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Despite the maximum intensification of chemotherapy and the increased use of hematopoietic stem cell transplantation (HCT) in pediatric patients with acute myeloid leukemia (AML), nearly 40% of patients still experience relapse, and cure in this setting remains a significant challenge. Recent improvements in AML characterization, including advances in flow cytometry and comprehensive genomic sequencing, have led to a better understanding of AML biology and the identification of multiple potential therapeutic targets. Novel agents targeting genomic lesions, cell surface antigens, and other mechanisms that permit oncogenesis or immune escape are being incorporated into current treatment strategies or are under investigation in efforts to improve outcomes and decrease the toxicities and late effects associated with traditional intensive chemotherapeutic and HCT treatment. However, multiple challenges still exist, including the biologic and immunophenotypic heterogeneity of childhood AML, the differences in underlying biology as compared to adult AML, and the significant potential for on-target/off-tumor toxicity associated with therapies directed at targets common to myeloid cells, both leukemic and normal. This article reviews the current landscape of genomic and cell surface targets for children with AML with a focus on the currently available targeted therapeutic agents, those in active clinical investigation, and those still in development.

Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL), and primary mediastinal B-cell lymphoma are the most common aggressive pediatric mature B-cell non-Hodgkin lymphomas (B-NHLs). Despite excellent survival with current chemotherapy regimens, therapy for Burkitt lymphoma and DLBCL has a high incidence of short- and long-term toxicities. Patients who experience relapse generally have a very poor prognosis. Therefore, novel approaches using targeted therapies to reduce toxicities and improve outcomes in the relapse setting are needed. The addition of rituximab, a monoclonal antibody against CD20, to upfront therapy has improved survival outcomes for high-risk patients and may allow decreased total chemotherapy in those with low-risk disease. Antibody–drug conjugates have been combined with chemotherapy in relapsed/refractory (R/R) NHL, and multiple antibody–drug conjugates are in development. Additionally, bispecific T-cell–engaging antibody constructs and autologous CAR T-cells have been successful in the treatment of R/R acute leukemias and are now being applied to R/R B-NHL with some successes. PD-L1 and PD-L2 on tumor cells can be targeted with checkpoint inhibitors, which restore T-cell–mediated immunity and antitumor responses and can be added to conventional chemotherapy and immune-directed therapies to augment responses. Lastly, trials of small molecule inhibitors targeting cell signaling pathways in NHL subtypes are underway. This article reviews many of the targeted therapies under development that could be considered for future trials in R/R pediatric mature B-NHL.

Current therapies for relapsed/refractory (R/R) pediatric myeloid neoplasms are inadequately effective. Real-world data (RWD) can improve care by augmenting traditional studies and include individuals not eligible for clinical trials. The Therapeutic Advances in Childhood Leukemia and Lymphoma (TACL) consortium recently completed T2016-003, a phase 1 study of decitabine, vorinostat, fludarabine, cytarabine, and granulocyte colony-stimulating factor (G-CSF) in R/R acute myeloid leukemia (AML), which added epigenetic drugs to a cytotoxic backbone. We report results of RWD from six centers that treated 28 pediatric patients (26 with AML, two with other myeloid neoplasms) identically to the TACL study but who were not enrolled. This allowed unique analyses and the ability to compare data with the 35 TACL study patients. The overall response rate (ORR) (complete response [CR] plus CR with incomplete count recovery) among 26 RWD evaluable patients was 65%. The ORR of 13 patients with relapsed AML with epigenetic alterations was 69% (T2016-003 + RWD: 68%, n = 25), of eight patients with refractory AML was 38% (T2016-003 + RWD: 41%, n = 17) and of five patients with therapy-related AML (t-AML) was 80% (T2016-003 + RWD: 75%, n = 8). The mean number of Grade 3/4 toxicities experienced by the T2016-003-eligible RWD population (n = 22) (one per patient-cycle) was not meaningfully different than those (n = 6) who would have been TACL study-ineligible secondary to comorbidities (two per patient-cycle). Overall, this therapy was well tolerated and effective in pediatric patients with R/R myeloid neoplasms, particularly those with epigenetic alterations, t-AML, and refractory disease.

Survival outcomes for relapsed/refractory pediatric acute myeloid leukemia (R/R AML) remain dismal. Epigenetic changes can result in gene expression alterations which are thought to contribute to both leukemogenesis and chemotherapy resistance. We report results from a phase I trial with a dose expansion cohort investigating decitabine and vorinostat in combination with fludarabine, cytarabine, and G-CSF (FLAG) in pediatric patients with R/R AML [NCT02412475]. Thirty-seven patients enrolled with a median age at enrollment of 8.4 (range, 1-20) years. There were no dose limiting toxicities among the enrolled patients, including two patients with Down syndrome. The recommended phase 2 dose of decitabine in combination with vorinostat and FLAG was 10 mg/m2 . The expanded cohort design allowed for an efficacy evaluation and the overall response rate among 35 evaluable patients was 54% (16 complete response (CR) and 3 complete response with incomplete hematologic recovery (CRi)). Ninety percent of responders achieved minimal residual disease (MRD) negativity (

International Working Group (IWG) and European LeukemiaNet (ELN) response definitions are utilized to evaluate the efficacy of new agents for childhood acute myeloid leukemia (AML) for regulatory purposes. However, these criteria are not consistent with definitions used in pediatric AML trials or with standard pediatric practice to proceed with subsequent therapy cycles prior to IWG/ELN-defined count recovery. We retrospectively analyzed data from the two most recent Phase 3 pediatric AML clinical trials conducted by the Children’s Oncology Group (COG) to assess the incidence, timing, and prognostic significance of count recovery following induction chemotherapy. Of the patients with fewer than 5% bone marrow blasts at the end of first induction, 21.5% of patients proceeded to a second induction cycle prior to achieving ANC ≥ 500 cells/μL and platelets ≥ 50,000 cells/μL, both well below the IWG/ELN thresholds of ANC > 1000 cells/μL and platelets > 100,000 cells/μL. In these two sequential childhood AML Phase 3 trials, neither ANC nor platelet recovery predicted survival. Intensification of treatment through the initiation of subsequent therapy cycles prior to attainment of IWG/ELN-defined CR is common practice in clinical trials for children with AML, suggesting that updated response definitions are needed for pediatric AML.

Infants with B-cell acute lymphoblastic leukemia (B-ALL) have poor outcomes because of chemotherapy resistance leading to high relapse rates. Tisagenlecleucel, a CD19-directed chimeric antigen receptor T-cell (CART) therapy, is US Food and Drug Administration approved for relapsed or refractory B-ALL in patients ≤25 years; however, the safety and efficacy of this therapy in young patients is largely unknown because children M1 marrow) were refractory to this therapy (n = 5). Overall, tisagenlecleucel was tolerable in this population, with only 3 patients experiencing ≥grade 3 cytokine release syndrome. No neurotoxicity was reported. This is the largest report of tisagenlecleucel use in infant B-ALL and shows that this therapy is safe and can be effective in this population. Incorporating this novel immunotherapy into the treatment of infant B-ALL offers a promising therapy for a highly aggressive leukemia.

Asparaginase, a critical component of current pediatric acute leukemia treatment protocols, is associated with a number of serious side effects, one of which is pancreatitis. Pancreatitis can result in significant morbidity and mortality from necrosis, pseudocyst formation, hemorrhage, systemic inflammation, intestinal perforation, and sepsis. Another rare complication of pancreatitis is posterior reversible encephalopathy syndrome, likely mediated by systemic inflammation secondary to pancreatic autodigestion and proinflammatory cytokine-mediated vascular endothelial damage. Here, we review this association in the literature and report 2 pediatric patients with leukemia who developed posterior reversible encephalopathy syndrome in the setting of asparaginase-associated pancreatitis.

No guidelines exist for which intensive chemotherapy regimen is best in pediatric or young adult patients with high-risk posttransplant lymphoproliferative disorder (PTLD). We retrospectively reviewed patients with PTLD who received interval-compressed short-course etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin (SC-EPOCH) regimens at our institution. Eight patients were included with median age of 12 years. All patients achieved a complete response with a manageable toxicity profile. Two patients developed second, clonally unrelated, EBV-positive PTLD and one patient had recurrence at 6 months off therapy. No graft rejection occurred during therapy. All eight patients are alive with median follow-up of 29 months.

e15081 Background: Methotrexate (MTX) is a cornerstone of therapy for several types of cancer. HDMTX-induced mucositis can impact quality of life and delay subsequent chemotherapy. Objective: The objective of this study was to understand the factors increasing risk for mucositis in patients receiving HDMTX in a multicenter cohort. Methods: A multi-center retrospective study collected data on pediatric and young adult patients ages 0-32 years at diagnosis who received at least one dose of HDMTX (>500 mg/m2) at Children’s Healthcare of Atlanta or Cincinnati Children’s Hospital Medical Center from January 2010 through December 2020. Demographic and clinical variables were manually abstracted, while medications and lab values were electronically pulled from the electronic medical record. Common Terminology Criteria for Adverse Events v5 was used to identify the presence and grade of mucositis after HDMTX administration. Institutional review board approval was obtained at each site. Chi-square and t-tests, as appropriate, were calculated using GraphPad Prism v9. MTX concentrations were fit to a published pharmacokinetic model to estimate clearance using NONMEM. Results: The cohort is described in Table. The rate of mucositis was highest after the first HDMTX administration (54.6%), when the MTX clearance is slowest (30.1%2 and albumin was lowest (14.3%2 (OR 1.75 (CI: 1.503 to 2.028), p

Infant leukemia is a rare, distinct subgroup of pediatric acute leukemias diagnosed in children under 1 year of age and characterized by unique, aggressive biology. Here, we review its clinical presentation, underlying molecular biology, current treatment strategies, and novel therapeutic approaches. Infant leukemias are associated with high-risk molecular features and high rates of chemotherapy resistance. International collaborative clinical trials have led to better understanding of the underlying molecular biology, refined risk-based stratification, and investigated the use of hematopoietic stem cell transplantation. However, intensification of chemotherapy has failed to improve outcomes, and current regimens are associated with significant treatment-related and long-term toxicities. Infants with leukemia remain a challenging group to treat. We must continue collaborative efforts to move beyond traditional cytotoxic chemotherapy, incorporate molecularly targeted strategies and immunotherapy, and increase access to clinical trials to improve outcomes for this high-risk group of patients.

Asparaginase, a critical component of current pediatric acute leukemia treatment protocols, is associated with a number of serious side effects, one of which is pancreatitis. Pancreatitis can result in significant morbidity and mortality from necrosis, pseudocyst formation, hemorrhage, systemic inflammation, intestinal perforation and sepsis. Another rare complication of pancreatitis is posterior reversible encephalopathy syndrome (PRES), likely mediated by systemic inflammation secondary to pancreatic autodigestion and pro-inflammatory cytokine-mediated vascular endothelial damage. Here we review this association in the literature and report two pediatric patients with leukemia who developed PRES secondary to asparaginase-associated pancreatitis.

Infant leukemia is a rare, distinct subgroup of pediatric acute leukemias diagnosed in children under 1 year of age and characterized by unique, aggressive biology. Here, we review its clinical presentation, underlying molecular biology, current treatment strategies, and novel therapeutic approaches.Infant leukemias are associated with high-risk molecular features and high rates of chemotherapy resistance. International collaborative clinical trials have led to better understanding of the underlying molecular biology, refined risk-based stratification, and investigated the use of hematopoietic stem cell transplantation. However, intensification of chemotherapy has failed to improve outcomes, and current regimens are associated with significant treatment-related and long-term toxicities. Infants with leukemia remain a challenging group to treat. We must continue collaborative efforts to move beyond traditional cytotoxic chemotherapy, incorporate molecularly targeted strategies and immunotherapy, and increase access to clinical trials to improve outcomes for this high-risk group of patients.

Chimeric antigen receptor (CAR) T-cells, engineered autologous T-cells that target antigens found in leukemia, have shown durable remissions in relapsed acute lymphoblastic leukemia (ALL). Infant ALL with KMT2A rearrangements (KMT2Ar) is a rare, aggressive form of leukemia associated with extramedullary disease both at diagnosis and at relapse, and overall outcomes for these patients are dismal. Here we report the successful use of tisagenlecleucel, a CAR T-cell product approved for relapsed/refractory ALL, in a patient with KMT2Ar infant ALL who was treated for combined marrow and extramedullary (renal) relapse.

Background: Methotrexate (MTX) is a cornerstone of therapy for pediatric patients with acute lymphoblastic leukemia (ALL). Administration of high dose (HD) MTX requires hospitalization and concurrent intravenous fluids and leucovorin while awaiting drug excretion. HDMTX has been associated with acute adverse events (AEs), such as mucositis, neurotoxicity, and myelosuppression, that can impact quality of life and ability to administer subsequent chemotherapy. There are limited data evaluating differences in AEs after HDMTX among demographic groups. Objective: The objective of this study was to describe AEs for patients receiving HDMTX (defined as >500 mg/m2 to account for dose reductions from protocol dosing) and to compare rates by age, race, ethnicity and dose number using a multicenter cohort. Methods: A multi-center retrospective study collected data on pediatric ALL patients ages 0-21 years at diagnosis who received at least one dose of HDMTX at Children's Healthcare of Atlanta or Cincinnati Children's Hospital Medical Center from January 2010 through December 2020. Demographic (age, sex, race, ethnicity) and clinical (vital status, Down Syndrome, HDMTX doses) variables were manually abstracted from the electronic medical record. Algorithms were developed a priori based on Common Terminology Criteria for Adverse Events v5 to identify the presence and grade of targeted AEs after HDMTX administration. The following AEs were abstracted for the time period from each HDMTX dose until the next HDMTX or other chemotherapy administration: mucositis, neurotoxicity, neutropenia, and thrombocytopenia. Only grade 4 neutropenia and grades 3-4 thrombocytopenia were collected. Institutional review board approval was obtained at each site. Descriptive and inferential statistics, including chi-square, Fisher's exact test, and generalized estimating equations (GEE) as appropriate, were calculated to evaluate differences in AEs by dichotomized age ( Results: Across sites, 543 patients with ALL patients received HDMTX (2064 administrations). The median age at first HDMTX was 8.0 years (0.1-21.0); 230 (42.4%) were female, 381 (70.2%) were White, and 441 (81.2%) were Non-Hispanic or Latino (Table 1). The median number of HDMTX administrations was 4.0 (Range 1-10). In total, 469 (86.4%) patients had at least one AE. Mucositis occurred in 386 (71.1%) patients, grade 4 neutropenia occurred in 243 (50.1%) and grade 3-4 thrombocytopenia occurred in 156 (32.2%, Table 2). Mucositis, neurotoxicity, and thrombocytopenia were significantly more likely in patients 10+ years (p=0.02, p Conclusion: AEs after administration of HDMTX are common, with 86% of patients experiencing at least one AE after receipt of HDMTX and half of administrations leading to at least one AE. Greater than half of patients experienced mucositis and neutropenia. Older patients experienced significantly more mucositis, neurotoxicity, and thrombocytopenia. Unsurprisingly, we found that overall the rate of AEs was highest after the first HDMTX administration and decreased significantly across doses, which is likely due to dose reductions in HDMTX or concurrent antimetabolite therapy and to increased supportive care (hydration and leucovorin) after experience of an AE. Chart abstraction is ongoing at a third hospital that will increase the sample size of patients, particularly those of Hispanic/Latino ethnicity, to delineate potential differences by race and ethnicity. In addition, current analyses are evaluating the impact of supportive care and dosing changes between administrations on the burden of HDMTX-related AEs and differences by age. The results of this study will provide valuable data regarding who is at highest risk for AEs and can be used to tailor supportive care during this potentially toxic chemotherapy. Figure 1 Figure 1. Disclosures Bernhardt: Bristol Myers Squibb: Research Funding; BTG International: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Jazz Pharmaceuticals: Consultancy; Mesoblast: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees. O'Brien: Jazz: Honoraria; Pfizer: Honoraria, Research Funding. Ramsey: BTG Specialty Pharmaceuticals: Honoraria, Research Funding.

Imatinib, a tyrosine kinase inhibitor has improved survival in pediatric patients with Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia. There are no formal drug interactions listed between methotrexate and tyrosine kinase inhibitors. Four pediatric patients with Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia had delayed methotrexate clearance during their first cycle of high-dose methotrexate while receiving imatinib, resulting in acute kidney injury. For subsequent high-dose methotrexate cycles, imatinib was withheld resulting in decreased acute kidney injury, shorter time to methotrexate clearance, less toxicity, and shorter hospitalizations. For pediatric patients with acute lymphoblastic leukemia receiving imatinib, we recommend escalated supportive care measures including increased hyperhydration and leucovoruin frequency. For patients with toxicities secondary to delayed clearance or need for glucarpidase, we recommend holding imatinib with subsequent high-dose methotrexate courses.

Hypersensitivity to pegaspargase is associated with inferior survival in pediatric patients with acute lymphoblastic leukemia and lymphoblastic lymphoma. In the past year, drug-supply shortages have led to the lack of an available alternative to pegaspargase. Rather than omit asparaginase from the treatment of acute lymphoblastic leukemia or lymphoblastic lymphoma patients with hypersensitivity to pegaspargase, we continued pegaspargase treatments for nine pediatric patients, utilizing a rapid desensitization protocol. There were no adverse events related to the pegaspargase during desensitization, and all patients who were checked had asparaginase serum levels above the threshold of 0.1 IU/mL at 7 to 14 days after pegaspargase therapy.

1. Lauren Pommert, MD* 2. Hayley Friedman, MD, MS* 3. David Wathen, DO* 4. Shermini Saini, MD* 1. *Saint Louis University at SSM Cardinal Glennon Children’s Medical Center, Saint Louis, MO. A previously healthy 16-year-old Asian-American boy presents to the emergency department with the acute onset of jaundice and an approximately 1 week history of dark, tea-colored urine, described by the patient as “almost black,” with dysuria. In the previous 3 weeks, he has had progressive fatigue, decreased appetite, dizziness, blurred vision, headaches, and sore throat. His immunizations are up to date. Family history is not contributory. He has no known sick contacts and no recent medications. He endorses unprotected sexual activity but denies illicit drug use, travel, or animal contacts. Physical examination reveals a diffusely jaundiced boy with scleral icterus and a heart rate of 92 beats per minute, respiratory rate of 20 breaths per minute, and blood pressure of 120/70 mm Hg. His lungs are clear, and he has no murmur, pharyngeal erythema or exudate, abdominal tenderness, hepatosplenomegaly, or lymphadenopathy. Laboratory results reveal the following: Urinalysis shows 2+ protein, 3+ blood, 2+ ketones, 1+ bilirubin, urobilinogen 4.0 EU/dL, and 2 to …

Background: Patients (pts) diagnosed with multiple myeloma (MM) are at risk for developing secondary hematologic malignancies (SHM). The etiology of SHM-associated genetic alterations (GAs) is unclear. We hypothesized that the GAs present in MM-associated SHMs would have a distinct profile compared to de novo or other therapy related hematologic malignancies. Aims: For MM pts who develop SHM, compare GAs at Autologous Stem Cell Transplant (ASCT) and at diagnosis of SHM. Assess for presence of previously reported deleterious myeloid GAs and determine if there is clonal evolution from the autograft. Methods: We retrospectively identified 9 MM pts with SHM post-ASCT. Autograft (auto) cells and SHM Fresh Frozen Plasma Extraction (FFPE) samples underwent whole exome sequencing. GAs with known clinical significance, variant allele frequency (VAF) ≥0.05 or ≤0.9, and high or moderate impact on the gene-encoded protein were included for analysis. From literature review, we identified 89 reported GAs (kmGAs) in myeloid malignancies. Targeted deep sequencing for these mutations was performed to obtain the VAF in both the auto and SHM FFPE samples. Results: 9 adult pts (age 56-71) with MDS, AML, or ALL were included. 8 auto samples and 9 SHM samples were available. All pts received induction therapy prior to ASCT (44% and 55% with lenalidomide/thalidomide or bortezomib containing regimens, respectively). Lenalidomide maintenance was utilized in 60% of pts. Whole exome sequencing revealed 118,614 GAs in all samples. 2074 GAs were included. Average mutational burden was similar between the auto and SHM samples. For paired samples (matched auto and SHM samples for each pt), 1173 GAs with kmGAs of GATA2, SETBP1, and ATM were present. GATA2 and SETBP1 were present in 3 and 5 auto samples, and 4 and 6 SHM samples, respectively. SETBP1 and GATA2 were present in paired samples for 3 and 1 pt, respectively. Targeted deep sequencing revealed significant mutations in SHM samples, but not auto samples, for ABCA12, ASXL1, BCOR, BRAF, EXH2, KDM5A, KMT2A, KMT2D, NOTCH1, PRPF8, TET2, and TP53. The most highly represented mutation was TP53 which was present in 6 pts, followed by KMT2A in 3 pts, KMT2D in 3 pts, PRPF8 in 2 pts, and TET2 in 2 pts. The patient who carried the most significant mutations carried the diagnosis of ALL, harboring 11 genetic mutations in the SHM sample only. For paired samples, KDM5A, KMT2D, FLT3, SETBP1, ZRSR2, PRPF8, TET2, and TP53 showed mutations in both auto and SHM samples, showing stable or decreased VAFs. GATA2 showed two moderate impact missense mutations, one in a pt with a VAF of 0.58 in the auto sample and 0.40 in the SHM. The other GATA2 variant appeared as a novel mutation in one pt's SHM sample and was also present in two other pts with VAFs of 0.5 and 0.49 in the auto sample increasing to 0.81 and 0.70 in the SHM sample, respectively. TP53 showed the highest number of variants. Analysis showed 6 high impact variants with VAFs ranging from 0.05-0.80 and 3 moderate impact variants with VAFs ranging from 0.08-0.89. These mutations were represented in both the auto and SHM samples included. There were several TP53 alterations with the most frequent being structural interaction variants, missense variants, and frameshift variants. Conclusion: This limited cohort demonstrates that mutational profile for pts with SHM is distinct from de-novo myeloid malignancies, and the average mutational burden did not change from pre-transplant to the development of SHM. In this population, TP53, KMT2A, GATA2, and KMT2D represented the most frequent SHM mutations. Targeted deep sequencing revealed that most significant variants were present only in SHM samples suggesting a novel mutation rather than clonal evolution from the auto sample. Disclosures Hari: Incyte Corporation: Consultancy; Takeda: Consultancy; BMS: Consultancy; Amgen: Consultancy; GSK: Consultancy; Janssen: Consultancy.

Acute lymphoblastic leukemia (ALL) is the most common single malignancy in children, representing 25% of all new cancer diagnoses. Advances in genomic sequencing has demonstrated that inherited genetic risk factors play a larger role in leukemia development than previously appreciated. We identified a father-daughter dyad with childhood B cell acute lymphoblastic leukemia (B-ALL) and obtained their diagnostic bone marrow samples from the Children's Oncology Group (COG) bank in addition to germline samples via remission marrow (daughter) or buccal swab (father). Whole Exome Sequencing (WES) was performed and compared to a panel of normal to identify large genomic changes and single nucleotide variants. In parallel, RNA-sequencing (RNA-seq) was performed on the diagnostic marrows. We discovered a novel germline chromosomal structural variant in chromosome 1q32.2 within the TRAF3IP3 gene. TRAF3IP3 regulates B cell lymphopoiesis and this mutation likely resulted in a predisposition to leukemia by causing expansion of immature B-cell precursors which are highly vulnerable to secondary somatic mutations. This mutation has not been previously described in ALL, however based on the function of TRAF3IP3 in B cell lymphopoiesis, we conclude this likely represents a mutation predisposing to the development of leukemia. WES revealed this dyad had no shared SNVs that are associated with leukemia in the literature and that they had only a few shared SNVs within the leukemia samples, none of which were identified as clinically significant; which suggests the spectrum of their somatic mutations were distinctly different. Given the lack of concordance in their somatic mutational spectrum, we wondered if the two leukemia samples would exhibit a shared transcriptome, implying convergent leukemogenic pathways were altered within the two specimens since they were both clinically reported as hyperdiploid. In comparing the leukemia gene expression profiles identified by RNA-seq to 216 cases of sporadic B-ALL from the TARGET database (The Therapeutically Applicable Research to Generate Effective Treatments program), we discovered that these two leukemia samples did not cluster together but did cluster with other cases of childhood B-ALL. We suspect that this germline TRAF3IP3 mutation increased this dyad's susceptibility to leukemia development but that the somatic mutational spectrum drove the leukemia development and dictated its phenotype. This research may have identified a novel gene involved in leukemogenesis which may also be involved in de novo cases of ALL. Additional studies are needed to further characterize this TRAF3IP3 structural variant, the co-occurring somatic mutations within these leukemia samples and their combined role in leukemogenesis. Disclosures No relevant conflicts of interest to declare.

Children diagnosed with acute leukemia are challenged not only by the life-threatening disease itself but a myriad of potential lethal complications related to treatment, some of which can result in end-organ dysfunction requiring pediatric intensive care unit (PICU) management. Such complications of leukemia treatment and/or the disease itself range from hyperleukocytosis and tumor lysis syndrome to typhlitis, pancreatitis, and serious coagulopathies. It is important that healthcare providers caring for children and adolescent patients with acute leukemia can recognize these potential complications in order to appropriately triage and manage them. As the overall survival for children with acute leukemia continues to improve, research has focused on novel strategies to further decrease the burden of therapy and lower the rates of toxic death while maintaining these very good outcomes. This chapter provides an overview of some of the more common oncologic emergencies occurring in children with acute leukemia that may require PICU care, focusing on the diagnosis and management.

Three primary categories of gynecologic cancer are found in pediatric and adolescent patients: stromal carcinomas including juvenile granulosa cell tumors and Sertoli-Leydig cell tumors, rhabdomyosarcomas arising from the vagina and cervix (sarcoma botryoides), and ovarian germ cell tumors which comprise a wide range of histologies. These entities are rare and treatment approaches have focused on decreasing late effects of chemotherapy treatment. Here, we review presentation, histologic classifications, diagnosis, and treatment recommendations for pediatric gynecologic cancers. Event-free and overall survival for these cancers is high, and the goals of treatment are minimization of morbidity and preservation of fertility with unilateral salpingo-oophorectomies and limited staging. Surveillance of tumor markers after surgery is helpful in monitoring for disease progression and adjuvant chemotherapy is often reserved for patients at recurrence. Recent literature supports avoiding chemotherapy even in high-grade germ cell tumors in the pediatric population.

Key Points Optimal salvage therapy for refractory HLH is unknown. In our patient, ruxolitinib treatment led to clinical remission of refractory HLH.

Introduction: Despite progress in the treatment of acute myeloid leukemia (AML) over the past few decades, long-term survival of children, adolescents and young adults remains poor. Most treatment failure is secondary to the development of chemotherapy resistance resulting in relapsed or refractory disease. Epigenetic changes in leukemia cells, such as DNA methylation and/or histone acetylation, can lead to alterations in gene expression thereby causing resistance to chemotherapeutic agents. These epigenetic changes are potentially reversible with agents that demethylate DNA and/or inhibit histone deacetylation which ultimately leads to restoration of normal gene expression and chemosensitivity. We are reporting an ongoing phase I trial of decitabine and vorinostat, two epigenetic modifying agents, followed by chemotherapy in children, adolescents and young adults with relapsed or refractory AML. Methods: T2016-003 is a phase I study that was developed and activated in the TACL consortium in July 2017 for patients 1 to 25 years of age with relapsed or refractory AML. The study followed a standard 3 + 3 phase I cohort escalation design. Three dose levels of decitabine were investigated: dose level 1 (7.5 mg/m2); dose level 2 (10 mg/m2); and dose level 3 (15 mg/m2). Patients received decitabine (at assigned dose level) and vorinostat (age 18 years, 200 mg twice daily) days 1 to 5 followed by fludarabine (30 mg/m2, days 6 to 10), cytarabine (2000 mg/m2, days 6 to 10) and granulocyte colony stimulating factor (G-CSF) (5 μ/kg/dose, days 5 until neutrophil recovery) (FLAG). Intrathecal therapy was given up to 72 hours prior to the initial doses of decitabine/vorinostat, with additional intrathecal therapy for central nervous system disease. Patients could receive up to two cycles of therapy. End of course evaluation by bone marrow minimal residual disease (MRD) testing using flow cytometry was performed between days 35 and 42 or upon adequate blood count recovery. Results: Twenty-five patients have enrolled to date with 24 evaluable for dose limiting toxicity (DLT) and response. Median age was 7 (range, 1 to 20) years. Fourteen patients (58.3%) had relapsed after a prior bone marrow transplant and 7 (29.2%) had refractory disease at time of enrollment. There were no dose limiting toxicities at dose level 1 (n=3, 7.5 mg/m2) or 2 (n=3, 10 mg/m2) of decitabine. However, at dose level 3 (n=12, 15 mg/m2), 3 subjects reported Grade 4 invasive fungal infection (Aspergillus terreus, Candida parapsilosis and Rhizomucor pusillus) leading to de-escalation of decitabine to dose level 2. The study continued dose expansion at dose level 2 without DLT, enrolling 7 additional patients. Twenty-two subjects have completed the study and are evaluable for response. Responses were noted at all dose levels. Eight subjects (36.4%) achieved a complete response (CR) or complete response with incomplete hematologic recovery (CRi). Five of the 8 subjects who achieved a CR/CRi were also negative for MRD. Eight subjects had known epigenetic lesions (i.e. KMT2Ar, CEBPα, IDH2) with 6 (75%) achieving a CR, 4 of whom (66.7%) were also MRD negative. Conclusion: Overall, we identified decitabine (10 mg/m2) in combination with vorinostat and followed by FLAG chemotherapy to be well-tolerated and an effective regimen in pediatric patients with relapsed AML, particularly in subjects with known epigenetic lesions. The study continues to enroll at dose level 2 of decitabine for a total accrual goal of 33 subjects. Correlative analysis of peripheral blood and bone marrow investigating methylation, histone acetylation and gene expression is ongoing. Disclosures Burke: Amgen, Inc.: Consultancy, Speakers Bureau.