Central nervous system status is prognostic in T-cell acute lymphoblastic leukemia: a Children's Oncology Group report.

To determine the prognostic significance of central nervous system (CNS) leukemic involvement in newly diagnosed T-cell acute lymphoblastic leukemia (T-ALL), outcomes on consecutive, phase 3 Children's Oncology Group clinical trials were examined. AALL0434 and AALL1231 tested efficacy of novel agents within augmented-Berlin-Frankfurt-Münster (aBFM) therapy. In addition to testing study-specific chemotherapy through randomization, the AALL0434 regimen delivered cranial radiation therapy (CRT) to most participants (90.8%), whereas AALL1231 intensified chemotherapy to eliminate CRT in 88.2% of participants. In an analysis of 2164 patients with T-ALL (AALL0434, 1550; AALL1231, 614), 1564 had CNS-1 (72.3%), 441 CNS-2 (20.4%), and 159 CNS-3 (7.3%). The 4-year event-free-survival (EFS) was similar for CNS-1 (85.1% ± 1.0%) and CNS-2 (83.2% ± 2.0%), but lower for CNS-3 (71.8% ± 4.0%; P = .0004). Patients with CNS-1 and CNS-2 had similar 4-year overall survival (OS) (90.1% ± 0.8% and 90.5% ± 1.5%, respectively), with OS for CNS-3 being 82.7% ± 3.4% (P = .005). Despite therapeutic differences, outcomes for CNS-1 and CNS-2 were similar regardless of CRT, intensified corticosteroids, or novel agents. Except for significantly superior outcomes with nelarabine on AALL0434 (4-year disease-free survival, 93.1% ± 5.2%), EFS/OS was inferior with CNS-3 status, all of whom received CRT. Combined analyses of >2000 patients with T-ALL identified that CNS-1 and CNS-2 status at diagnosis had similar outcomes. Unlike B-ALL, CNS-2 status in T-ALL does not impact outcome with aBFM therapy, without additional intrathecal therapy, with or without CRT. Although nelarabine improved outcomes for those with CNS-3 status, novel approaches are needed. These trials were registered at www.clinicaltrials.gov as #NCT00408005 (AALL0434) and #NCT02112916 (AALL1231).

Novel therapies for pediatric acute lymphoblastic leukemia.

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.

Decitabine and vorinostat with FLAG chemotherapy in pediatric relapsed/refractory AML: Report from the therapeutic advances in childhood leukemia and lymphoma (TACL) consortium.

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 (<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.

CREATE Childhood Cancer Rehabilitation Program development: Increase access through interprofessional collaboration.

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.

Real-world experience in treating pediatric relapsed/refractory or therapy-related myeloid malignancies with decitabine, vorinostat, and FLAG therapy based on a phase 1 study run by the TACL consortium.

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.

Langerhans cell histiocytosis with BRAF p.N486_P490del or MAP2K1 p.K57_G61del treated by the MEK inhibitor trametinib.

Activating variants of the MAPK pathway have been found in some Langerhans cell histiocytosis (LCH) lesions. Inhibition of the MAPK pathway with trametinib (MEK inhibitor) has been shown to induce responses in LCH patients. Two adolescent males with LCH driven by BRAF p.N486_P490del have received trametinib for >1 year with no reactivation in one and partial response in another (including stable lung disease). A third male with neonatal LCH and MAP2K1p.K57_G61del had a complete response to trametinib with no active disease after 22 months. All patients continue on trametinib monotherapy with tolerable skin and creatine phosphokinase toxicity.

Symptomatic Hyperammonemia With Erwinia chrysanthemi-derived Asparaginase in Pediatric Leukemia Patients.

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.

Efficient Synthetic Approach to Linear Dasatinib-DNA Conjugates by Click Chemistry.

A pair of synthetic approaches to linear dasatinib-DNA conjugates via click chemistry are described. The first approach involves the reaction of excess azido dasatinib derivative with 5'-(5-hexynyl)-tagged DNAs, and the second involves the reaction of excess alkynyl-linked dasatinib with 5'-azido-tagged DNA. The second approach using alkynyl-derived dasatinib and 5'-azido-tagged DNA yielded the corresponding dasatinib-DNA conjugates in higher yield (47% versus 10-33% for the first approach). Studies have shown these linear dasatinib-DNA conjugates-derived gold nanoparticles exhibit efficacy against leukemia cancer cells with reduced toxicity toward normal cells compared to that of free dasatinib.

Chemotherapy Options for Poor Responders to Neoadjuvant Chemotherapy for Orbital Granulocytic Sarcoma.

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.

Report of a patient with a constitutional missense mutation in SMARCB1, Coffin-Siris phenotype, and schwannomatosis.

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.

Critical hypercalcemia following discontinuation of denosumab therapy for metastatic giant cell tumor of bone.

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.

Survival differences between adolescents/young adults and children with B precursor acute lymphoblastic leukemia after allogeneic hematopoietic cell transplantation.

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.

The role of nelarabine in the treatment of T-cell acute lymphoblastic leukemia/lymphoma: challenges, opportunities, and future directions.

INTRODUCTION: Nelarabine is a guanine nucleoside analog and functions to terminate DNA synthesis in dividing cells. Pre-clinical and clinical studies have shown that it preferentially accumulates in T-cells where it exerts its cytotoxic effects. After generations of treatment protocol advances, it has been incorporated into numerous treatment regimens against T-lineage acute lymphoblastic leukemia/lymphoma (T-ALL/LLy). On 8 March 2023, the FDA approved the use of nelarabine for its use in T-ALL due to clear evidence of clinical benefits. This announcement concludes a nearly 6-decade period of evaluation for nelarabine and its role in the management of high-grade, aggressive T-cell malignancies. AREAS COVERED: We review the medicinal biology of nelarabine, its evaluation through decades of clinical studies, its dose-limited adverse effects, and its areas of highest impact in the treatment of T-ALL/LLy. EXPERT OPINION: We provide a context of when nelarabine might be considered in treatments against T-ALL/LLy, and also alternative strategies when it has or has not been used in therapies prior to relapse. We anticipate that an increasing number of treatment regimens will include nelarabine as a part of front-line therapy.

Matched Targeted Therapy for Pediatric Patients with Relapsed, Refractory, or High-Risk Leukemias: A Report from the LEAP Consortium.

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.

Intrathecal Methotrexate Containing the Preservative Benzyl Alcohol Erroneously Administered in Pediatric Leukemia Patients: Clinical Course and Preventive Process.

Administration of intrathecal chemotherapy for leukemia is a common procedure in pediatric oncology. The direct delivery of drug into the cerebral spinal fluid requires that no preservative be used. Preserved drugs administered in error can result in significant neurotoxicity. A case series is described where preservative-containing methotrexate was incidentally administered intrathecally. All patients were treated at Children's Hospitals and Clinics of Minnesota. Medical records of the patients affected were reviewed and abstracted for this report. Four children with acute lymphoblastic leukemia received 1 dose of intrathecal methotrexate that contained 0.07% benzyl alcohol in January 2019. Overall, minimal to no symptoms were seen after dosing. The error was traced to a drug shortage in which benzyl alcohol-containing methotrexate was obtained and incorrectly stocked. A novel replacement drug procurement process was developed within our institution. The process includes sequestered queues where a drug awaits evaluation and independent double check of entry accuracy in the electronic health record and pharmacy parenteral dose preparation software prior to release and use. In contrast to IV administration, intrathecal benzyl alcohol at concentrations ≥ 0.9% can cause significant neurotoxicity. Although minimal, if any, neurotoxicity was seen in patients who received a 10-fold lower concentration of benzyl alcohol than previously associated with complications, all institutions should recognize the potential for this error and implement similar safety precautions to ensure that this type of error will not occur.

More precisely defining risk peri-HCT in pediatric ALL: pre- vs post-MRD measures, serial positivity, and risk modeling.

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.

The Role of the Central Nervous System Microenvironment in Pediatric Acute Lymphoblastic Leukemia.

Acute lymphoblastic leukemia (ALL) is the most common cancer in children. While survival rates for ALL have improved, central nervous system (CNS) relapse remains a significant cause of treatment failure and treatment-related morbidity. Accordingly, there is a need to identify more efficacious and less toxic CNS-directed leukemia therapies. Extensive research has demonstrated a critical role of the bone marrow (BM) microenvironment in leukemia development, maintenance, and chemoresistance. Moreover, therapies to disrupt mechanisms of BM microenvironment-mediated leukemia survival and chemoresistance represent new, promising approaches to cancer therapy. However, in direct contrast to the extensive knowledge of the BM microenvironment, the unique attributes of the CNS microenvironment that serve to make it a leukemia reservoir are not yet elucidated. Recent work has begun to define both the mechanisms by which leukemia cells migrate into the CNS and how components of the CNS influence leukemia biology to enhance survival, chemoresistance, and ultimately relapse. In addition to providing new insight into CNS relapse and leukemia biology, this area of investigation will potentially identify targetable mechanisms of leukemia chemoresistance and self-renewal unique to the CNS environment that will enhance both the durability and quality of the cure for ALL patients.

Pediatric Acquired von Willebrand Disease With Berlin Heart Excor Ventricular Assist Device Support.

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.

Drug conjugated nanoparticles activated by cancer cell specific mRNA.

We describe a customizable approach to cancer therapy in which a gold nanoparticle (Au-NP) delivers a drug that is selectively activated within the cancer cell by the presence of an mRNA unique to the cancer cell. Fundamental to this approach is the observation that the amount of drug released from the Au-NP is proportional to both the presence and abundance of the cancer cell specific mRNA in a cell. As proof-of-principle, we demonstrate both the efficient delivery and selective release of the multi-kinase inhibitor dasatinib from Au-NPs in leukemia cells with resulting efficacy in vitro and in vivo. Furthermore, these Au-NPs reduce toxicity against hematopoietic stem cells and T-cells. This approach has the potential to improve the therapeutic efficacy of a drug and minimize toxicity while being highly customizable with respect to both the cancer cell specific mRNAs targeted and drugs activated.