9548 Background: Platinums have significant activity in a wide variety of pediatric tumors, and oxaliplatin exhibits synergy with 5FU and LV in adults with colorectal cancer in FOLFOX regimens. The primary objectives of this study are to determine the maximum tolerated dose (MTD) of the modified FOLFOX6 regimen in pediatric tumors. Secondary objectives include safety, PK pharmacokinetic (PK) and PET scan efficacy analyses. Methods: Pts age <21 years with advanced cancers and adequate organ function are eligible. Patients are stratified by tumor type (CNS or non-CNS) to better delineate the potential neurotoxicity in patients with altered neurologic function. Pts received oxaliplatin starting at 85 mg/m 2 and LV 400 mg/m 2 over 2 hours on day 1 followed by a 5FU bolus of 400 mg/m 2 then 2,400 mg/m 2 continuous infusion over 46 hours, every 2 weeks (3 courses = 1 cycle), with integrated PK sampling in a limited dose escalation design. Standard 3+3 dose escalation, definitions of dose limiting toxicity (DLT), and dose modification for toxicity are implemented. The MTD is expanded to 15 patients to confirm and further characterize tolerability and toxicity. Results: To date, 15 very heavily pre-treated patients (7 M, 8 F) have received 25 cycles (range 1–4, median 2) of treatment at 2 dose levels. One of 8 pts at dose level 2 (oxaliplatin 100 mg/m 2 ) developed DLT (delay in repeat treatment > 14 days due to grade 3 platelets). Treatment has been well tolerated. The most frequently reported related grade 3–4 adverse events (AEs) are reversible leukocytes (29%), neutropenia (43%), platelets (35%) and lymphopenia (21%). 31 of 90 courses (34%) have been delayed for neutropenia and thrombocytopenia. Anti-tumor activity to date includes a confirmed partial response lasting 15 weeks in a patient with osteosarcoma, and prolonged stable disease in 5 other pts with brain tumors (2), hepatoblastoma (2) and sarcoma (1). Conclusions: The modified FOLFOX6 regimen has significant but reversible myelosuppression in heavily pre-treated pediatric patients, but is tolerable and has promising activity in several tumor types. Cohort expansion continues at 100 mg/m 2 of oxaliplatin. PET scan and pharmacokinetic analyses will be presented. No significant financial relationships to disclose.
The Children's Oncology Group (COG) protocol AALL0434 evaluated the safety and efficacy of multi-agent chemotherapy with Capizzi-based methotrexate/pegaspargase (C-MTX) in patients with newly diagnosed pediatric T-cell lymphoblastic lymphoma (T-LL) and gained preliminary data using nelarabine in high-risk patients.
Early T-cell precursor acute lymphoblastic leukaemia (ETP ALL) is an aggressive malignancy of unknown genetic basis. We performed whole-genome sequencing of 12 ETP ALL cases and assessed the frequency of the identified somatic mutations in 94 T-cell acute lymphoblastic leukaemia cases. ETP ALL was characterized by activating mutations in genes regulating cytokine receptor and RAS signalling (67% of cases; NRAS, KRAS, FLT3, IL7R, JAK3, JAK1, SH2B3 and BRAF), inactivating lesions disrupting haematopoietic development (58%; GATA3, ETV6, RUNX1, IKZF1 and EP300) and histone-modifying genes (48%; EZH2, EED, SUZ12, SETD2 and EP300). We also identified new targets of recurrent mutation including DNM2, ECT2L and RELN. The mutational spectrum is similar to myeloid tumours, and moreover, the global transcriptional profile of ETP ALL was similar to that of normal and myeloid leukaemia haematopoietic stem cells. These findings suggest that addition of myeloid-directed therapies might improve the poor outcome of ETP ALL. This work shows that treatments used for acute myeloid leukaemia and targeted therapies could be used for early T-cell precursor acute lymphoblastic leukaemia. The early T-cell precursor (ETP) subtype of childhood acute lymphoblastic leukaemia (ALL) has a poor prognosis when treated with standard chemotherapy. Whole genome sequencing is used here to gain insights into the genetic basis of the condition. The results reveal a high frequency of activating mutations in genes regulating cytokine receptor and Ras signalling, lesions that disrupt haemopoiesis (many of which arise from chromosomal rearrangements that generate novel chimeric in-frame fusion genes), and inactivating mutations in histone modifying genes. This mutation pattern resembles that of myeloid malignancies, suggesting that myeloid-directed therapies such as high-dose cytarabine, or targeted therapies that inhibit cytokine receptor and JAK signalling, might be effective in ETP ALL.
<p>T-cell ALL cell lines were treated for 48hr with five doses of ABT-199 and ABT-263. Apoptosis was assessed by Annexin V and Propidium Iodide (PI) staining. The mean % viability of three independent experiments is graphed +/- standard error. The calculated IC50 in μM for each of the BH3 mimetics is listed.</p>
