Orthotopic patient-derived xenografts of paediatric solid tumours.

Paediatric solid tumours arise from endodermal, ectodermal, or mesodermal lineages. Although the overall survival of children with solid tumours is 75%, that of children with recurrent disease is below 30%. To capture the complexity and diversity of paediatric solid tumours and establish new models of recurrent disease, here we develop a protocol to produce orthotopic patient-derived xenografts at diagnosis, recurrence, and autopsy. Tumour specimens were received from 168 patients, and 67 orthotopic patient-derived xenografts were established for 12 types of cancer. The origins of the patient-derived xenograft tumours were reflected in their gene-expression profiles and epigenomes. Genomic profiling of the tumours, including detailed clonal analysis, was performed to determine whether the clonal population in the xenograft recapitulated the patient's tumour. We identified several drug vulnerabilities and showed that the combination of a WEE1 inhibitor (AZD1775), irinotecan, and vincristine can lead to complete response in multiple rhabdomyosarcoma orthotopic patient-derived xenografts tumours in vivo.

Impact of Neoadjuvant Chemotherapy on Image-Defined Risk Factors in High-Risk Neuroblastoma.

PURPOSE: Image-defined risk factors (IDRFs) are associated with surgical risks in neuroblastoma. We sought to evaluate the impact of neoadjuvant therapy on IDRFs and associated ability to achieve gross total resection (GTR) of locoregional disease in patients with high-risk neuroblastoma. METHODS: We retrospectively reviewed charts of patients treated on four consecutive high-risk neuroblastoma protocols over a 20-year period at a single institution. The number of IDRFs at diagnosis and just prior to surgery, and the percent decrease of tumor volume from just prior to surgery to the end of induction were determined. RESULTS: Eighty-eight patients were included. There were 438 IDRFs (average 5.0 ± 3.1 per patient) at diagnosis and 198 (average 2.3 ± 1.9 per patient) after neoadjuvant chemotherapy (p < 0.01). A reduction in IDRFs was seen in 81.8% of patients with average decrease of 2.9 ± 2.5 per patient. The average percent reduction in tumor volume was 89.8 ± 18.9% and correlated with the number of IDRFs present after chemotherapy (p < 0.01). Three or fewer IDRFs prior to surgery was associated with the highest odds ratio for > 90% GTR at 9.33 [95% confidence interval 3.14-31.5]. CONCLUSION: Neoadjuvant chemotherapy reduced the number of IDRFs in the majority of patients with high-risk neuroblastoma. The number of IDRFs present after neoadjuvant therapy correlated with the extent of resection.

Induction Chemotherapy With an Anti-GD2 Monoclonal Antibody (Dinutuximab) and Cytokines in Children With Newly Diagnosed High-risk Neuroblastoma: A Case Series.

Although outcomes for patients with high-risk neuroblastoma improved after the addition of a chimeric anti-GD2 monoclonal antibody (dinutuximab) as treatment for minimal residual disease, nearly half of these patients die of disease. Recent studies demonstrated efficacy of the combination of chemotherapy with anti-GD2 mAb in patients with relapsed or newly diagnosed disease. This retrospective case series describes 6 patients treated at St Jude Children's Research Hospital with an induction regimen containing dinutuximab and chemotherapy, followed by consolidation and postconsolidation therapy. The treatment was well tolerated with expected toxicities. All patients completed induction therapy and demonstrated a clinical response. Further studies are warranted.

Clinical impact of post-induction resolution of pulmonary lesions in metastatic Ewing sarcoma.

BACKGROUND: Patients with metastatic Ewing sarcoma experience poor outcomes despite intensive systemic and local therapy. Early chemotherapy response of pulmonary metastases has been associated with prognosis in other pediatric malignancies. We reviewed the outcomes of patients with Ewing sarcoma and pulmonary metastases treated at our institution based on therapy received and early pulmonary response. MATERIALS AND METHODS: We retrospectively reviewed patients with newly diagnosed Ewing sarcoma and pulmonary metastases at St. Jude Children's Research Hospital between 1979 and 2015. Data obtained included demographic and treatment characteristics including chemotherapy, local control measures, whole lung irradiation (WLI) administration, autologous stem cell transplantation, and outcomes. Patients were evaluated for radiographic post-induction pulmonary complete response (CR). We estimated event-free survival (EFS) and overall survival (OS) and used Cox proportional hazards regression to examine the effects of clinical and treatment factors on outcomes. RESULTS: Fifty-four patients (median age, 12.9 years) were evaluated. Post-induction pulmonary CR was observed in 33 (61%) patients. WLI was delivered to 16 patients (4/33 with pulmonary CR and 12/21 with non-CR). At median 3.6 years follow-up, five-year EFS and OS were 30.8% ± 6.4% and 49.6% ± 7.1%, respectively. Post-induction pulmonary CR was associated with prolonged EFS (P < 0.001) but not improved OS (P = 0.065). Post-induction pulmonary CR was associated with a lower incidence of lung failure (P = 0.031). CONCLUSIONS: Post-induction pulmonary CR is associated with improved EFS in patients with Ewing sarcoma who present with pulmonary metastases.

FDG-PET CT in the evaluation of primary and secondary pancreatic malignancies.

PURPOSE: Primary pancreatic carcinoma and pancreatic metastases are rare in the pediatric population. Pancreatoblastoma is the most common pancreatic malignant tumor in young children and solid-pseudopapillary tumor in teenagers. Pancreatic adenocarcinoma is extremely rare under the age of 40 and is usually associated with underlying genetic abnormalities. Secondary malignancies of the pancreas occur more frequently than primary pancreatic malignancies in children and are most commonly seen with non-Hodgkin lymphomas (NHL) and mesenchymal sarcomas. The purpose of this study was to characterize the metabolism of primary and secondary tumors of the pancreas in pediatric patients. MATERIALS AND METHODS: A retrospective analysis of all primary and secondary pancreatic malignancies imaged with 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) computed tomography (CT) was conducted. RESULTS: Three patients with primary pancreatic cancers were identified, one each with pancreatoblastoma, solid-pseudopapillary tumor, and adenocarcinoma. Each tumor showed elevated uptake of FDG. Metastatic disease in the pancreas was identified in 12 patients-five NHL (including three Burkitt lymphomas), six sarcomas (three osteosarcomas, two rhabdomyosarcomas, and one Ewing sarcoma family tumor), and one malignant rhabdoid tumor. Elevated but variable uptake of FDG was found in each of the tumors of patients with metastatic disease within the pancreas. CONCLUSION: Both primary malignancies and metastatic disease within the pancreas, though very rare in children, adolescents, and young adults, are metabolically active and can be functionally characterized using FDG-PET CT.

Orbital Metastasis Is Associated With Decreased Survival in Stage M Neuroblastoma.

BACKGROUND: Approximately 30% of patients with metastatic (stage M) neuroblastoma present with periorbital ecchymosis from orbital osseous disease. Though locoregional disease is staged by imaging, the prognostic significance of metastatic site in stage M disease is unknown. We hypothesize that, compared to nonorbital metastasis, orbital metastasis is associated with decreased survival in patients with stage M neuroblastoma, and that periorbital ecchymosis reflects location and extent of orbital disease. PROCEDURE: Medical records and imaging from 222 patients with stage M neuroblastoma seen at St. Jude Children's Research Hospital between January 1995 and May 2009 were reviewed. Thirty-seven patients were <18 months of age at diagnosis and 185 were ≥18 months of age. Overall survival (OS) and 5-year survival (5YS) were compared for patients with and without orbital, calvarial and nonorbital osseous metastasis, and with and without periorbital ecchymosis (log-rank test). Associations of periorbital ecchymosis with orbital metastasis location/extent were explored (Fisher's exact test, t-test). RESULTS: In patients ≥18 months of age, only orbital metastasis was associated with decreased 5YS (P = 0.0323) and OS (P = 0.0288). In patients <18 months of age, neither orbital, calvarial, or nonorbital bone metastasis was associated with OS or 5YS. Periorbital ecchymosis was associated with higher number of involved orbital bones (P = 0.0135), but not location or survival. CONCLUSIONS: In patients ≥ 18 months of age with stage M neuroblastoma, orbital metastatic disease is associated with decreased 5YS and OS. In future clinical trials, orbital disease may be useful as an imaging-based risk factor for substratification of stage M neuroblastoma.

The role of chest computed tomography (CT) as a surveillance tool in children with high-risk neuroblastoma.

BACKGROUND: Standardization of imaging obtained in children with neuroblastoma is not well established. This study examines chest CT in pediatric patients with high-risk neuroblastoma. PROCEDURE: Medical records and imaging from 88 patients with high-risk neuroblastoma, diagnosed at St. Jude Children's Research Hospital between January, 2002 and December, 2009, were reviewed. Surveillance imaging was conducted through 2013. Ten patients with thoracic disease at diagnosis were excluded. Event free survival (EFS) and overall survival (OS) were estimated. Size specific dose estimates for CT scans of the chest, abdomen, and pelvis were used to estimate absolute organ doses to 23 organs. Organ dosimetry was used to calculate cohort effective dose. RESULTS: The 5 year OS and EFS were 51.9% ± 6.5% and 42.6% ± 6.5%, respectively. Forty-six (58.9%) patients progressed/recurred and 41 (52.6%) died of disease. Eleven patients (14%) developed thoracic disease progression/recurrence identified by chest CT (1 paraspinal mass, 1 pulmonary nodules, and 9 nodal). MIBG (metaiodobenzylguanidine) scans identified thoracic disease in six patients. Five of the 11 had normal chest MIBG scans; three were symptomatic and two were asymptomatic with normal chest MIBG scans but avid bone disease. The estimated radiation dose savings from surveillance without CT chest imaging was 42%, 34% when accounting for modern CT acquisition (2011-2013). CONCLUSIONS: Neuroblastoma progression/recurrence in the chest is rare and often presents with symptoms or is identified using standard non-CT imaging modalities. For patients with non-thoracic high-risk neuroblastoma at diagnosis, omission of surveillance chest CT imaging can save 35-42% of the radiation burden without compromising disease detection.

Subsequent malignant neoplasms in pediatric patients initially diagnosed with neuroblastoma.

BACKGROUND: Most prior studies evaluating subsequent malignant neoplasms (SMNs) in patients with neuroblastoma are restricted to long-term survivors and/or their treatment exposures. This study investigates SMNs in patients diagnosed with neuroblastoma at our institution. METHODS: Records of 646 patients treated for neuroblastoma at St Jude Children's Research Hospital between 1961 and 2005 were reviewed. Data from patients with SMNs were analyzed and the 20- and 30-year cumulative incidence of SMNs and standardized incidence ratio were calculated. RESULTS: Twenty-one patients had a SMN. The 20- and 30-year cumulative incidences of a SMN were 2.6%±0.7% and 4.6%±1.1%, respectively. The standardized incidence ratio was 8.3 (95% confidence interval, 5.0-13.0). Five patients developed a SMN within 5 years from diagnosis. The median latency for the development of acute myeloid leukemia/myelodysplastic syndrome (n=4), sarcomas (n=7), and carcinomas (n=5) were 3.6, 9, and 24.2 years, respectively. Nine patients died from their SMN, including all with acute myeloid leukemia/myelodysplastic syndrome. CONCLUSIONS: Patients with neuroblastoma have an increased risk of secondary neoplasia. Modification of risk-adapted therapies will likely alter the affected patient population and the incidence of SMNs. Future studies are necessary to link SMNs to treatment exposures and to evaluate the risk of SMNs beyond 30 years from diagnosis.

Quantitative determination of liposomal irinotecan and SN-38 concentrations in plasma samples from children with solid tumors: Use of a cryoprotectant solution to enhance liposome stability.

Preclinical studies have demonstrated that liposomal irinotecan (CPT-11), a topoisomerase I inhibitor, has broad activity against adult cancers, including pancreatic, gastric, colon, lung, glioma, ovarian, and breast cancer. Encapsulation of irinotecan into liposomes can modify its pharmacokinetic properties dramatically. Also, the pharmacokinetic profiles of liposomal drug formulations are not fully understood; thus, bioanalytical methods are needed to separate and quantify nonencapsulated vs. encapsulated concentrations. In this study, two robust, specific, and sensitive LC-MS/MS methods were developed and validated to separate and quantify the nonencapsulated CPT-11 (NE-CPT-11) from the sum-total CPT-11 (T-CPT-11) and its major metabolite, SN-38, in human plasma after intravenous administration of liposomal irinotecan. NE-CPT-11 and SN-38 were separated from plasma samples by using solid-phase extraction, and T-CPT-11 was measured by protein precipitation. The liposomal CPT-11 formulation was unstable during sample storage and handling, resulting in elevated NE-CPT-11 concentration. To improve the stability of liposomal CPT-11, a cryoprotectant solution was added to human plasma samples prior to storage and processing. CPT-11, SN-38, and their respective internal standards, CPT-11-d10 and SN-38-d3, were chromatographically separated on a reversed-phase C18 analytical column. The drugs were detected on a triple quadrupole mass spectrometer in the positive MRM ion mode by monitoring the transitions 587.3 > 124.1 (CPT-11) and 393.0 > 349.1 (SN-38). The calibration curves demonstrated a good fit across the concentration ranges of 10-5000 ng/mL for T-CPT-11, 2.5-250 ng/mL for NE-CPT-11, and 1-500 ng/mL for SN-38. The accuracy and precision were within the acceptable limits, matrix effects were nonsignificant, recoveries were consistent and reproducible, and the analytes were stable under all tested storage conditions. Finally, the LC-MS/MS methods were successfully applied in a phase I clinical pharmacokinetic study of nanoliposomal irinotecan (Onivyde®) in pediatric patients with recurrent solid malignancies or Ewing sarcoma.

DNAJB1-PRKACA fusion neoantigens elicit rare endogenous T cell responses that potentiate cell therapy for fibrolamellar carcinoma.

Fibrolamellar carcinoma (FLC) is a liver tumor with a high mortality burden and few treatment options. A promising therapeutic vulnerability in FLC is its driver mutation, a conserved DNAJB1-PRKACA gene fusion that could be an ideal target neoantigen for immunotherapy. In this study, we aim to define endogenous CD8 T cell responses to this fusion in FLC patients and evaluate fusion-specific T cell receptors (TCRs) for use in cellular immunotherapies. We observe that fusion-specific CD8 T cells are rare and that FLC patient TCR repertoires lack large clusters of related TCR sequences characteristic of potent antigen-specific responses, potentially explaining why endogenous immune responses are insufficient to clear FLC tumors. Nevertheless, we define two functional fusion-specific TCRs, one of which has strong anti-tumor activity in vivo. Together, our results provide insights into the fragmented nature of neoantigen-specific repertoires in humans and indicate routes for clinical development of successful immunotherapies for FLC.

Comparison of PET-CT and conventional imaging in staging pediatric rhabdomyosarcoma.

BACKGROUND: Over the past decade, PET-CT has been used to assess rhabdomyosarcoma (RMS) in children. However, the role of PET-CT in staging RMS is unknown. PROCEDURE: Thirty subjects with RMS, median age 7.3 years, underwent PET-CT before therapy. PET-CTs and conventional imaging (CI) were independently reviewed by two radiologists and two nuclear medicine physicians to determine the presence of metastases. Accuracy, sensitivity, and specificity of PET-CT for detecting metastases were compared to CI using biopsy and clinical follow-up as reference standards. Maximum standardized uptake values (SUV(max)) of primary tumors, lymph nodes, and pulmonary nodules were measured. RESULTS: Primary tumors had an average SUV(max) of 7.2 (range, 2.5-19.2). Accuracy rates for 17 subjects with nodal disease were 95% for PET-CT and 49% for CI. PET-CT had 94% sensitivity and 100% specificity for nodal disease. Of seven pulmonary nodules detected by CI, three were not identified by PET-CT, two were indeterminate, and one was malignant with a SUV(max) (3.4) > twice that of benign nodules. Two subjects had bone disease; both were identified by PET-CT but only one by CI. Four subjects had bone marrow disease, two had positive PET-CTs but none had positive CI. Two subjects had soft tissue metastases detected by PET-CT but not CI. CONCLUSIONS: PET-CT performed better than CI in identifying nodal, bone, bone marrow, and soft tissue disease in children with RMS. CI remains essential for detection of pulmonary nodules. We recommend PET-CT for staging of children with RMS. CI with Tc(99m) bone scan can be eliminated.

Treatment of High-Risk Neuroblastoma with Dinutuximab and Chemotherapy Administered in all Cycles of Induction.

Administration of chemoimmunotherapy using concurrent chemotherapy and an anti-GD2 monoclonal antibody (mAb), dinutuximab (DIN), demonstrated efficacy for the treatment of relapsed and refractory neuroblastoma. Chemoimmunotherapy, using a humanized anti-GD2 mAb, demonstrated a signal of activity in a phase 2 study for the treatment of patients with newly diagnosed high-risk neuroblastoma (HRNBL). In this single-institution retrospective study, patients with HRNBL received an Induction chemotherapy regimen plus DIN in all Induction cycles. Toxicity and response data were abstracted from the electronic medical record. Toxicities were graded by CTCAE v.5.0. The end of Induction (EOI) objective response rate was determined using the Revised International Neuroblastoma Response Criteria. Twenty-seven patients with HRNBL (23 newly diagnosed, 16 females, median age 3.9 years) started Induction chemoimmunotherapy from 27 January 2017 to 28 December 2022. All patients received DIN with all cycles of Induction therapy, and all but one patient completed Induction therapy. The most common non-hematologic grade ≥ 3 toxicities included fever (44%), hypoxemia (20%), and hypoalbuminemia (11%). End of Induction responses included eighteen with a complete response (CR), seven with a partial response (PR), one with progressive disease (PD), and zero with a minor response or stable disease. Twenty-six of twenty-seven patients (96%) completed all Induction cycles and were evaluable for a response. The EOI response of PR or better in the evaluable cohort was 96%. Dinutuximab was well tolerated with all Induction cycles, demonstrated an encouraging EOI response rate, and should be evaluated in a randomized study.

Clinical Response to a PARP Inhibitor and Chemotherapy in a Child with BARD1-Mutated Refractory Neuroblastoma: A Case Report.

Despite advances in the treatment of high-risk neuroblastoma, approximately half of these patients die from the disease. Targeted therapy based on synthetic lethality associated with homologous recombination deficiency (HRD) caused by germline mutations in homologous recombination repair genes has shown great efficacy in several adult solid tumors. Here we report the first successful treatment of a pediatric patient with refractory neuroblastoma and a germline pathogenic mutation in BARD1 using a PARP inhibitor, talazoparib, in combination with cytotoxic chemotherapy and radiation therapy. Allele-specific expression in RNA-seq indicates bi-allelic loss of BARD1 in tumor; however, the HRD score was below the threshold currently used for HRD classification in adult cancers. Our study demonstrates that the use of PARP inhibition in combination with DNA-damaging agents should be considered in children with BARD1-mutated neuroblastoma and cautions against the use of HRD score alone as a biomarker for this pediatric population.

Venetoclax Penetrates the Blood Brain Barrier: A Pharmacokinetic Analysis in Pediatric Leukemia Patients.

Infiltration of malignant cells into the central nervous system in hematological malignancies correlates with poor clinical outcomes. Investigations into the penetration of venetoclax into the central nervous system have been limited. We report venetoclax pharmacokinetics in plasma and cerebrospinal fluid samples from a Phase 1 study in pediatric patients with relapsed or refractory malignancies that demonstrate venetoclax ability to cross into the central nervous system. Venetoclax was detected in cerebrospinal fluid (CSF) samples, with concentrations ranging from < 0.1 to 26 ng/mL (mean, 3.6 ng/mL) and a plasma:CSF ratio ranging from 44 to 1559 (mean, 385). Plasma:CSF ratios were comparable among patients with AML and ALL and no clear trend was observed in the ratios over the course of treatment. Moreover, improvement in central nervous system (CNS) involvement status was observed in patients who had measurable concentrations of venetoclax in the CSF. CNS resolution was observed for up to six months while on treatment. These findings highlight the potential role of venetoclax and provide the opportunity to further investigate its utility in improving clinical outcomes for patients with CNS complications.

Progression-Free Survival and Patterns of Response in Patients With Relapsed High-Risk Neuroblastoma Treated With Irinotecan/Temozolomide/Dinutuximab/Granulocyte-Macrophage Colony-Stimulating Factor.

PURPOSE: Although chemoimmunotherapy is widely used for treatment of children with relapsed high-risk neuroblastoma (HRNB), little is known about timing, duration, and evolution of response after irinotecan/temozolomide/dinutuximab/granulocyte-macrophage colony-stimulating factor (I/T/DIN/GM-CSF) therapy. PATIENTS AND METHODS: Patients eligible for this retrospective study were age < 30 years at diagnosis of HRNB and received ≥ 1 cycle of I/T/DIN/GM-CSF for relapsed or progressive disease. Patients with primary refractory disease who progressed through induction were excluded. Responses were evaluated using the International Neuroblastoma Response Criteria. RESULTS: One hundred forty-six patients were included. Tumors were MYCN-amplified in 50 of 134 (37%). Seventy-one patients (49%) had an objective response to I/T/DIN/GM-CSF (objective response; 29% complete response, 14% partial response [PR], 5% minor response [MR], 21% stable disease [SD], and 30% progressive disease). Of patients with SD or better at first post-I/T/DIN/GM-CSF disease evaluation, 22% had an improved response per International Neuroblastoma Response Criteria on subsequent evaluation (13% of patients with initial SD, 33% with MR, and 41% with PR). Patients received a median of 4.5 (range, 1-31) cycles. The median progression-free survival (PFS) was 13.1 months, and the 1-year PFS and 2-year PFS were 50% and 28%, respectively. The median duration of response was 15.9 months; the median PFS off all anticancer therapy was 10.4 months after discontinuation of I/T/DIN/GM-CSF. CONCLUSION: Approximately half of patients receiving I/T/DIN/GM-CSF for relapsed HRNB had objective responses. Patients with initial SD were unlikely to have an objective response, but > 1 of 3 patients with MR/PR on first evaluation ultimately had complete response. I/T/DIN/GM-CSF was associated with extended PFS in responders both during and after discontinuation of treatment. This study establishes a new comparator for response and survival in patients with relapsed HRNB.

Bevacizumab, With Sorafenib and Cyclophosphamide Provides Clinical Benefit for Recurrent or Refractory Osseous Sarcomas in Children and Young Adults.

Objective: Children and adolescents with recurrent and metastatic solid tumors have a poor outcome. A previous phase 1 study (ANGIO1) targeting angiogenesis with bevacizumab, sorafenib, and cyclophosphamide, demonstrated a signal of activity in a subset of patients. Here we report the results of a cohort of pediatric and young adult patients treated at the recommended phase 2 doses. Methods: Electronic medical records of patients with refractory or recurrent solid tumors who received ANGIO1 therapy were reviewed. Treatment cycles lasted 21 days and included bevacizumab, sorafenib, and cyclophosphamide. Toxicities were assessed using Common Terminology Criteria for Adverse Events, v5.0. Responses were evaluated using Response Evaluation Criteria in Solid Tumors (RECIST1.1). Results: Thirty-nine patients (22 male, 17 female; median age 15 years; range 1-22 years) received the treatment regimen. The most common diagnoses included bone sarcomas (n=21; 14 Ewing sarcoma, 7 osteosarcoma) and soft tissue sarcomas (n=9; 2 rhabdomyosarcoma, 3 synovial sarcoma, 2 desmoplastic small round cell tumors, and 2 high-grade sarcoma). The most common Grade 3 non-hematologic toxicities included hypertension (2, 5.4%) and hematuria (2, 5.4%). Five patients (13.5%) had a pneumothorax (3 at progressive disease, 1 post lung biopsy, and 1 spontaneous). Common Grade 3/4 hematologic toxicities were lymphopenia (19, 51%) and leukopenia (13, 35%). Sixteen patients (43.2%) developed palmar-plantar erythrodysesthesia Grade 2 or less. A total of 297 cycles were administered. Twenty-three patients required a dose reduction of cyclophosphamide, sorafenib or bevacizumab during therapy, all of whom continued to have clinical benefit following dose modification. One patient (Ewing sarcoma) achieved a complete response after 11 cycles; 2 patients (Ewing sarcoma, high grade sarcoma) achieved a partial response following cycles 2 and 4, respectively and 20 patients had stable disease as a best response. Conclusions: Intravenous bevacizumab combined with oral sorafenib and metronomic cyclophosphamide was tolerated and required minimal supportive care or additional clinic visits. Disease stabilization for prolonged time periods was observed in greater than half of the treated patients. Patients with bone sarcoma demonstrated a signal of activity suggesting possible benefit from incorporation of the therapy as a maintenance regimen in upfront setting, or as a palliative regimen.

CPX-351 induces remission in newly diagnosed pediatric secondary myeloid malignancies.

Secondary myelodysplastic syndromes and acute myeloid leukemia (sMDS/AML) are rare in children and adolescents and have a dismal prognosis. The mainstay therapy is hematopoietic cell transplantation (HCT), but there has been no innovation in cytoreductive regimens. CP X-351, a fixed 5:1 molar ratio of liposomal cytarabine to daunorubicin, has shown favorable safety and efficacy in elderly individuals with secondary AML and children with relapsed de novo AML. We report the outcomes of 7 young patients (6 with newly diagnosed sMDS/AML and 1 with primary MDS/AML) uniformly treated with CP X-351. Five patients had previously received chemotherapy for osteosarcoma, Ewing sarcoma, neuroblastoma, or T-cell acute lymphoblastic leukemia; 1 had predisposing genomic instability disorder (Cornelia de Lange syndrome) and 1 had MDS-related AML and multiorgan failure. The median age at diagnosis of myeloid malignancy was 17 years (range, 13-23 years). Patients received 1 to 3 cycles of CP X-351 (cytarabine 100 mg/m2 plus daunorubicin 44 mg/m2) on days 1, 3, and 5, resulting in complete morphologic remission without overt toxicity or treatment-related mortality. This approach allowed for adding an FLT3 inhibitor as individualized therapy in 1 patient. Six patients were alive and leukemia-free at 0.5 to 3.3 years after HCT. One patient died as a result of disease progression before HCT. To summarize, CP X-351 is an effective and well-tolerated regimen for cytoreduction in pediatric sMDS/AML that warrants prospective studies.