Autologous Hematopoietic Cell Rescue Research Articles

Marrow-ablative consolidation chemotherapy (HDCT) to decrease the development of choroid plexus carcinoma (CPC) specific relapse in high-risk TP53-mutated (germline or somatic) young children with newly diagnosed CPC.

2088 Background: Choroid plexus carcinomas (CPC) are highly malignant, early childhood cancers in which the loss of TP53 function is a central element of their development and defines unfavorable disease. To date, CPC-free survival rates have remained poor; recent data from St. Jude including complete TP53 mutation status, yielded CPC-free survival of only 29% with a non-marrow-ablative chemotherapy strategy. The rarity of CPC has constrained the ability to explore the role of HDCT with autologous hematopoietic progenitor cell rescue (AuHPCR). Previously reported results of the "Head Start" (HS) HDCT approach showed some promise of cure, but were limited by small patient numbers, short follow-up and incomplete TP53 mutation data. Consequently, the role of HDCT and AuHPCR in TP53-mutated CPC remains unclear. Methods: We have analyzed data on TP53 status, therapy, treatment responses, CPC-free and overall survivals (OS) and second cancers from the largest cohort of such patients, all who received initial therapy with the intent/consideration of undergoing consolidative HDCT. Results: Twenty-seven children with CPC (median age, 16 months) received HS-like induction chemotherapy regimens or ICE with the intent of utilizing consolidative HDCT. Twenty-three of 27 completed HDCT consolidation; the remaining 4 patients did not proceed with HDCT due to parental choice. Somatic or germline TP53 mutations were identified in 17 patients, while 4 patients exhibited TP53 wild type (TP53wt); TP53 status remains untested or unavailable in 6 patients. Five-year CPC-free survival and OS for the entire cohort were 47.8% and 44.4%. CPC-free survival for those with TP53 germline mutations (n=12) was 66%, for those with somatic tumor TP53 mutations (n=5) was 40% and for those with confirmed TP53wt (n=4) was 50%. The 5-year CPC-free survival for all 23 patients who underwent HDCT and AuHPCR was 52%, comprising 3/4 TP53wt patients, 10/12 TP53 germline mutated patients and all 5 TP53 somatic tumor mutated patients. Notably, all six survivors with TP53 mutations had undergone HDCT with AuHPCR, and all but one avoided irradiation. Eight out of 12 patients with documented genotypic (TP53 germline mutated) Li-Fraumeni Cancer Predisposition Syndrome (LFS) developed second malignancies. Conclusions: Our data indicate that HDCT with AuHPCR consolidation is associated with improved CPC-free survival compared with historical reports in young children with high-risk TP53 mutated CPC. However, the ultimate development of second cancers substantially affects outcomes for those with LFS, irrespective of HDCT treatment. These data justify the inclusion of HDCT and AuHPCR in the prospective international trial under development for young children with newly diagnosed TP53 mutated CPC.

The Management of Children with Pre-School Medulloblastoma – A Review of Four Decades of Multi-Disciplinary and Multi-Institutional Collaboration.

Background: The management and consequent survival and quality of survival for young children with medulloblastoma have undergone substantial improvement over the last four decades. While many of these changes reflect improvements in pediatric neurosurgical, neuro- imaging and radiation oncologic technology and training, as well as in supportive care experience and expertise, this review will focus particularly upon improvements in chemotherapeutic approaches. Methods: This review focuses only upon prospective clinical trials conducted in young children with newly-diagnosed medulloblastoma since the 1980s. The upper age limits for these trials varied from under three to up to six years of age at diagnosis. Results: Certain but not all trials endeavoring to improve outcomes for young children with now- recognized pathological and molecular low-risk characteristics, specifically the Sonic Hedgehog (SHH) sub-type, representing some 50-60% of young children with medulloblastoma, have reaped substantial gains in event-free and overall survival, irradiation-free survival as well as neuropsychological outcomes. Those successful trials utilized either induction including intravenous high-dose methotrexate and intraventricular (intra-Ommaya) methotrexate without consolidation by marrow-ablative chemotherapy with autologous hematopoietic progenitor cell rescue (AuHPCR), or induction with or without intravenous high-dose methotrexate (but not intra-ventricular methotrexate) followed by consolidation with marrow-ablative chemotherapy with AuHPCR. These two approaches have consistently produced superior outcomes compared with other trials. For children with molecularly-characterized Groups 3 or 4 medulloblastoma, representing those at high-risk of relapse, some modest improvements have been made over the years, but much room for improvement remains, especially for those presenting with the highest- risk molecular characteristics (CMYC-amplified Group 3 medulloblastoma) as well as for children with metastatic disease at initial diagnosis. Conclusions: Substantial gains in improving outcomes for young children with medulloblastoma have been achieved with acceptable short- and long-term morbidities of treatment. However, the inclusion of intra-ventricular therapies (conventional chemotherapeutic, radio-labeled monoclonal antibody or adaptive cellular immunotherapeutic approaches) as well as the identification of targeted systemic therapies (biological and/or immunological) and their incorporation into prospective multi-center clinical trials, must be investigated prospectively if we are to improve outcomes for those children at high-risk for relapse, even with the inclusion of refined irradiation therapeutic approaches.

Final report of the phase II NEXT/CNS-GCT-4 trial: GemPOx followed by marrow-ablative chemotherapy for recurrent intracranial germ cell tumors.

Patients with relapsed intracranial germinoma can achieve durable remission with standard chemotherapy regimens and/or reirradiation; however, innovative therapies are required for patients with relapsed and/or refractory intracranial nongerminomatous germ cell tumors (NGGCTs) due to their poor prognosis. Improved outcomes have been reported using reinduction chemotherapy to achieve minimal residual disease, followed by marrow-ablative chemotherapy (HDCx) with autologous hematopoietic progenitor cell rescue (AuHPCR). We conducted a phase II trial evaluating the response and toxicity of a 3-drug combination developed for recurrent intracranial germ cell tumors consisting of gemcitabine, paclitaxel, and oxaliplatin (GemPOx). A total of 9 patients with confirmed relapsed or refractory intracranial GCT were enrolled after signing informed consent, and received at least 2 cycles of GemPOx, of which all but 1 had relapsed or refractory NGGCTs. One patient with progressive disease was found to have pathologically confirmed malignant transformation to pure embryonal rhabdomyosarcoma (without GCT elements), hence was ineligible and not included in the analysis. Patients who experienced sufficient responses proceeded to receive HDCx with AuHPCR. Treatment response was determined based on radiographic tumor assessments and tumor markers. A total of 7 patients achieved sufficient response and proceeded with HDCx and AuHPCR, and 5 subsequently received additional radiotherapy. A total of 2 patients developed progressive disease while receiving GemPOx. Myelosuppression and transaminitis were the most common treatment-related adverse events. With a mean follow-up of 44 months, 4 patients (3 NGGCTs, 1 germinoma) are alive without evidence of disease. GemPOx demonstrates efficacy in facilitating stem cell mobilization, thus facilitating the feasibility of both HDCx and radiotherapy.

BIOM-49. A PILOT STUDY OF CEREBROSPINAL FLUID EXOSOMAL SMALL RNA-SEQUENCING IN PEDIATRIC MEDULLOBLASTOMA PATIENTS ON THE NEXT CONSORTIUM “HEAD START” 4 PROTOCOL

Abstract BACKGROUND Head Start 4 is a randomized clinical trial to determine whether dose-intensive tandem consolidation, compared with a single cycle, with autologous hematopoietic progenitor cell rescue provides a survival benefit in pediatric patients with medulloblastoma or other embryonal tumors. The trial incorporates upfront molecular subgrouping and non-mandatory, prospective blood and cerebrospinal fluid (CSF) collection. This pilot study aimed to identify exosomal non-coding RNAs (exo-ncRNAs) that might serve as novel diagnostic and/or treatment response biomarkers. METHODS CSF(1-2mLs) from 11 controls (non-tumor) and 27 medulloblastoma participants including 23 obtained at baseline, 22 at the end of induction, 3 post-consolidation, and 4 relapse time points, were profiled. Exosome isolation and small RNA-sequencing were performed by System Biosciences. Differential gene expression (DGE) was performed in R (DESeq2). Variations in gene expression profiles between samples were visualized using principal component analysis. RESULTS After limiting to ncRNAs with expression of 2 counts per million in 50% or more of the samples in each comparison, ~9,500 ncRNAs were detected. DGE analyses revealed 118 ncRNAs with log2 fold change(FC) >2 and 1 ncRNA with log2FC< -2 in baseline CSF samples compared to controls. In contrast, 11 ncRNAs(log2FC >2) and 1 ncRNA(log2FC< -2) were detected in end of induction CSF samples compared to controls. Comparing end of induction to baseline CSF samples accounting for paired samples, 0 ncRNAs(log2FC >2) and 52 ncRNAs(log2FC< -2) were detected. CONCLUSIONS Overall, our data indicate that exosomal small RNA-sequencing of limited CSF volumes is feasible. Differential expression and distinct clustering between tumor baseline samples compared to non-tumor controls was observed. CSF-derived exo-ncRNAs at end of induction also demonstrated “normalization” of ncRNA profiles, signifying CSF biomarkers may serve a role in diagnosis and molecular response assessment. A comprehensive analysis including multi-marker predictive model development and molecular subgrouping will be undertaken at completion of study enrollment.

ETMR-16. Embryonal tumors with multi-layered rosettes: A case series in treatment for newly diagnosed children

Abstract BACKGROUND: Embryonal tumors with multi-layered rosettes (ETMRs) are rare pediatric brain tumors with poorly defined prognostic features, standard of care treatments or outcome data. Recent data suggest that high-dose chemotherapy and radiotherapy is correlated with improved survival compared to chemotherapy alone. CASE DESCRIPTIONS: Four patients with newly diagnosed ETMRs were treated with 2 cycles of induction chemotherapy per PBTC-026 using isotretinoin, vorinostat, vincristine, cisplatin, etoposide, cyclophosphamide with added intrathecal topotecan. Second look surgery was performed if not in complete remission (CR). Consolidation was with three cycles of marrow-ablative chemotherapy (carboplatin and thiotepa) with autologous hematopoietic cell rescue followed by focal irradiation and 12 cycles of maintenance chemotherapy with intrathecal topotecan, vorinostat and isotretinoin. Patient 1 was a 3-year-old female with right parietal tumor, localized, and achieved gross total resection (GTR). Patient 2 was an 11-month-old male with posterior fossa tumor, localized, and achieved subtotal resection. Patient 3 was a 9-month-old female with posterior fossa tumor with near GTR, and metastasis to T12/L1 and L3/L4. [DTB1] [HNT2] Patient 4 was a 34-month-old male with a right frontal lobe tumor, localized and achieved GTR. Patient 1 is now 18 months from diagnosis and in CR. Patient 2 had second look surgery both after induction and consolidation but suffered neurologic injury to the brainstem which led family to decline further therapy. He is currently 14 months from diagnosis with stable residual disease. Patient 3 had local disease recurrence following radiation therapy at 10 months post diagnosis[DTB3] [HNT4] , prior to maintenance. Patient 4 remains in CR at 13 months from diagnosis, currently in maintenance with vorinostat and isotretinoin but declined intrathecal topotecan. CONCLUSION: This case series adds to current knowledge of intensive multi-modal therapy for newly diagnosed ETMR. Further study to define standard optimal treatments in this high-risk group of patients is warranted.

LTBK-05. Outcomes of Infants and Young Children with Newly Diagnosed Localized (M0) SHH Medulloblastoma Treated on The NEXT Consortium “Head Start” 4 Protocol

Advances in RNA and DNA profiling have identified four core molecular subgroups of medulloblastoma of prognostic significance: Sonic Hedgehog (SHH) subtype, WNT subtype, Group 3, and Group 4. Infants and young children with SHH medulloblastoma have demonstrated a favorable outcome in clinical trials utilizing either high-dose chemotherapy (“Head Start”) or a combination of intravenous and intraventricular methotrexate (HIT-SKK). Two recently conducted clinical trials (COG ACNS1221 and St. Jude – SJYC07) failed to demonstrate similar survival advantage with conventional dose chemotherapy and without intraventricular methotrexate. “Head Start” 4 (HS 4) is a prospective randomized clinical trial that tailors treatment based on medulloblastoma molecular subgroups and response to induction chemotherapy to compare the efficacy of one versus versus three (tandem) cycles of myeloablative therapy. Eligibility includes newly diagnosed children less than six years of age with localized medulloblastoma. Eligible patients with SHH medulloblastoma were considered “low-risk” and non-randomly assigned to receive three cycles of induction chemotherapy (vincristine, cisplatin, cyclophosphamide, etoposide, and high-dose methotrexate) followed by consolidation with single cycle of myeloablative chemotherapy (thiotepa, carboplatin, etoposide) and autologous hematopoietic progenitor cell rescue. Patients with less than a complete response after three induction cycles received two additional cycles prior to consolidation therapy. Only children between 6 -10 years old, or those with confirmed residual tumor post-consolidation, were meant to receive irradiation after consolidation. Twenty-eight children with localized SHH medulloblastoma were enrolled on the trial with a median age of 2.1 years (range: 0.3-5.9 years). Median follow-up for this cohort is 29.6 months (range: 7.0-58.6 months). The estimated 3-year event-free (EFS) and overall survival (OS) is 96% (CI: 89-100%) and 100%, respectively. The estimated 3-year EFS for SHH subtype 1 and 2 patients is 100% and 95%, respectively (p=0.65). None of the M0 SHH medulloblastoma patients received irradiation.

Chemotherapy strategies for young children newly diagnosed with desmoplastic/extensive nodular medulloblastoma up to the era of molecular profiling – a comparative outcomes analysis of prospective multi-center European and North American trials.

Abstract Aims Survival has been poor in several multi-center/national trials since the 1980s, either delaying, avoiding or minimizing brain irradiation in young children with medulloblastoma. The introduction of German regimens supplementing “standard” chemotherapy with both intravenous high-dose (HD-MTX) and intraventricular (IVENT-MTX) methotrexate, and North American regimens incorporating marrow-ablative chemotherapy with autologous hematopoietic cell rescue (HDCx+AuHCR), have reported encouraging outcomes. We performed a comparative outcomes analysis of these differing strategies for young children with desmoplastic/extensive nodular medulloblastoma. Method Data from 12 trials reported between 2005 and 2020 for children <six-years-old with desmoplastic/extensive nodular medulloblastoma were reviewed; event-free (EFS) survival+/-standard errors were compared. Results The German HIT-SKK’92 and HIT-SKK’00 trials incorporating HD-MTX and IVENT-MTX reported 85+/-8% and 95+/-5% 5-10-year EFS respectively; a third trial (ACNS1221) incorporating HIT-SKK therapy but without IVENT-MTX reported only 49+/-10% EFS. Three trials (Head Start I and II combined and CCG-99703) employing induction chemotherapy without HD-MTX, followed by one or three HDCx+AuHCR cycles, reported 3-5-year EFS of 67+/-16% and 79+/-11%. Two trials employing HD-MTX-containing induction chemotherapy (Head Start III and ACNS0334), followed by one or three HDCx+AuHCR cycles, reported 3-5-year EFS of 89+/-6% and 100%, respectively. Finally, four trials utilizing neither IVENT-MTX nor HDCx+AuHCR (UK-CNS-9204, CCG-9921, COG-P9934 and SJYC07) reported 2-5 year EFS of 35+/-11%, 77+/-9%, 58+/-8% and 53+/-9% respectively. Conclusion A trend towards better EFS for young children with desmoplastic/extensive nodular medulloblastoma is observed in trials including eitherHD-MTX and IVENT-MTX or including HD-MTX-containing induction chemotherapy and HDCx+AuHCR. Trials excluding HD-MTX, IVENT-MTX and HDCx+AuHCR have poorer outcomes.

Prognostic factors for patients with relapsed central nervous system nongerminomatous germ cell tumors.

We aimed toidentify prognostic factors that may help better understand the behavior of relapsed central nervous system nongerminomatous germ cell tumors. We identified nine studies, including 101 patients; 33 patients (33%) were alive 12 months post-initial relapse. Sixty percent of patients with serum/cerebrospinal fluid (CSF) alpha-fetoprotein (AFP) level ≤25 ng/mL at initial diagnosis were survivors compared with 28% among patients with serum/CSF AFP level >25 ng/mL (P = 0.01). Seventy-one percent of patients who achieved complete response/continued complete response (CR/CCR) by the end of therapy at relapse were survivors compared with 7% among patients who had less than CR/CCR (P < 0.0001). Forty-eight percent of patients who received marrow-ablative chemotherapy followed by autologous hematopoietic cell rescue (HDCx/AuHCR) following relapse were survivors compared with 12% among patients who did not receive HDCx/AuHCR (P = 0.0001). Local relapse site, gross total surgical resection, and radiotherapy at relapse were not associated with improved outcomes.

ATRT-26. META-ANALYSIS OF TREATMENT MODALITIES IN METASTATIC ATYPICAL TERATOID/RHABDOID TUMORS IN CHILDREN

BACKGROUNDMetastatic atypical teratoid/rhabdoid tumors (AT/RT) are aggressive central nervous system tumors that present during infancy and are associated with dismal outcomes. Patients receive multimodal treatment including surgical resection, systemic chemotherapy and one or more of intrathecal chemotherapy (IT), marrow-ablative chemotherapy with autologous hematopoietic cell rescue (AuHCR) and radiation therapy (XRT). While data regarding treatment modalities for AT/RT patients exist, no comprehensive data have been published regarding the metastatic patient population.METHODSWe performed a meta-analysis of 1,578 articles published through September 2018, including 44 studies with a total of 123 subjects. Additionally, seven patients were incorporated through chart review of patients treated at Nationwide Children’s Hospital.RESULTSAnalysis of 130 patients revealed a 3-year overall survival (OS) of 25%. Age at diagnosis had a significant impact on survival (p=0.0355); 3-year OS for infants < 18 months was 21%; 18–36 months was 26%; and > 36 months was 36%. Location of the primary tumor, metastatic stage and extent of surgical resection did not have significant impact on OS. On univariate analysis, XRT (p<0.0001), IT (p=0.01) and AuHCR (p<0.0001) were found to significantly improve survival. The most substantial effect was noted in patients who received AuHCR (3-year OS of 60% versus 9% in those who did not). On multivariable analysis XRT (p=0.0006), IT (p=0.0124) and AuHCR (p<0.0001) were independently associated with reduced risk of death.

RARE-31. RECURRENT CHOROID PLEXUS CARCINOMA IN THE SETTING OF LI-FRAUMENI SYNDROME: REPORT OF TWO CHILDREN MANAGED WITH INTENSIVE RE-INDUCTION AND MARROW-ABLATIVE CONSOLIDATION CHEMOTHERAPY WITHOUT IRRADIATION FOLLOWED BY MOLECULARLY-TARGETED BIOLOGICAL THERAPY

BACKGROUNDThe optimal management for children with recurrent choroid plexus carcinoma (CPC), is not established. We report two children with germline TP53 mutations, whose CPC relapses were managed with marrow-ablative chemotherapy and oral biologically-targeted therapies. PATIENTS: Patient A: A 17 months old male presented with non-metastatic bilateral CPC. A de novo mosaic germline TP53 mutation was identified. After near-total resections, 16 months of standard chemotherapy were administered; 18 months later, localized tumor growth developed, again near-totally resected. Two cycles of re-induction chemotherapy were administered followed by three cycles of thiotepa/carboplatin with autologous hematopoietic cell rescue (AuHCR) and subsequently 21 months of sirolimus and thalidomide, continuing without residual or recurrent disease. Patient B: A 30 months old male presented with left lateral ventricular non-metastatic CPC. A de novo TP53 germline mutation was identified. Following sub-total resection, craniospinal irradiation with boost was administered followed by eight cycles of standard chemotherapy; 18 months later, localized recurrence developed; gross total resection was followed by 15 months of standard dose chemotherapies; four months thereafter, a second local recurrence developed, again gross totally resected. He then received one cycle of high-dose cyclophosphamide followed by three cycles of thiotepa/carboplatin with AuHCR. Subsequently he received sirolimus and thalidomide for 12 months, complicated by progressive pancytopenia. A small localized CPC recurrence was noted, gross totally resected, concomitant with myelodysplastic syndrome; he underwent an allogeneic matched unrelated donor marrow transplantation.CONCLUSIONSMarrow-ablative chemotherapy with post-transplant targeted biological therapy may afford durable survival for select children with recurrent CPC.

MBCL-19. CHEMOTHERAPY STRATEGIES FOR YOUNG CHILDREN NEWLY DIAGNOSED WITH DESMOPLASTIC/EXTENSIVE NODULAR MEDULLOBLASTOMA UP TO THE ERA OF MOLECULAR PROFILING – A COMPARATIVE OUTCOMES ANALYSIS OF PROSPECTIVE MULTI-CENTER EUROPEAN AND NORTH AMERICAN TRIALS

BACKGROUND/OBJECTIVESurvival has been poor in several multi-center/national trials since the 1980s, either delaying, avoiding or minimizing brain irradiation in young children with medulloblastoma. The introduction of German regimens incorporating both intravenous high-dose (HD-MTX) and intraventricular (IVENT-MTX) methotrexate, and North American regimens utilizing marrow-ablative chemotherapy with autologous hematopoietic cell rescue (HDCx+AuHCR), have reported encouraging outcomes. We performed a comparative outcomes analysis of these strategies for young children with desmoplastic/extensive nodular medulloblastoma (D/ENMB).DESIGN/METHODSData from 12 trials reported between 2005 and 2019 for children <six-years-old with D/ENMB were reviewed; event-free (EFS) with standard errors were compared.RESULTSThe German HIT-SKK’92 and HIT-SKK’00 trials incorporating HD-MTX and IVENT-MTX reported 85+/-8% and 95+/-5% 5-10-year EFS respectively; a third trial (ACNS1221) incorporating HIT-SKK therapy but without IVENT-MTX reported 49+/-10% EFS. Three trials (Head Start I/II combined and CCG-99703) employing induction chemotherapy without HD-MTX, followed by 1/3 HDCx+AuHCR cycles, reported 3-5-year EFS of 67+/-16% and 79+/-11%. Two trials employing HD-MTX-containing induction chemotherapy (Head Start III and ACNS0334), followed by 1/3 HDCx+AuHCR cycles, reported 3-5-year EFS of 89+/-6% and 100%, respectively. Finally, four trials utilizing neither IVENT-MTX nor HDCx+AuHCR (UK-CNS-9204, CCG-9921, COG-P9934 and SJYC07) reported 2-5-year EFS of 35+/-11%, 77+/-9%, 58+/-8% and 53+/-9%.CONCLUSIONSA trend towards better EFS for young children with D/ENMB is observed in trials including either HD-MTX as well as IVENT-MTX or including HD-MTX-containing induction chemotherapy and HDCx+AuHCR. Trials excluding HD-MTX, IVENT-MTX and HDCx+AuHCR have poorer outcomes.

MBCL-37. CHEMOTHERAPY STRATEGIES FOR YOUNG CHILDREN NEWLY DIAGNOSED WITH CLASSIC (CLMB) OR ANAPLASTIC/LARGE CELL (A/LCMB) MEDULLOBLASTOMA UP TO THE ERA OF MOLECULAR PROFILING – A COMPARATIVE OUTCOMES ANALYSIS

BACKGROUND/OBJECTIVEThe introduction of German regimens, supplementing “standard” chemotherapy with both intravenous high-dose (HD-MTX) and intraventricular (IVENT-MTX) methotrexate, and North American regimens incorporating marrow-ablative chemotherapy with autologous hematopoietic cell rescue (HDCx+AuHCR), report encouraging outcomes for young children with medulloblastoma. We performed a comparative outcomes analysis of treatment strategies for young children with ClMB or A/LCMB. DESIGN/METHODSData from 12 prospective multi-center trials published between 2005 and 2019 for children <six-years-old with ClMB or A/LCMB were reviewed; survivals were compared.RESULTSCOG-9921, UKCCSG-CNS9204, COG-P9934 and SJYCO7 employing standard chemotherapy with either no or risk-based irradiation, reported 3-5-year event-free survival (EFS) of 17+/-5%, 33+/-28% (ClMB), 14+/-7% and 13.8+/-9% (ClMB) respectively, with reported EFS of 0% for A/LCMB in UKCCSG-CNS9204 and SJYCO7. HIT-SKK’87, HIT-SKK’92 and HIT-SKK’00 incorporating HD-MTX and IVENT-MTX reported 2-10-year EFS of 30–34+/-10–11% for ClMB and 33+/-27% (HIT-SSK’00) for A/LCMB. Head Start HS-I-II combined, CCG-99703 and HS-III employing induction chemotherapy, with or without HD-MTX, followed by single or tandem HDCx+AuHCR reported 3-5-year EFS of 42+/-14%, 50+/-11% and 27+/-6% for ClMB, with EFS for A/LCMB of 38+/-13% (HS-III). Finally, 5-year overall survivals for ACNS0334, without or with induction HD-MTX, are 39% and 69% respectively for ClMB and A/LCMB combined.CONCLUSIONSA trend towards better outcomes for young children with ClMB and A/LCMB is observed in trials including either HD-MTX and IVENT-MTX or including HD-MTX-containing induction chemotherapy and HDCx+AuHCR. Trials excluding HD-MTX, IVENT-MTX and HDCx+AuHCR have poorer outcomes.

GCT-40. PROGNOSTIC FACTORS FOR PATIENTS WITH RELAPSED CENTRAL NERVOUS SYSTEM (CNS) NON-GERMINOMATOUS GERM CELL TUMORS (NGGCTs)

BACKGROUNDPatients with relapsed CNS NGGCTs experience poor outcomes. Our aim to explore prognostic factors that may guide future clinical trials.METHODSA review of clinical trials that included patients with relapsed CNS NGGCTs was performed.RESULTSSeventy-four patients were identified; only 14 patients (19%) were long-term survivors. Patients who relapsed >24 months after initial diagnosis had a survival rate of 47% compared with 15% of patients who relapsed in <24 months after initial diagnosis (p= 0.015). Patient with serum/cerebrospinal fluid (CSF) alpha-fetoprotein (AFP) level <25 ng/ml at relapse had a survival rate of 40% compared with 0% among patients with serum/CSF AFP level >25 ng/ml at relapse (p= 0.0015). Patients who achieved complete response/continued complete response (CR/CCR) by the end of therapy had a survival rate of 59% compared with 3% among patients who had less than CR/CCR by the end of therapy (p= 0.0001). Patients who received marrow-ablative chemotherapy followed by autologous hematopoietic cell rescue (HDCx/AuHCR) at relapse had a survival rate of 33% compared with 9% of patients who did not receive HDCx/AuHCR at relapse (p=0.056). The extent of surgical resection, receiving radiotherapy, and beta-human chorionic gonadotropin levels at relapse were not statistically associated with improved outcomes.CONCLUSIONTiming of relapse (>24 months after initial diagnosis), serum/CSF AFP <25 ng/ml at relapse, achieving CR/CCR after treatment were associated with a positive impact on survival. Receiving HDCx/AuHCR at relapse was associated with an improved outcome trend among the patients.

RARE-35. PINEOBLASTOMA IN CHILDREN SIX YEARS OF AGE OR LESS: FINAL REPORT OF THE HEAD START I, II AND III EXPERIENCE

BACKGROUNDWe report the outcomes of patients with pineoblastoma enrolled on the Head Start I-III trials.METHODSTwenty-three children were enrolled between 1991–2009. Treatment included maximal surgical resection followed by five cycles of intensive-chemotherapy and consolidation with marrow-ablative chemotherapy and autologous hematopoietic cell rescue (HDCx/AuHCR). Irradiation following consolidation was reserved for children over six years of age or those with residual tumor at the end of induction.RESULTSThe median age was 3.12 years (range:0.44–5.72). Three patients withdrew from the protocols and two patients experienced chemotherapy-related mortality. Eight patients experienced progressive disease (PD) during induction chemotherapy. Ten patients received HDCx/AuHCR; eight experienced PD post-consolidation. Seven patients received craniospinal irradiation (CSI) with a median dose of 20.7 Gy (range:18–36 Gy) with boost(s) (median dose 27 Gy, range:18–36 Gy); three received CSI as adjuvant therapy (2 post-HDCx/AuHCR) and four upon progression/recurrence. The 5-year progression-free survival (PFS) and overall survival (OS) were 9.7% (95%,CI:2.6–36.0%) and 13% (95%,CI:4.5–37.5%), respectively. Three patients survived beyond five years. Nineteen patients relapsed in the following sites: local site (n=4), distal site (n=6), local and distal sites (n=9). Favorable OS prognostic factors were CSI (hazard ratio (HR)=0.30 (0.11–0.86), p=0.025), and HDCx/AuHCR (HR=0.40 (0.16–0.99), p=0.047).CONCLUSIONCSI and HDCx/AuHCR were statistically associated with improved survival. The overall poor outcomes and high PD rate during later induction cycles and following consolidation chemotherapy warrants consideration of fewer induction cycles before consolidation and the intensification of consolidation with multiple cycles of marrow-ablative chemotherapy.

ATRT-21. RHABDOID PREDISPOSITION SYNDROME: REPORT OF MOLECULAR PROFILES AND TREATMENT APPROACH IN THREE CHILDREN WITH SYNCHRONOUS ATYPICAL TERATOID/RHABDOID TUMOR AND MALIGNANT RHABDOID TUMOR

BACKGROUNDRhabdoid predisposition syndrome is characterized by germline alterations in SMARCB1 or SMARCA4, leading to synchronous or metachronous central nervous system (CNS) and extra-CNS rhabdoid tumors. Rare survivors have been reported to date.METHODSWe describe the molecular profiling and treatment regimen of three patients with synchronous atypical teratoid/rhabdoid tumor (ATRT) and malignant rhabdoid tumor of the kidney (MRT-K). All patients underwent radical nephrectomy of the kidney, and gross total resection of the primary CNS tumor was achieved for two patients. An intensive chemotherapy regimen was administered; an induction phase based on the modified Third Intergroup Rhabdomyosarcoma Study (IRS-III) for ATRT followed by a consolidation phase with three cycles of high-dose chemotherapy and autologous hematopoietic progenitor cell rescue, without irradiation. All three patients were enrolled on an institutional comprehensive genomic profiling protocol.RESULTSA germline focal 22q deletion, including SMARCB1, was detected in two patients, while the third patient had a maternally-inherited heterozygous frameshift variant in SMARCB1. Somatic loss of heterozygosity of 22q was identified in all patients, resulting in biallelic inactivation of SMARCB1. Divergent tumor subgroups were described using DNA methylation. The three MRT-K samples were classified as MYC subtype. One ATRT was classified as SHH while the other as TYR. One patient is currently three years off-therapy without evidence of disease, while the other two patients have completed the consolidation phase without recurrent disease.CONCLUSIONMolecular profiling of CNS and extra-CNS rhabdoid tumors revealed different epigenetic subgroups. An intensive multimodal therapeutic approach without irradiation may achieve prolonged survival.

EPEN-17. FAVORABLE OUTCOME TO INTENSIVE CHEMOTHERAPY WITHOUT IRRADIATION IN INFANTILE METASTATIC EPENDYMOMA WITH A NOVEL MOLECULAR PROFILE: A CASE REPORT

Metastatic disease at initial presentation of intracranial ependymoma is an uncommon occurrence with only rare reports of survival and is reportedly more prevalent in the youngest of children. Clinical and molecular characteristics associated with metastatic presentation, their prognostic implications, as well as optimal treatment options for such patients, have not been identified. CASE REPORT: A seven months old child presented with posterior fossa anaplastic ependymoma; following sub-total resection of primary tumor, a spine MRI revealed leptomeningeal dissemination along the cervical spinal cord and nerve roots of the cauda equina. The patient was successfully treated with five cycles of intensive induction chemotherapy (as per Head Start with high-dose methotrexate) followed by three sequential cycles of marrow-ablative chemotherapy and autologous hematopoietic progenitor cell rescue (AuHPCR) without irradiation; he is currently without evidence of the disease now 60 months following initial diagnosis. MOLECULAR/GENOMIC RESULTS: The patient was enrolled on a patient-centric comprehensive molecular profiling protocol, which included paired tumor-normal whole-exome sequencing, RNA sequencing of the disease-involved tissue, and DNA methylation classification. The genomic profile of the tumor was relatively unremarkable, revealing only a terminal gain of chromosome 3p and a terminal deletion of chromosome 22q, suggestive of an unbalanced translocation. Using RNA sequencing, we identified a novel SPECC1L-RAF1 gene fusion. The tumor harbors unique transcriptomic and DNA methylation profiles, failing to discretely classify with well-established ependymoma subgroups. CONCLUSION: Use of genomic profiling techniques provides meaningful information for disease characterization allowing for further expansion of the molecular spectrum associated with malignant disease.

GCT-66. FINAL REPORT OF THE PROSPECTIVE NEXT/CNS-GCT-4 CONSORTIUM TRIAL (GemPOx FOLLOWED BY MARROW-ABLATIVE CHEMOTHERAPY) IN PATIENTS WITH REFRACTORY/RECURRENT CNS GERM CELL TUMORS

BACKGROUNDWe report the responses, toxicities and long-term outcomes of gemcitabine, paclitaxel and oxaliplatin (GemPOx) regimen administered, in responsive patients, prior to single cycle marrow-ablative chemotherapy (thiotepa, etoposide and carboplatin) with autologous hematopoietic progenitor cell rescue (HDCx+AuHPCR).METHODSSince December 2009, 11 recurrent/refractory patients (10 MMGCT, 1 germinoma; 10 males; mean age 16.5 years, range 7–46 years) have been treated with up to four cycles of gemcitabine (800mg/M2), paclitaxel (170mg/M2) and oxaliplatin (100mg/M2) administered on one day at 14 days intervals.RESULTSAll 11 patients were enrolled on a prospective multi-center trial, which was closed in October 2019. Three patients achieved complete remissions (tumor marker and/or imaging studies), five achieved partial remissions, two developed disease progression (PD), and one was withdrawn after one cycle for severe paclitaxel neurotoxicity followed by rapid tumor progression and death. One patient with PD after one cycle had pathologically-confirmed metastatic transformation to pure embryonal rhabdomyosarcoma, and rapidly expired. A second patient, with pure pineal choriocarcinoma, progressed after the second GemPOx cycle, ultimately died of tumor progression. Eight of the 11 responsive patients subsequently underwent HDCx+AuHPCR; five of these received some form of radiotherapy. Seven patients (six MMGCT, one germinoma) are alive and disease-free without recurrence for a mean of 94 months (range 74–118 months) since completion of therapy.CONCLUSIONGemPOx is an effective re-induction regimen for patient with recurrent CNS germ cell tumors, with acceptable toxicities; when followed by marrow-ablative chemotherapy and subsequent irradiation/re-irradiation, the regimen produces encouraging long-term disease-free survival.

Meta-Analysis of Treatment Modalities in Metastatic Atypical Teratoid/Rhabdoid Tumors in Children

BackgroundMetastatic atypical teratoid/rhabdoid tumors (AT/RTs) are aggressive central nervous system tumors that present during infancy and are associated with dismal outcomes. Patients receive multimodal treatment including surgical resection, systemic chemotherapy, and one or more of intrathecal chemotherapy (IT), marrow-ablative chemotherapy with autologous hematopoietic cell rescue (AuHCR) and radiation therapy (XRT). While data regarding treatment modalities for AT/RT patients exist, no comprehensive data have been published regarding the metastatic patients. MethodsWe performed a meta-analysis of 1578 articles published through September 2018, including 44 studies with a total of 123 subjects. In addition, seven patients were included through chart review of patients treated at Nationwide Children’s Hospital. ResultsAnalysis of 130 patients revealed a 3-year overall survival (OS) of 25%. Age at diagnosis had a significant effect on survival (P = 0.0355); 3-year OS for infants less than 18 months was 21%, 18 to 36 months was 26%, and greater than 36 months was 36%. Location of the primary tumor, metastatic stage, and extent of surgical resection did not have a significant impact on OS. On univariate analysis, XRT (P < 0.0001), IT (P = 0.01), and AuHCR (P < 0.0001) were found to significantly improve survival. The most substantial effect was noted in patients who received AuHCR (3-year OS of 60% vs 9% in those who did not). On multivariable analysis, XRT (P = 0.0006), IT (P = 0.0124), and AuHCR (P < 0.0001) were independently associated with reduced risk of death. ConclusionsAlthough more research is warranted to make generalizable conclusions, these results suggest that treatment regimens for patients with metastatic AT/RTs should include AuHCR, XRT, and IT.

Pineoblastoma in children less than six years of age: The Head Start I, II, and III experience.

We report the outcomes of patients with pineoblastoma and trilateral retinoblastoma syndrome enrolled on the Head Start (HS) I-III trials. Twenty-three children were enrolled prospectively between 1991 and 2009. Treatment included maximal surgical resection followed by five cycles of intensive chemotherapy and consolidation with marrow-ablative chemotherapy and autologous hematopoietic cell rescue (HDCx/AuHCR). Irradiation following consolidation was reserved for children over six years of age or those with residual tumor at the end of induction. Median age was 3.12 years (range, 0.44-5.72). Three patients withdrew from the study treatment and two patients experienced chemotherapy-related death. Eight patients experienced progressive disease (PD) during induction chemotherapy and did not proceed to HDCx/AuHCR. Ten patients received HDCx/AuHCR; eight experienced PD post-consolidation. Seven patients received craniospinal irradiation (CSI) with a median dose of 20.7Gy (range, 18-36Gy) with boost(s) (median dose 27Gy; range, 18-36Gy); three received CSI as adjuvant therapy (two post-HDCx/AuHCR) and four upon progression/recurrence. The five-year progression-free survival (PFS) and overall survival (OS) were 9.7% (95% confidence intervals [CI]: 2.6%-36.0%) and 13% (95% CI: 4.5%-37.5%), respectively. Only three patients survived beyond five years. Favorable OS prognostic factors were CSI (hazard ratio [HR]=0.30 [0.11-0.86], P=0.025) and HDCx/AuHCR (HR=0.40 [0.16-0.99], P=0.047). Within the HS I-III trials, CSI and HDCx/AuHCR were statistically associated with improved survival. The high PD rate during later induction cycles and following consolidation chemotherapy warrants consideration of fewer induction cycles prior to consolidation and the potential intensification of consolidation with multiple cycles of marrow-ablative chemotherapy and irradiation.

Neuropsychological outcomes on Head Start III: a prospective, multi-institutional clinical trial for young children diagnosed with malignant brain tumors.

Current pediatric brain tumor treatment focuses on titrating toxicity based on risk factors while simultaneously improving survivorship. The Head Start (HS) protocols I to IV (1991-present) use high-dose chemotherapy (HDCTx) with an aim of reducing or eliminating cranial irradiation in very young children, the most vulnerable to its effects. We examined estimated Full Scale IQ, overall Adaptive Functioning, Working Memory, Processing Speed, and Verbal and Nonverbal Memory outcome data for 43 HS III patients diagnosed between ages 2 months and 7 years from 15 institutions in the United States and Canada. At a mean of 5.12 years postdiagnosis, the HS III patients performed within the average to low-average ranges across these variables; however, individual variability was noted with scores ranging from superior to impaired, and the sample as a whole performed lower than age expectations. Performance did not significantly differ by sex or ethnicity, diagnosis, or for those treated with an intravenous methotrexate dose of 400 mg/kg vs 270 mg/kg. Additionally, performance did not significantly differ by age at diagnosis or length of follow-up. The results, indicating overall average to low-average neurocognitive functioning, are encouraging, though significant individual variability was noted. Those who were younger at diagnosis, received more intensive methotrexate, and were further out from treatment were not at significantly increased risk of cognitive decline within our sample, suggesting a strategy of using HDCTx and autologous hematopoietic progenitor cell rescue to reduce or eliminate irradiation may allow for continued CNS development in young children treated for a brain tumor.