Ami V. Desai

Atypical Chronic Myeloid Leukemia in Two Pediatric Patients.

Atypical chronic myeloid leukemia, BCR‐ABL1‐negative, (aCML) is a rare myeloid neoplasm. Recent adult data suggest the leukemic cells in a subset of patients are dependent on JAK/STAT signaling and harbor CSF3R‐activating mutations. We hypothesized that, similar to adult patients, the presence of CSF3R‐activating mutations would be clinically relevant in pediatric myeloid neoplasms as patients would be sensitive to the JAK inhibitor, ruxolitinib. We report two cases of morphologically similar pediatric aCML, BCR‐ABL1‐negative based on WHO 2008 criteria. One patient had CSF3R‐activating mutation (T618I) and demonstrated a robust response to ruxolitinib, which was used to bridge to a successful stem cell transplant. The other patient did not have a CSF3R‐activating mutation and succumbed to refractory disease <6 months from diagnosis. This report documents CSF3R‐T618I in pediatric aCML and demonstrates the efficacy of ruxolitinib in a pediatric malignancy. As the third documented case successfully treating aCML with ruxolitinib, this case highlights the importance of prompt CSF3R sequencing analysis for myeloproliferative and myelodysplastic/myeloproliferative neoplasms. Pediatr Blood Cancer

Establishing a high‐risk neuroblastoma cohort using the pediatric health information system database

International Classification of Diseases, 9th Revision (ICD‐9) code(s) for neuroblastoma do not exist, preventing identification of these patients in administrative databases. To overcome this challenge, a three‐step algorithm, using ICD‐9 codes, exclusion criteria, and manual review of chemotherapy billing data, was utilized to assemble a high‐risk neuroblastoma cohort (n = 952) from the Pediatric Health Information System (PHIS) Database and validated at a single institution [sensitivity 89.1%; positive predictive value (PPV) 96.1%]. This cohort provides a data source for future comparative effectiveness and clinical epidemiology studies in high‐risk neuroblastoma patients. Pediatr Blood Cancer 2014;61:1129–1131.

Emerging and investigational therapies for neuroblastoma

ABSTRACT Introduction: Treatment for children with clinically aggressive, high-risk neuroblastoma remains challenging. Less than 50% of patients with high-risk neuroblastoma will survive long-term with current therapies, and survivors are at risk for serious treatment-related late toxicities. Here, we review new and evolving treatments that may ultimately improve outcome for children with high-risk neuroblastoma with decreased potential for late adverse events. Areas covered: New strategies for treating high-risk neuroblastoma are reviewed including: radiotherapy, targeted cytotoxics, biologics, immunotherapy, and molecularly targeted agents. Recently completed and ongoing neuroblastoma clinical trials testing these novel treatments are highlighted. In addition, we discuss ongoing clinical trials designed to evaluate precision medicine approaches that target actionable somatic mutations and oncogenic cellular pathways. Expert opinion: Advances in genomic medicine and molecular biology have led to the development of early phase studies testing biologically rational therapies targeting aberrantly activated cellular pathways. Because many of these drugs have a wider therapeutic index than standard chemotherapeutic agents, these treatments may be more effective and less toxic than current strategies. However, to effectively integrate these targeted strategies, robust predictive biomarkers must be developed that will identify patients who will benefit from these approaches and rapidly match treatments to patients at diagnosis.

Resource Utilization and Toxicities After Carboplatin/Etoposide/Melphalan and Busulfan/Melphalan for Autologous Stem Cell Rescue in High-Risk Neuroblastoma Using a National Administrative Database

High‐dose chemotherapy with autologous stem cell rescue (ASCR) is a key component of high‐risk neuroblastoma therapy. Resources required to support patients treated with ASCR conditioning regimens [carboplatin/etoposide/melphalan (CEM) and busulfan/melphalan (BuMel)] have not been directly compared.

Toxicities of busulfan/melphalan versus carboplatin/etoposide/melphalan for high-dose chemotherapy with stem cell rescue for high-risk neuroblastoma

The optimal autologous stem cell rescue (HDC-SCR) regimen for children with high-risk neuroblastoma (HR-NBL) is not defined. Carboplatin/etoposide/melphalan (CEM) is the current US standard; however, European data suggest busulfan/melphalan (Bu/Mel) may have less toxicity. Published data regarding toxicities associated with CEM and Bu/Mel are limited. We conducted a single-institution retrospective cohort study of children with HR-NBL who received CEM or Bu/Mel preparative regimens. Toxicity data were analyzed using χ2 or Fisher’s exact, Wilcoxon two-sample or log-rank tests. Sinusoidal obstruction syndrome (SOS) was observed in 7/44 CEM (15.9%) and 5/21 (24%) Bu/Mel patients (P=0.50). Median time to SOS was longer following Bu/Mel than CEM (20 versus 9 days, P=0.02). Pulmonary hypertension (PHTN) was observed in ~20% of children after Bu/Mel and none after CEM (P=0.01). CEM patients had more nephrotoxicity (P=0.001), packed red blood cell (P=0.02) and platelet transfusions (P=0.008), and days on maximum pain support (P=0.0007). Time to engraftment, length of stay, documented infection rates and HDC-SCR-related mortality were similar. Nephrotoxicity and resource utilization associated with cytopenias and mucositis were greater after CEM. Pulmonary toxicities were more severe after Bu/Mel, and increased vigilance for PHTN may be warranted, particularly in children with hypoxemia out of proportion to respiratory distress.

Resource utilization and toxicities after single versus tandem autologous stem cell rescue in high-risk neuroblastoma using a national administrative database

High‐dose chemotherapy with autologous stem cell rescue (HDC‐ASCR) has improved event‐free survival for children with high‐risk neuroblastoma. Common regimens include carboplatin/etoposide/melphalan (CEM), busulfan/melphalan (BuMel), and tandem HDC‐ASCR [thiotepa/cyclophosphamide (TC) followed by CEM]. To complement clinical trial data and to evaluate the clinical burden associated with these regimens, resource ultilization (RU) was evaluated. An administrative database was used to evaluate RU in a previously developed high‐risk neuroblastoma cohort. Single CEM and BuMel patients were followed for 60 days from the first day of the HDC‐ASCR preparative regimen or until death, whichever came first. Tandem patients were followed from the first day of the first HDC‐ASCR preparative regimen through day 60 from the first day of the second HDC‐ASCR. Resources compared included inpatient days, ICU‐level care, and medications administered.

Significance of CNS 2 cerebrospinal fluid status post-induction in pediatric and adolescent patients with acute lymphoblastic leukemia

At diagnosis, there are prognostic implications of low‐level leukemic blasts (CNS 2) in the cerebrospinal fluid (CSF) of patients with acute lymphoblastic leukemia (ALL). However, the significance of post‐induction CNS 2 results and the impact of equipment on CNS 2 prevalence have not been well studied.

Clinical Assessment and Diagnosis of Germline Predisposition to Hematopoietic Malignancies: The University of Chicago Experience

With the increasing use of clinical genomics to guide cancer treatment and management, there is a rise in the identification of germline cancer predisposition syndromes and a critical need for patients with germline findings to be referred for surveillance and care. The University of Chicago Hematopoietic Malignancies Cancer Risk Team has established a unique approach to patient care for individuals with hereditary hematologic malignancies through close communication and coordination between our pediatric and adult programs. Dedicated program members, including physicians, nurses, genetic counselors, and clinical research assistants, screen individuals for cancer predisposition at initial diagnosis through survivorship, in addition to testing individuals with an established family history of a cancer predisposition syndrome. Sample procurement, such as a skin biopsy at the time of bone marrow aspirate/biopsy in individuals with a positive screen, has facilitated timely identification of clinical germline findings or has served as a pipeline for translational research. Our integrated translational research program has led to the identification of novel syndromes in collaboration with other investigators, which have been incorporated iteratively into our clinical pipeline. Individuals are referred for clinical assessment based on personal and family history, identification of variants in susceptibility genes via molecular tumor testing, and during evaluation for matched related allogeneic stem cell transplantation. Upon referral, genetic counseling incorporates education with mindfulness of the psychosocial issues surrounding germline testing at different ages. The training and role of genetic counselors continues to grow, with the discovery of new predisposition syndromes, in the age of improved molecular diagnostics and new models for service delivery, such as telemedicine. With the identification of new syndromes that may predispose individuals to hematologic malignancies, surveillance guidelines will continue to evolve and may differ between children and adults. Thus, utilizing a collaborative approach between the pediatric and adult oncology programs facilitates care within families and optimizes the diagnosis and care of individuals with cancer predisposition syndromes.

Abstract CT030: STARTRK-NG: A phase 1/1b study of entrectinib in children and adolescents with advanced solid tumors and primary CNS tumors, with or without TRK, ROS1, or ALK fusions

Background: The STARTRK-NG (Studies of Tumor Alterations Responsive to Targeting Receptor Kinases - Next Generation) trial is a Phase 1/1b dose-escalation and expansion study of entrectinib in pediatric patients with cancer. Entrectinib is a potent oral, CNS-penetrant, inhibitor of the tyrosine kinases TRKA/B/C (encoded by the genes NTRK1/2/3, respectively), ROS1, and ALK with IC50s Methods: This is a multicenter, dose escalation study in pediatric patients (aged 2-21 years) with relapsed or refractory extracranial solid tumors (Phase 1), with additional expansion cohorts (Phase 1b) in patients with primary brain tumors harboring TRK, ROS1, or ALK molecular alterations inclusive of gene fusions, neuroblastoma, and other non-neuroblastoma, extracranial solid tumors harboring TRK, ROS1, or ALK gene fusions (NCT02650401). During dose escalation, a 3+3 schema will be used to determine the pediatric RP2D of entrectinib with a starting dose of 250 mg/m2 (approximately 60% of the adult BSA-based RP2D), administered orally once daily in repeated 4-week cycles, with concordant pharmacokinetics and pharmacodynamics studies. Up to four dose levels will be evaluated. Dose modifications, if necessary, will follow a protocol-specific dosing nomogram for each dose level. Once the pediatric RP2D is determined, the Phase 1b expansion cohorts will be opened simultaneously, and prospective molecular profiling will be performed to determine eligibility except for patients with neuroblastoma. Citation Format: Ami V. Desai, Garrett M. Brodeur, Jennifer Foster, Suzanne Shusterman, Amit J. Sabnis, Magaret Macy, Cynthia Wetmore, Ellen Basu, Zachary Hornby, Vanessa Esquibel, Edna Chow Maneval, Pratik S. Multani, Elizabeth Fox. STARTRK-NG: A phase 1/1b study of entrectinib in children and adolescents with advanced solid tumors and primary CNS tumors, with or without TRK, ROS1, or ALK fusions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT030. doi:10.1158/1538-7445.AM2017-CT030