B-cell acute lymphoblastic leukemia with iAMP21 in a patient with Down syndrome due to a constitutional isodicentric chromosome 21.

Pediatric B-cell acute lymphoblastic leukemia (B-ALL) is associated with various specific cytogenetic and molecular markers that have significant influence on treatment and prognosis. A subset of children has a much higher risk of developing B-ALL due to constitutional genetic alterations such as trisomy 21 (Down's syndrome). In these patients, B-ALL is often associated with specific genomic profiles leading to leukemic transformation. In rare cases, constitutional structural chromosomal abnormalities involving chromosome 21, such as the der(15;21) Robertsonian translocation and a ring 21 chromosome, have been associated with intrachromosomal amplification of chromosome 21 (iAMP21) B-ALL. Here, we report the development of B-ALL in a child with Down's syndrome who carries a constitutional isodicentric chromosome 21 [idic(21)], described previously by Putra et al., 2017. This idic(21) appeared to be unstable during mitosis, leading to somatic rearrangements consistent with iAMP21 amplification, resulting in the development of leukemia. In this case, a single constitutional structural chromosome 21 rearrangement resulted in a B-ALL with Down syndrome-associated genomic lesions as well as genomic lesions not common to the Down syndrome subtype of B-ALL. Our findings highlight the need for counseling of individuals with constitutional structural chromosome 21 rearrangements regarding their risks of developing a B-ALL.

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.

Phase 2 study of nilotinib in pediatric patients with Philadelphia chromosome-positive chronic myeloid leukemia.

Chronic myeloid leukemia (CML) is rare in children and accounts for ≤15% of all myeloid leukemia cases. When we initiated this study with nilotinib, imatinib was the only tyrosine kinase inhibitor indicated for pediatric patients with Philadelphia chromosome-positive (Ph+) CML in chronic phase (CP); alternative treatment options were needed, particularly for patients who developed resistance or intolerance (R/I) to imatinib. This phase 2 study enrolled pediatric patients with either Ph+ CML-CP R/I to imatinib or dasatinib or newly diagnosed Ph+ CML-CP. Data presented are from analyses with minimum follow-up of up to 24 cycles (1 cycle is 28 days). Fifty-nine patients with Ph+ CML-CP were enrolled, and 58 were treated (R/I, n = 33; newly diagnosed, n = 25). Major molecular response (MMR) rate at cycle 6 in the R/I cohort was 39.4% (primary end point); 57.6% of patients achieved or maintained MMR and 81.8% achieved or maintained complete cytogenetic response (CCyR) by 24 cycles. In patients with newly diagnosed disease, rates of MMR by cycle 12 and CCyR at cycle 12 were 64.0% each (primary end points); by cycle 24, cumulative MMR and CCyR rates were 68.0% and 84.0%, respectively. The safety profile of nilotinib in pediatric patients was generally comparable with the known safety profile in adults, although cardiovascular events were not observed in this study, and hepatic laboratory abnormalities were more frequent; no new safety signals were identified. In summary, nilotinib demonstrated efficacy and a manageable safety profile in pediatric patients with Ph+ CML-CP. This trial was registered at www.clinicaltrials.gov as #NCT01844765.

Impact of a Best Practice Prevention Bundle on Central Line-associated Bloodstream Infection (CLABSI) Rates and Outcomes in Pediatric Hematology, Oncology, and Hematopoietic Cell Transplantation Patients in Inpatient and Ambulatory Settings.

BACKGROUND: Pediatric hematology, oncology, and hematopoietic cell transplantation (HCT) patients are at increased risk for bloodstream infections. The authors sought to evaluate the influence of a standardized best practice central venous catheter (CVC) maintenance bundle on the burden of and risk factors for mucosal barrier injury (MBI) and non-MBI central line-associated bloodstream infections (CLABSIs) across a common inpatient and ambulatory continuum in this high-risk population. METHODS: A retrospective cohort study of patients with underlying malignancy, hematologic disorders, and HCT recipients with a CVC in place at the time of CLABSI diagnosis in both inpatient and ambulatory settings from January 1, 2012 to December 31, 2016. Descriptive, nonparametric statistics were used to describe patient characteristics and outcomes. Logistic regression analyses were applied to identify potential risk factors for inpatient versus ambulatory and MBI versus non-MBI CLABSI. RESULTS: During the 5-year period, 118 of 808 (14.6%) patients had 159 laboratory-confirmed CLABSIs for ambulatory and inpatient CLABSI rates of 0.27 CLABSI/1000 and 2.2 CLABSI/1000 CVC days, respectively. CLABSI occurred more frequently in hospitalized patients after HCT and with underlying leukemia, most frequently caused by Gram-negative bacteria. MBI CLABSI accounted for 42% of all CLABSI with a 3-fold higher risk in hospitalized patients. Having multiple CVC or a CVC that was not a port independently associated with higher CLABSI risk. CONCLUSIONS: In our cohort, non-MBI CLABSI continued to account for the majority of CLABSI. CVC type is independently associated with higher overall CLABSI risk. Further studies are needed to reliably define additional prevention strategies when CLABSI maintenance bundles elements are optimized in this high-risk population.

High-dose methotrexate-induced epidermal necrosis in two pediatric patients.

Methotrexate-induced epidermal necrosis (MEN) is an uncommon but potentially fatal complication. We present two pediatric oncology patients, a 5-year-old girl and a 3-year-old boy, who developed MEN from high-dose methotrexate therapy for pre-B-cell acute lymphocytic leukemia. Following administration of systemic methotrexate, the patients developed erythematous lesions with subsequent skin erosions. Pre-medication with systemic corticosteroids and administration of folinic acid rescue following the methotrexate infusion allowed both patients to resume their chemotherapy regimen with methotrexate.

Outcomes after bloodstream infection in hospitalized pediatric hematology/oncology and stem cell transplant patients.

BACKGROUND: Pediatric hematology/oncology (PHO) patients receiving therapy or undergoing hematopoietic stem cell transplantation (HSCT) often require a central line and are at risk for bloodstream infections (BSI). There are limited data describing outcomes of BSI in PHO and HSCT patients. METHODS: This is a multicenter (n = 17) retrospective analysis of outcomes of patients who developed a BSI. Centers involved participated in a quality improvement collaborative referred to as the Childhood Cancer and Blood Disorder Network within the Children's Hospital Association. The main outcome measures were all-cause mortality at 3, 10, and 30 days after positive culture date; transfer to the intensive care unit (ICU) within 48 hours of positive culture; and central line removal within seven days of the positive blood culture. RESULTS: Nine hundred fifty-seven BSI were included in the analysis. Three hundred fifty-four BSI (37%) were associated with at least one adverse outcome. All-cause mortality was 1% (n = 9), 3% (n = 26), and 6% (n = 57) at 3, 10, and 30 days after BSI, respectively. In the 165 BSI (17%) associated with admission to the ICU, the median ICU stay was four days (IQR 2-10). Twenty-one percent of all infections (n = 203) were associated with central line removal within seven days of positive blood culture. CONCLUSIONS: BSI in PHO and HSCT patients are associated with adverse outcomes. These data will assist in defining the impact of BSI in this population and demonstrate the need for quality improvement and research efforts to decrease them.

A multiyear quality improvement project to increase influenza vaccination in a pediatric oncology population undergoing active therapy.

BACKGROUND: In an effort to reduce morbidity and mortality from vaccine preventable influenza infection, national consensus guidelines recommend vaccination of patients who are immunocompromised as a result of receiving cancer therapy. Quality improvement (QI) processes are a proven method used to improve vaccination rates. PROCEDURE: We conducted a QI initiative aimed at increasing influenza vaccination in oncology patients undergoing active treatment. Primary drivers for the project focused on patient education, staff and provider education, and communication regarding vaccine-eligible patients. We performed a retrospective analysis of influenza infection among the vaccine-eligible population. This approach has validity at our institution because of the consistent follow-up and hospital admission pattern of cancer patients on active therapy such that nearly all follow-up care is delivered at our institution. RESULTS: We successfully achieved greater than 87% vaccination of eligible patients each vaccine season (September to March). During the recommended timeframe for delivering influenza vaccine between September and December of each vaccine season, we offered the vaccine to 100% of patients on active therapy and vaccinated >90%. Barriers to success, including vaccine refusals, increased late in the vaccine season. Influenza infection was documented in 0.5-7.3% of the vaccine-eligible group. CONCLUSION: A robust influenza vaccination program implemented using a standardized QI approach can sustain a high vaccination rate in a pediatric oncology population receiving active treatment. The influenza infection rate was under 10% in the vaccinated group.

Prospective External Validation of the Esbenshade Vanderbilt Models Accurately Predicts Bloodstream Infection Risk in Febrile Non-Neutropenic Children With Cancer.

PURPOSE: The optimal management of fever without severe neutropenia (absolute neutrophil count [ANC] ≥500/µL) in pediatric patients with cancer is undefined. The previously proposed Esbenshade Vanderbilt (EsVan) models accurately predict bacterial bloodstream infections (BSIs) in this population and provide risk stratification to aid management, but have lacked prospective external validation. MATERIALS AND METHODS: Episodes of fever with a central venous catheter and ANC ≥500/µL occurring in pediatric patients with cancer were prospectively collected from 18 academic medical centers. Variables included in the EsVan models and 7-day clinical outcomes were collected. Five versions of the EsVan models were applied to the data with calculation of C-statistics for both overall BSI rate and high-risk organism BSI (gram-negative and Staphylococcus aureus BSI), as well as model calibration. RESULTS: In 2,565 evaluable episodes, the BSI rate was 4.7% (N = 120). Complications for the whole cohort were rare, with 1.1% (N = 27) needing intensive care unit (ICU) care by 7 days, and the all-cause mortality rate was 0.2% (N = 5), with only one potential infection-related death. C-statistics ranged from 0.775 to 0.789 for predicting overall BSI, with improved accuracy in predicting high-risk organism BSI (C-statistic 0.800-0.819). Initial empiric antibiotics were withheld in 14.9% of episodes, with no deaths or ICU admissions attributable to not receiving empiric antibiotics. CONCLUSION: The EsVan models, especially EsVan2b, perform very well prospectively across multiple academic medical centers and accurately stratify risk of BSI in episodes of non-neutropenic fever in pediatric patients with cancer. Implementation of routine screening with risk-stratified management for non-neutropenic fever in pediatric patients with cancer could safely reduce unnecessary antibiotic use.

The long-term efficacy and safety of nilotinib in pediatric patients with CML: a 5-year update of the DIALOG study.

The efficacy and safety of nilotinib in pediatric patients with imatinib/dasatinib resistant/intolerant (R/I) or newly diagnosed (ND) Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia in chronic phase (CML-CP) was demonstrated in the phase 2, open-label DIALOG study. In this final analysis, long-term efficacy and safety are presented for patients who completed 66 cycles (of 28 days) of treatment with nilotinib (230 mg/m2 twice daily) or discontinued early. Overall, 59 patients were enrolled and 58 were treated (R/I, n = 33; ND, n = 25; median time on treatment: 60.5 and 51.9 months, respectively). In the R/I cohort, the cumulative major molecular response (MMR; BCR::ABL1 international scale [IS] ≤ 0.1%) rate was 60.6%, and no patients had a confirmed loss of MMR. Among ND patients, the best overall MMR rate was 76.0%; 3 patients had a confirmed loss of MMR. The cumulative molecular response MR4 (BCR::ABL1IS ≤ 0.01%) and MR4.5 (BCR::ABL1IS ≤ 0.0032%) rates by 66 cycles were 27.3% and 12.1% in the R/I cohort, and 56.0% and 44.0% in the ND cohort, respectively. The safety profile of nilotinib was consistent with those of earlier reports. No on-treatment deaths occurred. These long-term (up to ∼5 years) data support the efficacy and safety of nilotinib in pediatric patients with Ph+ CML-CP. This trial was registered at www.clinicaltrials.gov.uk as #NCT01844765.

A phase 2 study of nilotinib in pediatric patients with CML: long-term update on growth retardation and safety.

The phase 2, open-label study (DIALOG) of nilotinib in pediatric patients with Philadelphia chromosome-positive chronic myelogenous leukemia (CML) met its coprimary end points, showing sustained nilotinib efficacy in patients with newly diagnosed (ND) or imatinib/dasatinib resistant/intolerant (R/I) CML. This update assessed growth and safety profiles in patients who had completed ≥48, 28-day treatment cycles of nilotinib 230 mg/m2 twice daily, or previously discontinued the study. Height was assessed regularly and reported using standard deviation scores (SDSs) based on World Health Organization growth charts. All data were summarized descriptively (cutoff, 6 March 2019). Overall, 33 patients in the R/I cohort and 25 patients in the ND cohort received nilotinib. Each cohort showed a negative slope in height SDS over the course of the study, indicating attenuated growth rates during nilotinib treatment: overall median change from baseline in height SDS after 48 cycles was -0.54 SDS (range, - 1.6 to 0.4) and -0.91 SDS (-1.4 to -0.1) in R/I and ND cohorts, respectively. Patients in the R/I cohort were shorter at baseline than those in the ND cohort, and remained so throughout the study. The most common all-cause adverse events were increased blood bilirubin (53.4%), headache (46.6%), pyrexia (37.9%), and increased alanine transferase (36.2%). Apart from the impact on growth, the safety profile of nilotinib was generally consistent with previous reports. This study was registered on www.clinicaltrials.gov at #NCT01844765.

Significance of minimal residual disease in pediatric mixed phenotype acute leukemia: a multicenter cohort study.

The rarity of mixed phenotype acute leukemia (MPAL) has precluded adequate data to incorporate minimal residual disease (MRD) monitoring into therapy. Fluidity in MPAL classification systems further complicates understanding its biology and outcomes; this includes uncertainty surrounding the impact of shifting diagnostic requirements even between iterations of the World Health Organization (WHO) classification. Our primary objective was to address these knowledge gaps. To do so, we analyzed clinicopathologic features, therapy, MRD, and survival in a centrally-reviewed, multicenter cohort of MPAL uniformly diagnosed by the WHO classification and treated with acute lymphoblastic leukemia (ALL) regimens. ALL induction therapy achieved an EOI MRD negative (<0.01%) remission in most patients (70%). EOI MRD positivity was predictive of 5-year EFS (HR = 6.00, p < 0.001) and OS (HR = 9.57, p = 0.003). Patients who cleared MRD by EOC had worse survival compared with those EOI MRD negative. In contrast to adults with MPAL, ALL therapy without transplantation was adequate to treat most pediatric patients. Earlier MRD clearance was associated with better treatment success and survival. Prospective trials are now necessary to validate and refine MRD thresholds within the pediatric MPAL population and to identify salvage strategies for those with poor predicted survival.

Myeloid sarcoma presenting as bilateral acute otitis externa in newly diagnosed acute myeloid leukemia.

Myeloid sarcoma (MS) is an extramedullary collection of immature myeloid cells that can commonly occur with acute myeloid leukemia (AML). While head and neck presentations are not unheard of, there have been few published pediatric cases of external auditory canal MS. Here, we report a case of a 14-year-old male who presented with MS masquerading as bilateral acute otitis externa. To the best of our knowledge, this is the first reported case of a bilateral presentation leading to a new diagnosis of AML. A literature review of head and neck presentations of MS is included.

A Quality Improvement Approach to Increase Exercise Assessment in Survivors of Childhood Leukemia.

INTRODUCTION: Survivors of childhood cancer are at increased risk of treatment-related cardiovascular disease, the severity of which is impacted by the level of regular exercise. Exercise assessments (EAs) are not a routine component of follow-up care. METHODS: We incorporated a quantitative EA tool into the clinic triage during follow-up visits for survivors of acute lymphoblastic leukemia. The nursing staff was surveyed on the use of the EA tool to gauge understanding and level of comfort with addressing patient questions. RESULTS: Over 27 months, the percentage of off-therapy acute lymphoblastic leukemia patients with documented EA increased from 0% to 80%. We noted degradation in EA completions in the last 6 months of the project, which we attributed to project nursing staff transition and failure to maintain education. Interventions that improved the percentage of completed EA included the incorporation the assessment tool into the electronic medical record and weekly reminders of scheduled eligible patients. A nurse incentive plan did not impact project success. Survey results revealed that the nursing staff were comfortable with the EA and did not view the new process as hurting patient flow. CONCLUSION: Implementation of an EA tool into routine clinic follow-up was successful. We met the project goal of assessing greater than 50% of the follow-up patients. This work will serve as the foundation for the next phase of the project, which will be to provide education on the importance of exercise and earlier intervention when a sedentary lifestyle is identified.

Acute Myeloid Leukemia with RAM Immunophenotype: A Pediatric Case with Unusual Morphologic Features.

The RAM immunophenotype has been recently described as a subtype of acute myelogenous leukemia (AML) that is characterized clinically by extremely poor prognosis. We present a case of AML with RAM immunophenotype in a 5-year-old patient that resulted in poor outcome despite early hematopoietic cell transplant. We describe the unusual morphologic features that, along with the distinct immunophenotype, may provide initial diagnostic clues and further justify the classification of this AML variant as a rather distinct subtype.

Promyelocytic Leukemia with No Retinoic Acid Receptor Alpha Abnormality but with RUNX1T1 Insertion to Chromosome 7q: A Classification and Management Dilemma.

A case of acute promyelocytic leukemia (APL) with RUNX1T1 insertion to 7q is described and compared to reported cases of APL with negative retinoic acid receptor alpha (RARA) abnormality. In this report, we describe the case of a 2-year-old boy who presented with bone pain and was found to have pancytopenia. Bone marrow examination showed morphologic and immunophenotypic findings typical of APL, but conventional cytogenetics, fluorescence in situ hybridization (FISH), and real-time polymerase chain reaction (RT-PCR) showed no evidence of RARA rearrangements. The only cytogenetic abnormality found was a small insertion in 7q, and three copies of RUNX1T1. Gene sequencing results became available after initiating therapy but were not informative. We describe the rarity of such cases and discuss how the typical morphologic and immunophenotypic findings of APL, coupled with the definite absence of RARA rearrangement (by FISH and RT-PCR), present a diagnostic and classification dilemma, raising the possibility of an unknown alternative mechanism for the leukemogenesis and maturation arrest seen in other APL variants. The diagnostic challenges and urgent management issues this unusual case raises may justify including it, along with similar cases, in a separate subtype of acute myeloid leukemia (AML) in future classifications.

Secondary Acute Myeloid Leukemia in a One-Year-Old Girl Diagnosed with JAK2-V617F Mutation Positive Myeloproliferative Neoplasm.

Myeloproliferative neoplasms (MPNs) are a group of clonal disorders characterized by hyperproliferation of hematologic cell lines and have been associated with tyrosine kinase JAK2-V617F mutations. Secondary acute myeloid leukemia (sAML) is a known complication of JAK2-V617F+ MPNs and bears a poor prognosis. Although the evolution of a JAK2-V617F+ MPN to a mixed-lineage leukemia has been reported in the pediatric population, no evolutions into sAML have been described. We present a case of a one-year-old girl diagnosed with JAK2-V617F+ MPN with evolution into sAML. Despite initial morphologic remission, she eventually relapsed and succumbed to her disease.

Use of ultrasound to facilitate difficult lumbar puncture in the pediatric oncology population.

In the pediatric hematology-oncology population, lumbar punctures (LP's) are commonly performed to administer intrathecal chemotherapy and obtain CSF samples. Difficult LP's can arise due to obesity, fibrous tissue formation due to repeated LP procedures, or spinal abnormalities. For difficult LP's that require imaging-guidance, fluoroscopy is generally?? Fluoroscopy, however, subjects the patient and healthcare providers to radiation while also potentially increasing procedure cost and time. We retrospectively studied the utility of ultrasound-guidance to facilitate LP in 4 pediatric hematology-oncology patients. All 4 patients had a history of difficult LP and 3 of 4 had previously required use of fluoroscopy. With the use of ultrasound, the LP was successfully performed in all 4 patients with one attempt (number of attempts not recorded in one patient). Procedure time was less than 20 minutes in all 4 patients. Our preliminary data suggests that ultrasound may be an efficacious alternative to fluoroscopy. By using ultrasound to identify the landmarks in the lumbar region, the appropriate puncture point can be determined allowing access to the intrathecal space with relative ease. This would decrease the need for fluoroscopy-guidance, the incidence of multiple punctures as well as reducing the procedure time and costs.

Cancer vaccines: emphasis on pediatric cancers.

The success that vaccines have had in the fight with infectious diseases has not been mirrored in their use in the fight against cancer. The major differences are that cancer vaccines have been tested in the therapeutic rather than the prophylactic setting, and in older adults rather than in the pediatric population. Cancers, as well as current standard treatments, are highly immunosuppressive, which further compromises the success of therapeutic vaccines. Cancer is considered to be primarily a disease of the older age and yet many children suffer from or succumb to cancers such as leukemias, glioblastomas, neuroblastomas and sarcomas. Standard therapy, even when curative, is accompanied by serious side effects, including secondary tumors later in life. Due to the greater capacity of a young immune system to recover after cancer treatment, therapeutic vaccines are expected to have a better chance to elicit protective immunity and prevent cancer recurrence in children. In this review, we discuss the current efforts at designing and testing cancer vaccines in children with the focus on specific tumor antigens expressed by pediatric cancers.