SHH, Group 3, and Group 4 for this irradiation-sparing cohort were 76.5%±10.3%, 0% and 0%, respectively; 5-year overall survival rates for SHH, Group 3 and Group 4 were 94.0%±5.7%, 0% and 26.7%±15.0%, respectively. There was a marked difference in outcome among infants/young children with SHH medulloblastoma vs Group 3/4 medulloblastoma treated with irradiation-sparing regimens. Most patients <10 years of age with SHH medulloblastoma were treated effectively with irradiation-sparing regimens, with high salvageability among those who progressed. Group 3/4 medulloblastoma patients treated without irradiation had extremely poor outcome.

Ras/Raf/MEK/ERK pathway activation is the primary driver of most pediatric low-grade gliomas (LGG). MEK162 is an orally bioavailable MEK1/2 inhibitor. The primary objective of this first-in-children multi-institutional open-label dose-escalation trial was to determine the maximum tolerated dose (MTD) of MEK162 oral suspension in children. Children aged 1-18 years with recurrent, refractory or progressive LGG and other non-hematologic malignancies associated with Ras/Raf pathway activation were enrolled according to a 3 + 3 dose-escalation design. Partial response (PR) and radiographic progressive disease (PD) were defined as ≥50% decrease and ≥25% increase in 2-dimensional tumor measurements. Nineteen eligible patients, aged 2-15 (median 9) years, including 17 with LGG, were enrolled and began treatment at five dose levels, from 16 to 32mg/m2/dose twice daily. There were no dose limiting toxicities (DLTs) in 18 DLT-evaluable patients; MTD was not reached. Most common drug-attributable grade ≥2 toxicities included (all grade 2 unless specified): asymptomatic elevated creatine kinase in 9 patients (53%; 1 grade 4, 3 grade 3), acneiform or maculopapular rash in 8 (47%; 2 grade 3), dry skin in 5 (29%; 2 grade 3), and lymphopenia in 4 (24%; 1 grade 3). To date, 4 patients have had clinical or radiographic PD (3 with LGG), and 4 LGG patients have had sustained PR. Twelve LGG patients have completed at least 36 weeks therapy, with a median 29% decrease in 2-dimensional tumor measurements. MEK162 is well tolerated in this pediatric population, with evidence of antitumor activity. A phase II study is ongoing.

Despite complete resection, 20% -50% of pediatric craniopharyngiomas experience recurrence. Subtotal resection followed by radiation achieves comparable results. More effective therapies are needed. In tumor cell lines, prolonged exposure to interferon optimizes the anti-proliferative and anti-angiogenic effect. Conjugating proteins with poly-ethylene-glycol (PEG) lengthens the plasma half-life by reducing sensitivity to proteolysis, providing protracted activity. Stratum II of the PBTC-039 study proposed to estimate the sustained objective response rate (ORR=CR + PR) associated with PEGIntron/Sylatron in progressive/recurrent craniopharyngiomas post RT. Simon’s 2-stage design with 10% unacceptable and 35% desirable ORR required a total sample size of 19 (α=β=0.1). An interim analysis was planned after 11 patients and ≥2 objective responses within the first year were needed to expand accrual. 12 patients were enrolled 11, (5 males and 6 females) were eligible and evaluable. Median age at diagnosis was 7.0 years (range, 2.0–12.4) and at study entry was 20.5 years (6.1–25). Median number of cycles received was 6 (1–17). No grade 4 adverse events (AE) were reported. Grade 3 attributable AEs included decreased neutrophil count, nausea, fatigue, fever, headache and anorexia (n=1 each). No objective responses were observed. With a median follow-up 12.9 months (3.2 - 25.7), 5/11 patients have progressed at a median of 8.2 months (2.9–19.5). Other off-treatment reasons were AE, alternative therapy/withdrawal and not meeting weight criteria. PFS estimate at 1-year was 68.2% ± 14.5%. One patient remains on treatment. Although well tolerated, stratum II was permanently closed after interim analysis due to lack of objective responses.

Metabolism of drugs in infants and young children is significantly different from older individuals due to differences in distribution, protein-binding capacity, hepatic metabolism and renal excretion. Body surface area (BSA) is used to dose chemotherapeutics in older children; however, this is inappropriate for infants and young children since it does not take into account the differences in extracellular water distribution. We describe four cases of sinusoidal obstruction syndrome (SOS) that occurred in young children while receiving induction chemotherapy with cisplatin, etoposide, vincristine, cyclophosphamide and high-dose methotrexate on the “Head Start (HS)” 4 clinical trial using BSA for dosing (mg/m2). Patients #1 and #2 were both 2-years old at diagnosis, received and tolerated the first two cycles with mg/kg dosing uneventfully, then turned 3-years old and received cycle #3 with mg/m2 dosing as per protocol guidelines, and developed SOS. Patient #3 was 3-years old at diagnosis, received induction chemotherapy with mg/m2 dosing, and developed SOS during the very first cycle. Patient #4 was 4-years old at diagnosis and received all 3 induction cycles with mg/m2 dosing, developed serious nephrotoxicity during cycle #1 followed by SOS during cycle #3. In contrast, none of the 40 patients treated on HS II protocol with identical chemotherapy regimen, but with mg/kg dosing, developed SOS. Caution should be exercised when dosing young children between 3-6 years of age by BSA. The HS 4 trial was amended and reopened after external, independent DSMB review to dose all chemotherapy drugs in children <6 years old with mg/kg dosing.