Autologous Hematopoietic Progenitor 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.

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.

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.

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.

CMET-15. META-ANALYSIS OF TREATMENT MODALITIES IN METASTATIC ATYPICAL TERATOID/RHABDOID TUMORS IN CHILDREN

The aim of this study is to investigate the efficacy of different treatment modalities associated with best outcomes in the management of metastatic central nervous system (CNS) atypical teratoid/rhabdoid tumors (AT/RT) in children, which represent around 20% of newly-diagnosed AT/RT cases and are associated with dismal prognosis. A review of 1,433 peer-reviewed manuscripts from 1993 through June 2017 revealed 27 studies with a total of 80 metastatic AT/RT patients. The 3-year overall survival (OS) was 30% (95% confidence interval: 21–40%). Though treatment protocols varied widely by institution, the most-effective at improving the OS were the Medical University of Vienna AT/RT protocol, which incorporates radiation therapy (RT), intrathecal chemotherapy (IT), marrow-ablative chemotherapy and autologous hematopoietic progenitor cell rescue (AuHPCR) (3-year OS = 100%), and the Dana Farber protocol, which incorporates RT and IT (3-year OS = 57%). Gross total resection of the primary tumor was not associated with a significant improvement in the OS (p = 0.938). These results are further supported by a multivariable analysis, in which RT (p = 0.0139), IT (p = 0.0322), and AuHPCR (p <0.0001) were all independently associated with a reduced risk of death, with AuHPCR having the greatest impact on OS (Hazard Ratio = 0.21). Multimodal treatment approach should be incorporated in the management of metastatic CNS AT/RT in children and may include AuHPCR, with adjuvant RT and IT. Given the rarity of published research focused on metastatic AT/RT, these conclusions may be an important step towards the creation of standard treatment guidelines for metastatic AT/RT patients.

Diffusion Tensor Imaging and Neurobehavioral Outcome in Children With Brain Tumors Treated With Chemotherapy

Childhood brain tumor survivors (CBTS) often experience treatment-related neurocognitive deficits affecting quality of life (QOL), but systemic chemotherapy contributions to outcomes are unclear. Our objective was to relate brain tissue changes to neurocognitive and QOL effects after systemic myeloablative chemotherapy with autologous hematopoietic progenitor cell rescue in CBTS. Regional brain volumes and diffusion tensor indices were correlated with neurocognitive, behavioral, and QOL measures, and compared between 8 CBTS (mean age 8.5 years, mean age at diagnosis 32 months), and 9 healthy controls (mean 9.3 years). Overall QOL, school, and psychosocial functioning were significantly lower in patients (P < .05). Most patients scored within normative ranges on neurocognitive and behavioral assessment. Elevated mean diffusivity and decreased fractional anisotropy, indicating gray and white matter injury, respectively, appeared in memory and executive functioning areas. Low scores on Inhibition on the Neuropsychological Assessment-II were correlated with elevated mean diffusivity in prefrontal cortex. Brain injury, decreased QOL, and to a lesser extent, executive functioning deficits appear in CBTS treated with myeloablative chemotherapy and autologous hematopoietic progenitor cell rescue. Early cognitive and psychological assessment and intervention are warranted in this population.

Infectious complications in the first year following autologous hematopoietic progenitor cell rescue for children with brain tumors

High-dose chemotherapy with autologous hematopoietic progenitor cell rescue (AuHPCR) for pediatric patients with brain tumors has become an important therapeutic modality to avoid or delay the long-term effects of cranial irradiation. Data on post-AuHPCR infectious complications in this population are lacking. This single institution retrospective review reports the prophylactic practices and infections in the first year following AuHPCR in pediatric patients with brain tumors. The medical record of patients who underwent AuHPCR for the treatment of a malignant brain tumor at Children's Hospital Los Angeles between 1988 and 2010 were reviewed. Patients without prior irradiation who were free of disease at 1 year without additional chemotherapy were evaluated for all infectious disease complications occurring from time of neutrophil engraftment to 1 year post-AuHPCR. Forty-three of the 115 eligible patients were included. The median time to neutrophil engraftment was 11 days (range: 8-43 days), and 20 Grade III/IV (no Grade V) infectious episodes developed in 15 patients (35%). Fourteen episodes of bacteremia (70%) were catheter-related, predominantly gram-negative (71%), and polymicrobial (50%). There were no fungal or pneumocystis infections and only 1 of 25 (4%) at-risk patients developed VZV reactivation. These data suggest patients with brain tumors undergoing AuHPCR have few late-occurring non-catheter-related post-transplant infections indicating that prophylaxis practices were sufficient. Central lines should be removed soon after engraftment, but those with central line infections should receive adequate treatment including gram-negative coverage. In addition, only at-risk patients who receive further irradiation may benefit from VZV reaction prophylaxis.

Intensive induction chemotherapy followed by myeloablative chemotherapy with autologous hematopoietic progenitor cell rescue for young children newly‐diagnosed with central nervous system atypical teratoid/rhabdoid tumors: The head start III experience

Atypical teratoid/rhabdoid tumor (AT/RT) of the central nervous system (CNS) is a rare embryonal neoplasm of early childhood with dismal outcome and no current uniformly accepted treatment. Given its highly aggressive nature and predilection for dissemination at diagnosis, intensive multimodal therapy is required. Nineteen children with newly diagnosed CNS AT/RT were treated on the head start (HS) III protocol. Treatment consisted of surgical resection, 5 cycles of induction chemotherapy, followed by consolidation with myeloablative chemotherapy and autologous hematopoietic progenitor cell rescue (AuHCR). Irradiation was given following recovery from consolidation based on patient age, disease extent at diagnosis, and treatment response to induction. Nineteen children (median age of 14 months) were treated on HS III between 2003 and 2009. Only four finished induction and three proceeded to consolidation. There are presently four survivors at 40, 42, 46, and 79 months from study enrollment. Eleven patients experienced tumor progression at a median time to progression of 4.1 months of whom 10 died with a median time from progression to death of 2.6 months. Five toxic deaths occurred, three of them while on the study. The 3-year event-free survival (EFS) and overall survival (OS) for the whole group was 21 ± 9% and 26 ± 10%, respectively. Five patients received irradiation at progression with only one long-term survivor. A minority of children with CNS AT/RT treated on HS III may be long-term survivors without irradiation. More effective therapies are desperately needed.

High‐dose chemotherapy and autologous hematopoietic progenitor cell rescue in children with recurrent medulloblastoma and supratentorial primitive neuroectodermal tumors

The role of myeloablative chemotherapy in children with recurrent medulloblastoma and supratentorial primitive neuroectodermal tumors (MB/ST-PNET) is controversial, in particular in patients who develop recurrent disease after craniospinal radiotherapy. In this retrospective analysis, the authors investigated the outcome of children with recurrent MB/ST-PNET who were referred for myeloablative chemotherapy and autologous hematopoietic progenitor cell rescue at Childrens Hospital Los Angeles. Thirty-three children were referred for myeloablative chemotherapy: Fourteen of those children were never transplanted because of pre-transplant adverse events, and 19, including 6 without and 13 with previous irradiation, underwent transplant. Conditioning regimens included a backbone of thiotepa, which was given either in a single cycle or in multiple sequential cycles. The 3-year post-transplant event-free survival rate in unirradiated versus previously irradiated children was 83% +/- 15% versus 20% +/- 12%, respectively (P = .04). One child who had never been exposed to radiotherapy died of toxicity; the other children received post-transplant radiotherapy and remained disease free. Nine previously irradiated children experienced 4 toxic deaths and 6 tumor recurrences (1 patient had both): An interval of <1 year between initial radiotherapy and myeloablative chemotherapy predicted a greater risk of toxic death (P = .02), whereas a history of meningeal metastases at diagnosis and a poor response to the initial rescue therapy predicted a greater risk of post-transplant recurrence (P = .03 and P = .08, respectively). Myeloablative doses of thiotepa-based chemotherapy and radiotherapy were able to cure most children who had radiotherapy-naive, chemoresponsive recurrences. Children who developed recurrences after craniospinal radiotherapy had poorer outcomes; however, cure was possible in those who had good prognostic features at presentation, chemoresponsive recurrences, and a long interval between initial radiotherapy and myeloablative chemotherapy.

Intensive induction chemotherapy followed by high dose chemotherapy with autologous hematopoietic progenitor cell rescue in young children newly diagnosed with central nervous system atypical teratoid rhabdoid tumors

Central nervous system (CNS) atypical teratoid rhabdoid tumors (AT/RT) are rare tumors of childhood with a dismal prognosis. Historically, surgery and standard dose chemotherapy have resulted in a median survival of 8.5 months from diagnosis. Thirteen children newly diagnosed with CNS AT/RT were treated with either the "Head Start I" (HS I) or "Head Start II" (HS II) regimens. Therapy included resection followed by five cycles of cisplatin, vincristine, cyclophosphamide, and etoposide. High dose methotrexate was added to each of the five induction courses in HS II. Consolidation for both regimens included carboplatin, thiotepa, and etoposide with autologous hematopoietic progenitor cell rescue (AHPCR). Six children, median age of 36 months, were treated on HS I between 1992 and 1997. Seven children, median age of 28 months, were treated on HS II between 1997 and 2002. One patient received craniospinal irradiation following AHPCR but prior to recurrence. There are presently three event-free survivors 42+, 54+, and 67+ months following diagnosis; none received RT. All three survivors were enrolled on HS II. Eight patients died of disease (six on HS I); one patient died from infection; one patient died from secondary malignancy following treatment for recurrent AT/RT. Three of seven children with CNS AT/RT treated on HS II have experienced long term remissions. Long term survival can be achieved in a subset of young children with CNS AT/RT following resection with the use of multi-drug chemotherapy including high dose methotrexate and myeloablative chemotherapy without radiation therapy (RT).

Outcome of children less than three years old at diagnosis with non‐metastatic medulloblastoma treated with chemotherapy on the “Head Start” I and II protocols

To determine the survival of infants and young children with non-metastatic medulloblastoma using intensive myeloablative chemotherapy and autologous hematopoietic progenitor cell rescue (AuHCR). Twenty-one children less than 3 years old at diagnosis with non-metastatic medulloblastoma were enrolled on two identical serial studies, "Head Start" I and "Head Start" II. After surgery, patients received five cycles of induction chemotherapy consisting of vincristine, cisplatin, cyclophosphamide and etoposide. Following induction, all patients underwent myeloablative chemotherapy using carboplatin, thiotepa and etoposide with AuHCR. Irradiation was used only at relapse. The 5-year event-free (EFS) and overall survival (OS) rates (+/-SE) for all patients, patients with gross total resection, and patients with residual tumor were 52 +/- 11% and 70 +/- 10%, 64 +/- 13% and 79 +/- 11%, and 29 +/- 17% and 57 +/- 19%, respectively. The 5-year EFS and OS ( +/- SE) for patients with desmoplastic and classical medulloblastoma were 67 +/- 16% and 78 +/- 14%, and 42 +/- 14 and 67 +/- 14%, respectively. There were four treatment related deaths. The majority of survivors (71%) avoided irradiation completely. Mean intellectual functioning and quality of life (QoL) for children surviving without irradiation was within average range for a majority of survivors tested. This strategy of brief intensive chemotherapy for young children with non-metastatic medulloblastoma eliminated the need for craniospinal irradiation 52% of the patients, and may preserve QoL and intellectual functioning. The excellent survival rates are somewhat dampened by high toxic mortality.

Myeloablative chemotherapy with autologous hematopoietic progenitor cell rescue for childhood central nervous system tumors

Myeloablative chemotherapy with autologous hematopoietic progenitor cell rescue has been evaluated in the treatment of children and young adults with brain tumors for whom conventional therapy is either too toxic (for example, radiotherapy in infants) or ineffective (for example, recurrent malignant tumors). With this strategy, myeloablative chemotherapy is administered to patients after initial surgery, and standard-dose chemotherapy. The success of myeloablative chemotherapy depends on the histological type of tumor, extent of disease and of surgical resection, and response to prior chemotherapy. Here, we review results of myeloablative chemotherapy with hematopoietic progenitor cell rescue in brain tumors of different histologies.

Tandem high‐dose chemotherapy with autologous peripheral hematopoietic progenitor cell rescue as consolidation therapy for patients with high‐risk Ewing family tumors

The role of tandem high-dose chemotherapy (HDC) with autologous peripheral hematopoietic progenitor cell rescue (APHPCR) in patients with Ewing Family Tumors (EFT) is controversial. We initiated treatment for eight consecutive patients with high-risk EFT with HDC and APHPCR from 1992 to 2003. There were no treatment related deaths. Four patients remain in complete remission, including three who did not undergo local therapy to bone at either the primary or metastatic sites. Our experience has shown that treatment of EFT patients with tandem HDC with APHPCR may benefit a subgroup of high-risk patients in whom optimal local therapy is not possible.