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Purpose of Review: This review summarizes the current novel therapy landscape in pediatric acute lymphoblastic leukemia (ALL), with a focus on key clinical trials which will shape the future direction of care for these children., Recent Findings: Recent landmark immunotherapy trials in B-ALL have demonstrated significant benefit for children, adolescents, and young adults with relapsed/refractory high-risk leukemia. Due to these successes, current trials are asking the question as to whether immunotherapy can be successfully incorporated upfront. Additionally, therapies targeting novel antigens or molecular pathways are being developed, providing new options for children previously thought to have incurable leukemia., Summary: As survival for ALL has relatively plateaued with maximizing intensity through conventional chemotherapy, continued preclinical and clinical study of novel immunotherapeutic and targeted agents is crucial to further improve outcomes in childhood leukemia., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Cancer and its treatment can lead to functional limitations affecting ongoing development in children and adolescents. We developed a pediatric cancer rehabilitation program that integrates evidence-based rehabilitative care into cancer treatment. The program utilizes the CREATE (collaboration, rehabilitation/research, education, assessment, treatment, evaluation) Childhood Cancer Rehabilitation model. We aim to describe the structural and process components of our rehabilitation program and provide an access and utilization analysis., Procedures: To evaluate the rehabilitation program, we identified new patients with oncologic diagnoses from 2002 to 2019 using our database. To evaluate rehabilitative care, descriptive data, including the timing and type of rehabilitation services utilized within 5 years of a child's diagnosis, were collected and reviewed. Statistical analysis focused on change over time., Results: Among 1974 children assessed, 1580 (80.0%) received care from at least one rehabilitation service. Between 2002 and 2018, the percentage of children receiving rehabilitation services grew significantly throughout all disciplines, except for outpatient speech-language pathology. Utilization differed by age and diagnosis. Integrating therapists in the clinic improved patient access, reduced the time to access outpatient services, and increased the number of attended visits. Additional factors supporting program growth included: identifying leaders, using a prospective surveillance model, education, and program evaluation., Conclusion: A multimodal interprofessional approach, such as the CREATE model, improves access to and the efficiency of evidence-based rehabilitation services promoting recovery, ongoing development, and quality of life., (© 2022 Wiley Periodicals LLC.)

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/m 2 . 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 (<0.1%) by centralized flow cytometry and 84% (n = 16) successfully proceeded to hematopoietic stem cell transplant. Two-year overall survival was 75.6% [95%CI: 47.3%, 90.1%] for MRD-negative patients vs. 17.9% [95%CI: 4.4%, 38.8%] for those with residual disease (p < .001). Twelve subjects (34%) had known epigenetic alterations with 8 (67%) achieving a CR, 7 (88%) of whom were MRD negative. Correlative pharmacodynamics demonstrated the biologic activity of decitabine and vorinostat and identified specific gene enrichment signatures in nonresponding patients. Overall, this therapy was well-tolerated, biologically active, and effective in pediatric patients with R/R AML, particularly those with epigenetic alterations., (© 2022 Wiley Periodicals LLC.)

Despite a remarkable increase in the genomic profiling of cancer, integration of genomic discoveries into clinical care has lagged behind. We report the feasibility of rapid identification of targetable mutations in 153 pediatric patients with relapsed/refractory or high-risk leukemias enrolled on a prospective clinical trial conducted by the LEAP Consortium. Eighteen percent of patients had a high confidence Tier 1 or 2 recommendation. We describe clinical responses in the 14% of patients with relapsed/refractory leukemia who received the matched targeted therapy. Further, in order to inform future targeted therapy for patients, we validated variants of uncertain significance, performed ex vivo drug-sensitivity testing in patient leukemia samples, and identified new combinations of targeted therapies in cell lines and patient-derived xenograft models. These data and our collaborative approach should inform the design of future precision medicine trials. SIGNIFICANCE: Patients with relapsed/refractory leukemias face limited treatment options. Systematic integration of precision medicine efforts can inform therapy. We report the feasibility of identifying targetable mutations in children with leukemia and describe correlative biology studies validating therapeutic hypotheses and novel mutations. See related commentary by Bornhauser and Bourquin, p. 1322 . This article is highlighted in the In This Issue feature, p. 1307 ., (©2021 American Association for Cancer Research.)

Detection of minimal residual disease (MRD) pre- and post-hematopoietic cell transplantation (HCT) for pediatric acute lymphoblastic leukemia (ALL) has been associated with relapse and poor survival. Published studies have had insufficient numbers to: (1) compare the prognostic value of pre-HCT and post-HCT MRD; (2) determine clinical factors post-HCT associated with better outcomes in MRD+ patients; and (3) use MRD and other clinical factors to develop and validate a prognostic model for relapse in pediatric patients with ALL who undergo allogeneic HCT. To address these issues, we assembled an international database including sibling (n = 191), unrelated (n = 259), mismatched (n = 56), and cord blood (n = 110) grafts given after myeloablative conditioning. Although high and very high MRD pre-HCT were significant predictors in univariate analysis, with bivariate analysis using MRD pre-HCT and post-HCT, MRD pre-HCT at any level was less predictive than even low-level MRD post-HCT. Patients with MRD pre-HCT must become MRD low/negative at 1 to 2 months and negative within 3 to 6 months after HCT for successful therapy. Factors associated with improved outcome of patients with detectable MRD post-HCT included acute graft-versus-host disease. We derived a risk score with an MRD cohort from Europe, North America, and Australia using negative predictive characteristics (late disease status, non-total body irradiation regimen, and MRD [high, very high]) defining good, intermediate, and poor risk groups with 2-year cumulative incidences of relapse of 21%, 38%, and 47%, respectively. We validated the score in a second, more contemporaneous cohort and noted 2-year cumulative incidences of relapse of 13%, 26%, and 47% (P < .001) for the defined risk groups.

Erwinia chrysanthemi-derived asparaginase is increasingly integral to acute lymphoblastic leukemia therapy. In our series, 16% of patients developed symptomatic hyperammonemia following Erwinia administration with symptoms including refractory nausea, vomiting, profound fatigue, malaise, and coma. This series of patients receiving Erwinia indicates higher than expected incidence of hyperammonemia, correlation between ammonia and asparaginase levels and therapeutic asparaginase activity levels despite dose reduction. The series provides evidence for investigation into which patients require intervention to prevent toxicity, which patients may have ammonia levels used as an asparaginase activity surrogate and which patients may achieve equivalent efficacy with abridged dosing.

Background: The balance of hemostasis and anticoagulation is a concern for patients dependent upon ventricular assist devices (VADs). Bleeding is a common complication with both short- and long-term use of these devices. A better understanding of the risk factors and etiologies of bleeding associated with these devices is needed and could improve the overall results. We sought to determine the relationship of mechanical circulatory assist device use with acquired von Willebrand disease (avWD) in children., Methods: Data were analyzed retrospectively via review of the medical record of 19 consecutive patients who were supported with the Berlin EXCOR VAD for greater than 24 hours. Laboratory testing for avWD was performed at the discretion of the clinical team, often in association with clinical bleeding., Results: Of 19 pediatric patients, 10 (52.6%) had laboratory testing consistent with avWD. Median time to detection of avWD was 35 days postimplantation of device (range 0-310 days). Both minor mucosal bleeding and bleeding requiring intervention were highly prevalent in patients in whom avWD was identified (10/10 [100%] and 7/10 [70%]). The mean age of all patients was 3.3 years, but patients found to have avWD tended to be older (mean 5.3 years) and supported with larger volume VADs., Conclusions: This experience demonstrates a high prevalence of avWD following EXCOR implantation. Bleeding, older age, and larger VAD size may be associated with avWD. These results should stimulate critical evaluation of individualized anticoagulation regimens in pediatric VAD patients., (© The Author(s) 2016.)

Opinion Statement: Granulocytic sarcoma (GS) is a rare manifestation of myeloid proliferation, characterized by formation of a mass comprised of immature cells of myeloid origin. Orbital granulocytic sarcoma is rarer still, with only a small fraction of GS patients having orbital involvement. Given the rarity of orbital GS, no unified therapy plan has been identified, as large prospective trials are not feasible, but it is widely accepted that patients with GS ought to be treated with systemic intensive chemotherapy consistent with standard of care regimens for acute myelogenous leukemia (AML) or chronic myelogenous leukemia (CML). Development of a treatment plan for GS in poor responders involves a systemic leukemia plan as novel therapeutics have not been investigated for treatment GS per se, but used more widely for AML. GS is most commonly associated with AML and thus will be addressed in that context in this review. Patients with GS associated with CML should receive CML-specific therapy. When conventional and traditional cytotoxic GS/AML chemotherapy regimens are insufficient, patients often require a combination of novel therapeutics, stem cell transplantation (SCT), and radiation. Much of the recent advancement in AML therapy, as well as in AML translational research, has been in targeting molecular facets of the disease and enabling more specificity with treatment. The aim of treating patients for whom conventional treatment was unsuccessful with personalized therapy has not yet been realized, but many of the novel therapeutics reviewed below have demonstrated promise and are cause for optimism. In our center, when a GS/AML patient is refractory to frontline therapy, we rely on novel chemotherapy therapeutic options as outlined below.

We report a patient with a constitutional missense mutation in SMARCB1, Coffin-Siris Syndrome (CSS), and schwannomatosis. CSS is a rare congenital syndrome with characteristic clinical findings. This thirty-three-year-old man was diagnosed early in life with the constellation of moderate intellectual disability, hypotonia, mild microcephaly, coarse facies, wide mouth with full lips, hypoplasia of the digits, and general hirsutism. At age 26, he was found to have schwannomatosis after presenting with acute spinal cord compression. Blood and tissue analysis of multiple subsequent schwannoma resections revealed a germline missense mutation of SMARCB1, acquired loss of 22q including SMARCB1 and NF2 and mutation of the remaining NF2 wild-type allele-thus completing the four-hit, three-event mechanism associated with schwannomatosis. Variations in five genes have been associated with the Coffin-Siris phenotype: ARID1A, ARID1B, SMARCA4, SMARCB1, and SMARCE1. Of these genes, SMARCB1 has a well-established association with schwannomatosis and malignancy. This is the first report of a patient with a constitutional missense mutation of SMARCB1 resulting in CSS and subsequent development of schwannomatosis. This finding demonstrates that a SMARCB1 mutation may be the initial "hit" (constitutional) for a genetic disorder with subsequent risk of developing schwannomas and other malignancies, and raises the possibility that other patients with switch/sucrose non-fermenting (SWI/SNF) mutations may be at increased risk for tumors., (© 2015 Wiley Periodicals, Inc.)

We report a 14 year-old female with Giant Cell Tumor of Bone, successfully treated with denosumab, who developed critical hypercalcemia after completion of therapy. Five months after her last denosumab treatment, serum calcium rose to 16.5 mg/dL (normal 8.7-10.8 mg/dL), nearly double her prior level of 8.4 mg/dL while receiving denosumab. She required emergent intervention to treat her hypercalcemia, which was attributed to rebound osteoclast activity and osteopetrotic bone. Denosumab is widely used in adults and increasingly in pediatric oncology populations and our experience demonstrates the need for close monitoring for electrolyte derangements following discontinuation., (© 2015 Wiley Periodicals, Inc.)

Risk-adapted therapy has been the cornerstone of treatment for pediatric B precursor acute lymphoblastic leukemia (B-ALL). Recently, age ≥ 13 years at diagnosis has been identified as a very high-risk feature for chemotherapy treated pediatric patients with B-ALL. Whether age at time of transplantation is associated with poor outcomes in adolescents and young adults (AYA) is unknown. We hypothesized that AYA receiving allogeneic hematopoietic cell transplantation (allo-HCT) would have greater relapse and inferior survival compared with children age <13 years. We reviewed the outcomes in 136 consecutive patients (age 0-30 years) with B-ALL who underwent myeloablative allo-HCT at our institution, including 79 children age <13 years (58%) and 57 AYA age 13-30 years (42%). Overall survival at 5 years was significantly lower in the AYA group (hazard ratio, 1.74; 95% confidence interval [CI], 1.04-2.95; P = .03). In addition, the AYA patients had a greater risk of transplantation-related mortality at 1 year (hazard ratio, 2.23; 95% CI, 1.01-4.90; P = .05), but no difference in relapse (relative risk, 0.85; 95% CI, 0.41-1.76; P = .66). Based on this analysis, AYA patients undergoing allo-HCT for B-ALL have significantly inferior survival and greater transplantation-related mortality compared with children age <13 years, but no difference in relapse, suggesting that allo-HCT may overcome relapse in AYA. Further improvements in peritransplantation care are needed to limit complications in AYA patients., (Copyright © 2013 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)