What Is Childhood Leukemia?

This JAMA Patient Page outlines the symptoms, diagnosis, and treatment of childhood leukemia.

Abnormal Global Longitudinal Strain During Anthracycline Treatment Predicts Future Cardiotoxicity in Children.

Global longitudinal strain (GLS) is a sensitive predictor of cardiotoxicity in adults with cancer. However, the significance of abnormal GLS during childhood cancer treatment is less well-understood. The objective was to evaluate the use of GLS for predicting later cardiac dysfunction in pediatric cancer survivors exposed to high-dose anthracyclines. This was a retrospective study of pediatric patients exposed to a doxorubicin isotoxic equivalent dose of ≥ 225 mg/m2. Transthoracic echocardiograms (TTE) were obtained prior to chemotherapy (T1), during anthracycline therapy (T2), and following completion of therapy (T3). Cardiotoxicity was defined as meeting at least one of the following criteria after anthracycline therapy: a decrease in left ventricle ejection fraction (LVEF) by 10% from baseline to a value < 55%, fractional shortening < 28%, or a decrease in GLS by ≥ 15% from baseline. Nineteen of 57 (33%) patients met criteria for cardiotoxicity at T3. Cardiotoxicity was associated with a lower LVEF at T2 (p = 0.0003) and a decrease in GLS by ≥ 15% at T2 compared to baseline (p = < 0.0001). ROC analysis revealed that the best predictor of cardiotoxicity at T3 was the percent change in GLS at T2 compared to baseline (AUC 0.87). A subgroup analysis revealed that a decrease in GLS by ≥ 15% from baseline at 0-6 months from completion of anthracycline therapy was associated with cardiotoxicity > 1-year post-treatment (p = 0.017). A decline in GLS during chemotherapy was the best predictor of cardiotoxicity post-treatment. GLS serves as an important marker of cardiac function in pediatric patients undergoing treatment with anthracyclines.

Successful Treatment of Patient With Ewing Sarcoma in the Setting of Inherited Cholestatic Liver Disease.

Progressive familial intrahepatic cholestasis type 1 (PFIC1) is an inherited, progressive cholestatic liver disease. Here, we present an approach to the treatment of Ewing sarcoma in a patient with PFIC1. The diagnosis of PFIC1 presents a unique challenge in the treatment of Ewing sarcoma, as the standard-of-care vincristine, doxorubicin, cyclophosphamide/ifosfamide and etoposide chemotherapy backbone for Ewing sarcoma therapy treatment relies heavily on intact hepatic metabolism. In addition, we report prolonged lymphopenia and severe infectious complications in this patient, both of which may be attributed to more severe immunosuppression in setting of poor hepatic metabolism of chemotherapeutic agents.

Burkitt lymphoma after solid-organ transplant: Treatment and outcomes in the paediatric PTLD collaborative.

Burkitt lymphoma arising in paediatric post-solid-organ transplantation-Burkitt lymphoma (PSOT-BL) is a clinically aggressive malignancy and a rare form of post-transplant lymphoproliferative disorder (PTLD). We evaluated 35 patients diagnosed with PSOT-BL at 14 paediatric medical centres in the United States. Median age at organ transplantation was 2.0 years (range: 0.1-14) and age at PSOT-BL diagnosis was 8.0 years (range: 1-17). All but one patient had late onset of PSOT-BL (≥2 years post-transplant), with a median interval from transplant to PSOT-BL diagnosis of 4.0 years (range: 0.4-12). Heart (n = 18 [51.4%]) and liver (n = 13 [37.1%]) were the most frequently transplanted organs. No patients had loss of graft or treatment-related mortality. A variety of treatment regimens were used, led by intensive Burkitt lymphoma-specific French-American-British/Lymphomes Malins B (FAB/LMB), n = 13 (37.1%), and a low-intensity regimen consisting of cyclophosphamide, prednisone and rituximab (CPR) n = 12 (34.3%). Median follow-up was 6.7 years (range: 0.5-17). Three-year event-free and overall survival were 66.2% and 88.0%, respectively. Outcomes of PSOT-BL patients receiving BL-specific intensive regimens are comparable to reported BL outcomes in immunocompetent children. Multi-institutional collaboration is feasible and provides the basis of prospective data collection to determine the optimal treatment regimen for PSOT-BL.

Multicenter study of pediatric Epstein-Barr virus-negative monomorphic post solid organ transplant lymphoproliferative disorders.

BACKGROUND: Pediatric Epstein-Barr virus-negative monomorphic post solid organ transplant lymphoproliferative disorder [EBV(-)M-PTLD] comprises approximately 10% of M-PTLD. No large multi-institutional pediatric-specific reports on treatment and outcome are available. METHODS: A multi-institutional retrospective review of solid organ recipients diagnosed with EBV(-)M-PTLD aged ≤21 years between 2001 and 2020 in 12 centers in the United States and United Kingdom was performed, including demographics, staging, treatment, and outcomes data. RESULTS: Thirty-six patients were identified with EBV(-)M-PTLD. Twenty-three (63.9%) were male. Median age (range) at transplantation, diagnosis of EBV(-)M-PTLD, and interval from transplant to PTLD were 2.2 years (0.1-17), 14 years (3.0-20), and 8.5 years (0.6-18.3), respectively. Kidney (n = 17 [47.2%]) and heart (n = 13 [36.1%]) were the most commonly transplanted organs. Most were Murphy stage III (n = 25 [69.4%]). Lactate dehydrogenase was elevated in 22/34 (64.7%) and ≥2 times upper limit of normal in 11/34 (32.4%). Pathological diagnoses included diffuse large B-cell lymphoma (n = 31 [86.1%]) and B-non-Hodgkin lymphoma (B-NHL) not otherwise specified (NOS) (n = 5 [13.9%]). Of nine different regimens used, the most common were: pediatric mature B-NHL-specific regimen (n = 13 [36.1%]) and low-dose cyclophosphamide, prednisone, and rituximab (n = 9 [25%]). Median follow-up from diagnosis was 3.0 years (0.3-11.0 years). Three-year event-free survival (EFS) and overall survival (OS) were 64.8% and 79.9%, respectively. Of the seven deaths, six were from progressive disease. CONCLUSIONS: EFS and OS were comparable to pediatric EBV(+) PTLD, but inferior to mature B-NHL in immunocompetent pediatric patients. The wide range of therapeutic regimens used directs our work toward developing an active multi-institutional registry to design prospective studies. PLAIN LANGUAGE SUMMARY: Pediatric Epstein-Barr virus-negative monomorphic post solid organ transplant lymphoproliferative disorders (EBV(-)M-PTLD) have comparable outcomes to EBV(+) PTLD, but are inferior to diffuse large B-cell lymphoma in immunocompetent pediatric patients. The variety of treatment regimens used highlights the need to develop a pediatric PTLD registry to prospectively evaluate outcomes. The impact of treatment regimen on relapse risk could not be assessed because of small numbers. In the intensive pediatric B-non-Hodgkin lymphoma chemoimmunotherapy group, 11 of 13 patients remain alive in complete remission after 0.6 to 11 years.

Gender, Parenting Status, and the Academic Productivity of Pediatricians During the COVID-19 Pandemic.

BACKGROUND: During the coronavirus disease 2019 pandemic, many women physicians experienced increased caregiver responsibilities, potentially leading to worsened gender inequities. METHODS: We surveyed faculty and trainees at a quaternary-care children's hospital regarding work environment, household obligations, and academic productivity to examine differential effects on productivity by gender and parenting status. We used descriptive statistics for demographics and analyzed Likert-scale responses with χ2 or Fisher's exact tests. We performed multivariable logistic regression to determine factors associated with self-reported academic productivity. We analyzed free-response comments using thematic analysis. RESULTS: The August 2021 survey was completed by 366 respondents (65% women; 46% response rate). Women were significantly more likely to report decreased academic productivity than men (66% [146/222] vs 30% [38/129], P <.001). Nearly one-half (49%) were parents with 80% utilizing childcare. Of these, 61% experienced unreliable childcare during the pandemic. Parents with unreliable childcare reported significantly decreased academic productivity compared with those with reliable childcare (76% [64/84] vs 36% [19/53], P <.001), and, among those with unreliable childcare, women disproportionally reported decreased academic productivity compared with men (88.5% [54/61] vs 43.5% [10/23], P <.001). After multivariable adjustment, women physicians with children were significantly more likely to report decreased academic productivity than men with children (adjusted odds ratio: 10.19, 95% confidence interval: 4.68-22.23). CONCLUSIONS: The coronavirus disease 2019 pandemic has differentially impacted men and women physicians, with women physician parents more likely to report decreased academic productivity than men with children. Unreliable childcare was a significant contributor to this disparity. Institutions must prioritize initiatives to improve gender equity in medicine.

Premedication prior to PEG-asparaginase is cost-effective in pediatric patients with acute lymphoblastic leukemia.

BACKGROUND: PEG-asparaginase is critical in pediatric acute lymphoblastic leukemia (ALL) therapy but is highly immunogenic. Severe allergic reactions lead to substitution of further PEG-asparaginase with Erwinia. Erwinia is associated with more frequent dosing, increased expense, and limited availability. Premedication may reduce rates of allergic reactions. PROCEDURES: This Markov model evaluated the cost-effectiveness of three strategies: premedication plus therapeutic drug monitoring (TDM), TDM alone, and no premedication or TDM. We modeled two scenarios: a standard-risk (SR) B-ALL patient receiving two asparaginase doses and a high-risk (HR) patient receiving seven asparaginase doses. The model incorporated costs of asparaginase, premedication, TDM and clinic visits, and lost parental wages associated with each additional Erwinia dose. We incorporated a five-year time horizon with a societal perspective. Outcomes were Erwinia substitutions avoided and differences in quality-adjusted life years (QALYs). Probabilistic and one-way sensitivity analyses evaluated model uncertainty. RESULTS: In both scenarios, premedication was the least costly strategy. In SR and HR scenarios, premedication with monitoring resulted in 8% and 7% fewer changes to Erwinia compared with monitoring alone and 3% and 2% fewer changes compared with no premedication/monitoring, respectively. Premedication resulted in the most QALYs gained in the SR patients. Individual variation of model inputs did not change premedication/monitoring favorability for either scenario. In probabilistic sensitivity analyses, premedication/monitoring was favored in >87% of iterations in both scenarios. CONCLUSION: Compared with other strategies, premedication use and asparaginase level monitoring in children with B-ALL is potentially cost-saving.

Pediatric Faculty and Trainee Attitudes Toward the COVID-19 Pandemic.

OBJECTIVES: The coronavirus disease 2019 (COVID-19) pandemic is an unprecedented event in modern medicine. In this study, we evaluate pediatric faculty and trainee attitudes and perspectives related to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and their roles in the COVID-19 pandemic. METHODS: We surveyed a pediatric hospital's faculty and trainees (n = 701) in April 2020 about their concerns related to SARS-CoV-2, trust in current recommendations, and attitudes toward trainee roles. We used descriptive statistics to analyze results and compared across sex and roles using logistic regression. RESULTS: Among 320 respondents (46% response rate), 73% were concerned with personal risk of SARS-CoV-2 infection and 88% were concerned with loved ones' risk. Twenty-four percent were concerned because of personal risk factors. Nearly half expressed concerns as their family's major provider and about salary changes (48% and 46%). Seventy-nine percent were concerned about lack of personal protective equipment and 43% about redeployment. Respondents endorsed varying levels of trust in recommendations related to COVID-19. Nearly three-fourths (72%) felt trainees are essential personnel. The majority were receptive to returning to usual patient care and training as the pandemic progresses. Significant differences exist across sex and roles related to levels of concern, trust, and trainee roles. CONCLUSIONS: In this study, we assess the concerns and perspectives of pediatric faculty and trainees related to the COVID-19 pandemic. Most view trainees as essential personnel and recognize the importance of direct patient care in their training. These results can be used to inform policy changes and trainee roles as the COVID-19 pandemic progresses.

Cost-effectiveness of levofloxacin prophylaxis against bacterial infection in pediatric patients with acute myeloid leukemia.

BACKGROUND: Infections are the leading cause of therapy-related mortality in pediatric patients with acute myeloid leukemia (AML). Although effectiveness of levofloxacin antibacterial prophylaxis in oncology patients is recognized, its cost-effectiveness is unknown. This study evaluated epidemiologic data regarding levofloxacin use and the cost-effectiveness of this strategy as the cost per bacteremia episode, intensive care unit (ICU) admission, and death avoided in children with AML. PROCEDURE: A retrospective cohort study using the Pediatric Health Information System (PHIS) database compared demographic and clinical characteristics and receipt of levofloxacin prophylaxis in children with AML admitted for chemotherapy from January 1, 2014, through December 31, 2018. We then developed a decision analysis model in this population that compared costs associated with bacteremia, ICU admission, or death secondary to bacteremia to levofloxacin prophylaxis cost from a healthcare perspective. Time horizon is one chemotherapy cycle. Probabilistic and one-way sensitivity analyses evaluated model uncertainty. RESULTS: Prophylaxis cost $8491 per bacteremia episode prevented compared with an average added hospital cost of $119 478. Prophylaxis cost $81 609 per ICU admission avoided, compared with an average added hospital cost of $94 181. Prophylaxis cost $220 457 per death avoided. In sensitivity analysis, at a willingness-to-pay threshold of $100 000 per bacteremia episode avoided, prophylaxis remained cost-effective in 94.6% of simulations. Prophylaxis use was more common in recent years in patients with relapsed disease and with chemotherapy regimens considered more intensive. CONCLUSION: Prophylaxis is cost-effective in preventing bacterial infections in patients with AML. Findings support increased use in patients considered at high risk of bacterial infection secondary to myelosuppression.

Experiences with Menses and Menstrual Suppression of Young Women with a History of Cancer.

Background: Adolescent and young adult (AYA) women undergoing multiagent chemotherapy are at risk for heavy menstrual bleeding (HMB). There is a paucity of data on the experiences with menses of AYA women with cancer, their risk for HMB, and how they perceive menstrual suppression. Objective: This study aimed to (1) describe the attitudes and experiences of AYA women with a history of cancer regarding their menses and menstrual suppression and to (2) investigate facilitators and barriers to improve this aspect of oncologic care. Design/Methods: AYA women with a history of cancer completed individual semistructured interviews regarding their experiences, attitudes, and preferences around menstrual health. Two independent reviewers conducted a thematic analysis of transcribed interviews to elicit major themes. Results: We interviewed 20 young women with a history of cancer (mean age 19.9 years) who were treated with chemotherapy within the past 5 years. Themes included the following: (1) negative feelings and worry about menstrual bleeding; (2) positive attitudes toward menstrual suppression; (3) misconceptions about menstrual health; and (4) desire for tailored discussions about menstrual suppression. Conclusions: AYA women with a cancer history elucidate clear opinions regarding menstruation during chemotherapy, and many hold misconceptions regarding menses and menstrual suppression. Enhanced patient-provider communication and patient educational resources around menstrual health and menstrual suppression are needed to improve comprehensive oncologic care during chemotherapy.

Current practices in menstrual management in adolescents with cancer: A national survey of pediatric oncology providers.

BACKGROUND: Adolescents and young adult (AYA) women with cancer are at risk of heavy menstrual bleeding (HMB) due to thrombocytopenia, coagulopathy, and/or disruption of the hypothalamic-pituitary-gonadal axis. Currently, little is known about current practices to help prevent and treat HMB in AYA women with cancer. METHODS: We surveyed providers from 100 pediatric oncology centers. Face and content validity were assessed prior to distribution. Descriptive statistics, Chi-squared and Fisher exact tests were used for analysis. RESULTS: Ninety-four percent of respondents have recommended preventative menstrual suppression. More than half of respondents agreed that patients with the following types of cancers should receive preventative menstrual suppression: sarcomas, acute leukemias, lymphomas, and germ cell tumors. The most preferred form of menstrual suppression was GnRH agonists. Almost 95% of respondents felt that it is important to consider menstrual suppression and that a formal guideline about initiation of menstrual suppression would be helpful. Only 46% felt comfortable personally managing menstrual suppression. CONCLUSIONS: The vast majority of pediatric oncologists who responded to this national survey have used preventative menstrual suppression and feel that it is important to consider in many types of AYA cancers. Although pediatric oncologists are most often managing menstrual suppression, they do not feel comfortable doing so and desire guidelines to help with management. Future studies to assess which patients require menstrual suppression and which menstrual suppression is best tolerated and efficacious is needed.

Outcomes of Hematopoietic Cell Transplantation in Patients with Germline SAMD9/SAMD9L Mutations.

Germline mutations in SAMD9 and SAMD9L genes cause MIRAGE (myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy) (OMIM: *610456) and ataxia-pancytopenia (OMIM: *611170) syndromes, respectively, and are associated with chromosome 7 deletions, myelodysplastic syndrome (MDS), and bone marrow failure. In this retrospective series, we report outcomes of allogeneic hematopoietic cell transplantation (HCT) in patients with hematologic disorders associated with SAMD9/SAMD9L mutations. Twelve patients underwent allogeneic HCT for MDS (n = 10), congenital amegakaryocytic thrombocytopenia (n = 1), and dyskeratosis congenita (n = 1). Exome sequencing revealed heterozygous mutations in SAMD9 (n = 6) or SAMD9L (n = 6) genes. Four SAMD9 patients had features of MIRAGE syndrome. Median age at HCT was 2.8 years (range, 1.2 to 12.8 years). Conditioning was myeloablative in 9 cases and reduced intensity in 3 cases. Syndrome-related comorbidities (diarrhea, infections, adrenal insufficiency, malnutrition, and electrolyte imbalance) were present in MIRAGE syndrome cases. One patient with a familial SAMD9L mutation, MDS, and morbid obesity failed to engraft and died of refractory acute myeloid leukemia. The other 11 patients achieved neutrophil engraftment. Acute post-transplant course was complicated by syndrome-related comorbidities in MIRAGE cases. A patient with SAMD9L-associated MDS died of diffuse alveolar hemorrhage. The other 10 patients had resolution of hematologic disorder and sustained peripheral blood donor chimerism. Ten of 12 patients were alive with a median follow-up of 3.1 years (range, 0.1 to 14.7 years). More data are needed to refine transplant approaches in SAMD9/SAMD9L patients with significant comorbidities and to develop guidelines for their long-term follow-up.

Succinate Dehydrogenase-Deficient Gastrointestinal Stromal Tumor With SDHC Germline Mutation and Bilateral Renal and Neck Cysts.

Gastrointestinal stromal tumors (GISTs) are rare in children. Succinate dehydrogenase (SDH)-deficient GISTs are wild type and lack KIT proto-oncogene receptor tyrosine kinase and platelet-derived growth factor receptor A ( KIT or PDGFRA) mutations. These tumors result from germline SDH mutations, somatic SDH mutations, or SDH epimutants. Germline mutations in SDH genes ( SDHA, SDHB, SDHC, or SDHD) suggest Carney-Stratakis syndrome, a paraganglioma syndrome with predisposition for GIST. Negative immunohistochemistry for SDHB indicates dysfunction of the mitochondrial complex regardless of the subunit affected. We present an adolescent male with an SDH-deficient GIST and SDHC germline mutation who developed bilateral renal cysts and neck cysts, not previously described in children with this mutation. Germline testing is critical when SDH mutations are discovered due to treatment and surveillance implications. Further investigations are necessary to fully define the phenotypic expression of this mutation.

Treatment of pediatric plasma cell myeloma type post-transplant lymphoproliferative disorder with modern risk-directed therapy.

Post-transplant lymphoproliferative disorder (PTLD) related plasma cell neoplasms are rare in pediatric patients. We report a pediatric liver transplant recipient with plasma cell myeloma type PTLD. Cytogenetics included 1q duplication, associated with poor prognosis in adult multiple myeloma, and t(8;14). High-risk cytogenetics has not been reported in pediatric plasma cell myeloma type PTLD. The patient was treated with bortezomib, dexamethasone, and lenalidomide with subsequent autologous stem cell transplant. He achieved a 6-year remission, demonstrating tolerance to and efficacy of this modern myeloma regimen in a pediatric patient. Unfortunately, he subsequently died from complications of repeat liver transplant.

Post-transplant lymphoproliferative disorder in pediatric intestinal transplant recipients: A literature review.

Intestinal transplantation is a successful treatment for children with intestinal failure, but has many potential complications. PTLD, a clinically and histologically diverse malignancy, occurs frequently after intestinal transplantation and can be fatal. The management of this disease is particularly challenging. The rejection-prone intestinal allograft requires high levels of immunosuppression, a precondition for PTLD. While EBV infection clearly plays a role in disease pathogenesis, the relatively naïve immune system of children is another likely contributor. As a result, pediatric intestine recipients have a higher risk of developing PTLD than other solid organ recipients. Other risk factors for disease development such as molecular and genomic changes that precipitate malignant transformation are not fully understood, especially among children. Studies on adults have started to describe the molecular pathogenesis of PTLD, but the genomic landscape of the malignancy remains largely undefined in pediatric intestinal transplant patients. In this review, we describe what is known about PTLD in pediatric patients after intestinal transplant and highlight current knowledge gaps to better direct future investigations in the pediatric population.

Transient juvenile myelomonocytic leukemia in the setting of PTPN11 mutation and Noonan syndrome with secondary development of monosomy 7.

Juvenile myelomonocytic leukemia (JMML) is a rare childhood neoplasm with poor prognosis except in the setting of Noonan syndrome, where prognosis is generally favorable. We present the case of a child with JMML in the setting of germline PTPN11 mutation and Noonan syndrome with suspected secondary development of monosomy 7 in the bone marrow. Diagnosed shortly after birth, she has been managed with active surveillance alone. Myeloblast percentages initially fluctuated; however, bone marrow biopsy at 4 years of age showed spontaneous remission despite persistence of the monosomy 7 clone, supporting a cautious approach in similar cases.