Faculty Bibliography

Asparaginase is a therapeutic enzyme used to treat leukemia and lymphoma, with immune responses resulting in suboptimal drug exposure and a greater risk of relapse. To elucidate whether there is a genetic component to the mechanism of asparaginase-induced immune responses, we imputed human leukocyte antigen (HLA) alleles in patients of European ancestry enrolled on leukemia trials at St. Jude Children's Research Hospital (n = 541) and the Children's Oncology Group (n= 1,329). We identified a higher incidence of hypersensitivity and anti-asparaginase antibodies in patients with HLA-DRB1*07:01 alleles (P = 7.5 x 10-5, OR = 1.64; P = 1.4 x 10-5, OR = 2.92, respectively). Structural analysis revealed that high-risk amino acids were located within the binding pocket of the HLA protein, possibly affecting the interaction between asparaginase epitopes and the HLA-DRB1 protein. Using a sequence-based consensus approach, we predicted the binding affinity of HLA-DRB1 alleles for asparaginase epitopes, and patients whose HLA genetics predicted high-affinity binding had more allergy (P = 3.3 x 10-4, OR = 1.38). Our results suggest a mechanism of allergy whereby HLA-DRB1 alleles that confer high-affinity binding to asparaginase epitopes lead to a higher frequency of reactions. Studies were registered at ClinicalTrials.gov, identifiers: NCT00137111, NCT00549848, NCT00005603, and NCT00075725.

Although great strides have been made in the improvement of outcome for newly diagnosed pediatric acute lymphoblastic leukemia because of refinements in risk stratification and selective intensification of therapy, the prognosis for relapsed leukemia has lagged behind significantly. Understanding the underlying biological pathways responsible for drug resistance is essential to develop novel approaches for the prevention of recurrence and treatment of relapsed disease. High throughput genomic technologies have the potential to revolutionize cancer care in this era of personalized medicine. Using such advanced technologies, we and others have shown that a diverse assortment of cooperative genetic and epigenetic events drive the resistant phenotype. Herein, we summarize results using a variety of genomic technologies to highlight the power of this methodology in providing insight into the biological mechanisms that impart resistant disease.

To address the therapeutic challenges in childhood relapsed ALL, a phase 1 study combining a survivin mRNA antagonist, EZN-3042, with reinduction chemotherapy was developed for pediatric patients with second or greater bone marrow relapses of B-lymphoblastic leukemia. EZN-3042 was administered as a single agent on days -5 and -2 and then in combination with a 4-drug reinduction platform on days 8, 15, 22, and 29. Toxicity and the biological activity of EZN-3042 were assessed. Six patients were enrolled at dose level 1 (EZN-3042 2.5 mg/kg/dose). Two dose-limiting toxicities were observed: 1 patient developed a grade 3 gamma-glutamyl transferase elevation and another patient developed a grade 3 gastrointestinal bleeding. Downmodulation of survivin mRNA and protein were assessed after single-agent dosing and decreased expression was observed in 2 of 5 patients with sufficient material for analysis. Although some biological activity was observed, the combination of EZN-3042 with intensive reinduction chemotherapy was not tolerated at a dose that led to consistent downregulation of survivin expression. The trial was terminated following the completion of dose level 1, after further clinical development of this agent was halted.

Although great advances have been made in the treatment of pediatric acute lymphoblastic leukemia, up to one out of five patients will relapse and their prognosis thereafter is dismal. We have previously identified recurrent deletions in TBL1XR1, which encodes for an F-box like protein responsible for regulating the nuclear hormone repressor (NCoR) complex stability. Here we model TBL1XR1 deletions in B-precursor ALL cell lines and show TBL1XR1 knockdown results in reduced glucocorticoid receptor recruitment to glucocorticoid responsive genes, and ultimately decreased glucocorticoid signaling caused by increased levels of NCoR1 and HDAC3. Reduction in glucocorticoid signaling in TBL1XR1 depleted lines resulted in resistance to glucocorticoid agonists, but not to other chemotherapeutic agents. Importantly, we show that treatment with the HDAC inhibitor SAHA restores sensitivity to prednisolone in TBL1XR1 depleted cells. Altogether, our data indicates that loss of TBL1XR1 is a novel driver of glucocorticoid-resistance in ALL and that epigenetic therapy may have future application in restoring drug sensitivity at relapse.

BACKGROUND: Recurrence occurs in almost 50% of patients with intracranial ependymoma, and their outcome following recurrence is poor. METHODS: We retrospectively reviewed the medical records of 22 patients with intracranial ependymoma and subsequent relapse(s) (59 recurrences) treated at Children's Hospital Los Angeles or New York University between January 1997 and December 2012. RESULTS: Median duration of follow-up was 52 months (7-171 months). Median age at initial diagnosis was 4 years (0.3-19 years) with 8 patients younger than 3 years at presentation. Eleven patients had anaplastic and 11 cellular pathologies. Eighteen patients had infratentorial tumors at diagnosis and 3 (all infratentorial) had metastatic spinal cord involvement at presentation. Cerebrospinal fluid involvement was not identified at diagnosis or relapse. Median time to first recurrence was 16 months (1.3 to 115 months). The number of recurrences in each patient ranged from 1 to 9 (median = 2). Thirty-seven recurrences (63%) were detected asymptomatically by surveillance imaging. Fifteen recurrences (26%) arose outside the initial tumor site. Recurrences were treated by surgical resection (45), with irradiation (30), and with various oral chemotherapies (23) with (7) or without (16) conventional chemotherapy. The 5 and 10 year overall survival rates from first recurrence were 0.37 +/- 0.14 and 0.25 +/- 0.14. CONCLUSION: Prolonged (5-10 year) survival from first relapse was noted in over one-quarter of our patients. It remains unclear whether early radiographic diagnosis, differing treatment modalities beyond radical surgical resection or possibly unrecognized biological differences contributed towards this prolonged survival. Pediatr Blood Cancer 2014;61:1195-1201. (c) 2014 Wiley Periodicals, Inc.

We previously reported preliminary findings that post induction imatinib mesylate (340 mg/m(2)/day), in combination with intensive chemotherapy, resulted in outcomes similar to blood and marrow transplant (BMT) for pediatric patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). We now report 5-year outcomes of imatinib plus intensive chemotherapy in 91 children (1-21 years) with and without allogeneic BMT (N=91). We explore the impacts of additional chromosomal abnormalities and minimal residual disease (MRD) by flow cytometry on outcomes. The 5-year disease-free survival was similar for Cohort 5 patients, treated with chemotherapy plus imatinib (70%+/-12%, n=28), sibling donor BMT patients (65%+/-11%, n=21) and unrelated donor BMT patients (59+/-15%; P=0.60, n=13). Patients with additional cytogenetic abnormalities had worse outcomes (P=0.05). End induction (pre-imatinib) MRD was not prognostic for Cohort 5 or allogeneic BMT patients, although limited by small numbers. The re-induction rate following relapse was similar to other higher-risk ALL groups. Longer-term follow-up confirms our initial observation of substantially good outcomes for children and adolescents with Ph+ ALL treated with imatinib plus intensive chemotherapy with no advantage for allogeneic BMT.

OBJECTIVE: /st> To determine the feasibility and toxicity profile of topotecan administered as a seven-day continuous intrathecal infusion for patients with leptomeningeal metastasis secondary to recurrent or progressive central nervous system cancer. Study design Two patients with central nervous system leptomeningeal metastasis were treated with a seven-day continuous infusion of topotecan (0.2 mg/day) administered via continuous intrathecal/intraventricular infusion at a rate of 0.6 mL/h, totaling 1.4 mg/course. CSF and plasma concentrations of topotecan closed lactone (the active metabolite) were quantified at various points during topotecan infusion. Patients were monitored for neurologic and systemic toxicities according to NCI common toxicity criteria. RESULTS: /st> Both patients tolerated the seven-day continuous topotecan without any significant adverse events. One patient received a second course 21 days after treatment initiation. CSF concentration of topotecan closed lactone ranged from 3.73 to 312 ng/mL (median = 131 ng/mL) and plasma topotecan closed lactone ranged from 0.44 to 1.78 ng/mL (median = 0.92 ng/mL). The median CSF topotecan concentration was greater than the median serum topotecan concentration by a 44-fold magnitude when samples were obtained at the same time point. None of the patients experienced any grade 3 or higher hematological toxicities or signs of arachnoiditis. CONCLUSION: /st> A seven-day continuous intrathecal infusion of topotecan is well tolerated and has the potential of maximizing central nervous system drug exposure.

In order to improve outcomes for CNS mixed malignant germ cell tumors (MMGCT) we sought to increase complete responses (CR) to initial therapy, through intensifying neoadjuvant chemotherapy (CHT1) with added ifosfamide, encouraging second-look surgery, and administering dose-intensive, stem cell-supported chemotherapy (CHT2) to patients with residual tumor, all prior to radiation therapy (RT). Diagnosis was confirmed by biopsy or elevated germ cell tumor markers. After tumor staging was completed, patients received four cycles of chemotherapy (cisplatin, etoposide and ifosfamide, "CHT1"). In patients with

PMID: 24700239

ISSN: 0167-594x

CID: 1037262