Leonard S. Sender

High-dose carboplatin, thiotepa, and etoposide with autologous stem-cell rescue for patients with recurrent medulloblastoma. Children's Cancer Group.

PURPOSE Medulloblastoma is a highly lethal disease when it recurs. Very few patients survive with conventional treatment. This study evaluated the use of high-dose carboplatin, thiotepa, and etoposide with autologous stem-cell rescue (ASCR) in patients with recurrent medulloblastoma. METHODS Chemotherapy consisted of carboplatin 500 mg/m2 (or area under the curve = 7 mg/mL x min via Calvert formula) on days -8, -7, and -6; and thiotepa 300 mg/m2 and etoposide 250 mg/m2 on days -5, -4, and -3; followed by ASCR on day 0. In addition to the study-prescribed therapy, 21 patients received other treatment: neurosurgical resection in seven, conventional chemotherapy in 17, and external-beam irradiation in 11 cases. RESULTS Twenty-three patients with recurrent medulloblastoma, aged two to 44 years (median, 13 years) at ASCR, were treated. Three patients died of treatment-related toxicities within 21 days of ASCR; multiorgan system failure in two, and Aspergillus infection with venoocclusive disease in one. Seven of 23 patients (30%) are event-free survivors at a median of 54 months post-ASCR (range, 24 to 78 months). Kaplan-Meier estimates of event-free (EFS) and overall survival are 34% +/- 10% and 46% +/- 11%, respectively, at 36 months post-ASCR. CONCLUSION This strategy may provide long-term survival for some patients with recurrent medulloblastoma.

A Phase I Trial of DFMO Targeting Polyamine Addiction in Patients with Relapsed/Refractory Neuroblastoma

Background Neuroblastoma (NB) is the most common cancer in infancy and most frequent cause of death from extracranial solid tumors in children. Ornithine decarboxylase (ODC) expression is an independent indicator of poor prognosis in NB patients. This study investigated safety, response, pharmacokinetics, genetic and metabolic factors associated with ODC in a clinical trial of the ODC inhibitor difluoromethylornithine (DFMO) ± etoposide for patients with relapsed or refractory NB. Methods and Findings Twenty-one patients participated in a phase I study of daily oral DFMO alone for three weeks, followed by additional three-week cycles of DFMO plus daily oral etoposide. No dose limiting toxicities (DLTs) were identified in patients taking doses of DFMO between 500-1500 mg/m2 orally twice a day. DFMO pharmacokinetics, single nucleotide polymorphisms (SNPs) in the ODC gene and urinary levels of substrates for the tissue polyamine exporter were measured. Urinary polyamine levels varied among patients at baseline. Patients with the minor T-allele at rs2302616 of the ODC gene had higher baseline levels (p=0.02) of, and larger decreases in, total urinary polyamines during the first cycle of DFMO therapy (p=0.003) and had median progression free survival (PFS) that was over three times longer, compared to patients with the major G allele at this locus although this last result was not statistically significant (p=0.07). Six of 18 evaluable patients were progression free during the trial period with three patients continuing progression free at 663, 1559 and 1573 days after initiating treatment. Median progression-free survival was less among patients having increased urinary polyamines, especially diacetylspermine, although this result was not statistically significant (p=0.056). Conclusions DFMO doses of 500-1500mg/m2/day are safe and well tolerated in children with relapsed NB. Children with the minor T allele at rs2302616 of the ODC gene with relapsed or refractory NB had higher levels of urinary polyamine markers and responded better to therapy containing DFMO, compared to those with the major G allele at this locus. These findings suggest that this patient subset may display dependence on polyamines and be uniquely susceptible to therapies targeting this pathway. Trial Registration Clinicaltrials.gov NCT#01059071

Socioeconomic Impacts on Survival Differ by Race/Ethnicity among Adolescents and Young Adults with Non-Hodgkin's Lymphoma.

Shorter survival has been associated with low socioeconomic status (SES) among elderly non-Hodgkins lymphoma (NHL) patients; however it remains unknown whether the same relationship holds for younger patients. We explored the California Cancer Registry (CCR), to investigate this relationship in adolescent and young adult (AYA) NHL patients diagnosed from 1996 to 2005. A case-only survival analysis was conducted to examine demographic and clinical variables hypothesized to be related to survival. Included in the final analysis were 3,489 incident NHL cases. In the multivariate analyses, all-cause mortality (ACM) was higher in individuals who had later stage at diagnosis (P < .05) or did not receive first-course chemotherapy (P < .05). There was also a significant gradient decrease in survival, with higher ACM at each decreasing quintile of SES (P < .001). Overall results were similar for lymphoma-specific mortality. In the race/ethnicity stratified analyses, only non-Hispanic Whites (NHWs) had a significant SES-ACM trend (P < .001). Reduced overall and lymphoma-specific survival was associated with lower SES in AYAs with NHL, although a significant trend was only observed for NHWs.

Melanoma in Pediatric, Adolescent, and Young Adult Patients

The family practitioner, pediatrician, and dermatologist all have potential roles in the primary prevention, diagnosis, and treatment of localized thin melanomas. Surgical and medical oncologists are often involved when controversy arises over the nature of the skin lesion or whether sentinel lymph node (SLN) biopsies and adjuvant therapy are to be contemplated. This overview of melanoma will deal with the primary and nodal pathology, surgery, and medical therapy of melanoma in pediatric, adolescent, and young adult patients--and will raise areas of controversy that are only recently being addressed in databases of cases from this age group.

Collection and use of peripheral blood stem cells in young children with refractory solid tumors

Fifteen children 4 years of age or under (8–46 months), weight 7.8 to 17 kg, underwent 44 peripheral blood stem cell (PBSC) collections. Diagnoses included PNET/ medulloblastoma (five), neuroblastoma (five), and others (five). PBSCs were collected following G-CSF/GM-CSF or chemotherapy plus G-CSF/GM-CSF mobilization. All PBSC collections were well tolerated. The average yield per collection was 6.80 × 108 mononuclear cells/kg (1.1–30 × 108/kg) or 57.60 × 106 CD34+/kg (1.37 to 480 × 106/kg). Eight patients underwent stem cell transplantation following myeloablative chemotherapy. Six of the eight children who received PBSC following myeloablative therapy also received autologous bone marrow (0.7 to 3.6 × 108 MNC/kg). One heavily pretreated patient experienced delayed hematologic reconstitution, while the remaining seven patients had a median ANC recovery to >0.5 × 103/μ l by day +10 (9–11 days) and platelets >50 × 103/μ l by day +15 (12–17 days). Seven patients received PBSCs following repetitive submyeloablative chemotherapy (ICE: ifosfamide 1.8 g/m2/day, etoposide 100 mg/m2/day × 5, carboplatin 400 mg/m2/day × 2) or other similar combination chemotherapy. Median days to recover ANC ⩾1 × 103/μ l and platelets ⩾100 × 103/μ l in children receiving ICE + PBSCs were 10 and 14 days, respectively, compared with 16 and 22 days in children receiving ICE + G-CSF in historical controls. In conclusion, collection and use of PBSCs to support either myeloablative chemotherapy or multicycle submyeloablative chemotherapy is well tolerated and may enhance hematological recovery in young children and infants.

A novel intensive induction therapy for high-risk neuroblastoma utilizing sequential peripheral blood stem cell collection and infusion as hematopoietic support

To determine the feasibility, toxicities, and the response rate (RR) of a dose intensive, submyeloablative, induction chemotherapy protocol termed EPiC (etoposide, carboplatin, and intensive cyclophosphamide) utilizing sequential peripheral blood stem cell (PBSC) collection and infusion as hematopoietic support in children with newly diagnosed Stage 4 neuroblastoma.

Peripheral blood stem cell support for multiple cycles of dose intensive induction therapy is feasible with little risk of tumor contamination in advanced stage neuroblastoma: A report from the Childrens Oncology Group

Poor outcome in Stage 4 neuroblastoma may be improved with increased dose intensity of therapy. We investigated the feasibility of sequential collection and infusion of peripheral blood stem cells (PBSCs) as hematopoietic support for non‐myeloablative dose intensive induction chemotherapy given every 21–28 days.

Kids, Adolescents, and Young Adult Cancer Study—A Methodologic Approach in Cancer Epidemiology Research

Advances have been made in treatment and outcomes for pediatric cancer. However adolescents and young adults (AYAs) with cancer have not experienced similar relative improvements. We undertook a study to develop the methodology necessary for epidemiologic cancer research in these age groups. Our goal was to create the Kids, Adolescents, and Young Adults Cancer (KAYAC) project to create a resource to address research questions relevant to this population. We used a combination of clinic and population-based ascertainment to enroll 111 cases aged 0–39 for this methodology development study. The largest groups of cancer types enrolled include: breast cancer, leukemia, lymphoma, and melanoma. The overall participation rate is 69.8% and varies by age and tumor type. The study included patients, mothers, and fathers. The methods used to establish this resource are described, and the values of the resource in studies of childhood and young adult cancer are outlined.

IL-2-activated cord blood mononuclear cells

BACKGROUND [corrected] Recent findings in cord blood (CB) research indicate the potential clinical usefulness of IL-2-activated CB in eradication of minimal malignant residual disease after hematopoietic stem cell transplantation. This feasible approach to immunotherapy merits further pre-clinical investigations using human tumor models of hematologic malignancy. METHODS The aim of our study was to compare the anti-tumor potential of CB mononuclear cells (MNC), matured in the presence of IL-2, to BM, and to determine phenotype and cytokine secretion in IL-2 CB MNC culture during the peak of their anti-leukemia cytotoxic activity. Phenotype change was analysed with flow cytometry, cytokine secretion with ELISA tests and cytotoxic activity with cytotoxicity assays. RESULTS Following IL-2 maturation, the phenotype of CB MNC was remarkably changed. Lengthening IL-2 culture to 8 days significantly increased CD8+, CD16+ CD56+, CD56+ and CD56+ CD8+ populations. Interestingly, FACS analyzes revealed the occurrence of CD8+ CD56+ cells that were not present in non-stimulated CB. Cultures progressively produced higher levels of INF-gamma, TNF-alpha and GM-SCF. The IL-2-activated cells manifested potent lytic capabilities against both NK- and LAK-sensitive tumor cell targets. DISCUSSION At the peak of cytotoxic activity during 8-day IL-2 CB MNC culture, we found increased numbers of various cytotoxic cells and increased secretion of cytokines that may contribute further to their potential therapeutic effect. The duration of CB IL-2 cultures may be crucial for successful application of CB in transplant situations to boost the CB GvL.

Abstract PR06: Precision medicine for newly diagnosed and refractory/recurrent pediatric cancer patients: Lessons learned from “N=1” studies

Whole genome sequencing has rapidly emerged as the preferred method for unbiased genomic interrogation. Leveraging this technology, we have developed a precision medicine clinical research protocol for pediatric, adolescent, and young adult cancer patients. The primary objective of this study is to arrive at genome informed treatment recommendations for individual patients suffering from aggressive and/or worsening disease in a clinically relevant time frame. The second objective is to survey the genomic landscape of newly diagnosed and recurrent/refractory patients. To accomplish this, we have employed an interdisciplinary workflow including a customized bioinformatic analysis pipeline, contextual biological interpretation of the data, and case reviews during weekly molecular tumor board meetings. Here we report the results of having sequenced over 50 patients diagnosed with both common and rare malignancies. Factors affecting the successful identification of therapeutically actionable targets and subsequent intervention are varied. The most consistent findings are the increased mutation burden in patients who have received chemotherapy and/or radiation prior to tissue collection. Lastly, we highlight the realistic opportunities, challenges, and insight gained from an ongoing single institution experience. This abstract is also presented as Poster 27. Citation Format: Troy A. McEachron, Keri B. Zabokrtsky, Aaron F. Sassoon, Sara Nasser, Tyler Izatt, Chad P. Garner, David W. Craig, John D. Carpten, Leonard S. Sender. Precision medicine for newly diagnosed and refractory/recurrent pediatric cancer patients: Lessons learned from “N=1” studies. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Integrating Clinical Genomics and Cancer Therapy; Jun 13-16, 2015; Salt Lake City, UT. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(1_Suppl):Abstract nr PR06.