Revaccination of children with acute lymphoblastic leukemia following completion of chemotherapy.

BACKGROUND: Intensive chemotherapy for acute lymphoblastic leukemia (ALL) may affect the immune system and potentially the immune memory causing antibodies provided by vaccination to disappear. There are disagreements regarding the guidelines for posttreatment immunization strategy. METHODS: Ninety-six children (aged 1-18 years at diagnosis) who completed chemotherapy for ALL were recruited. Antibody levels in the patient's serum against measles, varicella, polio, pertussis, hepatitis A, and hepatitis B were tested after completion of chemotherapy in patients who were fully vaccinated against these agents. Children who did not have positive serology to specific agents were revaccinated with a single dose accordingly. Antibody concentrations were measured again at least 4 weeks after revaccination. RESULTS: Positive antibody levels varied between the different agents. The highest percentage of positive serology was against polio (87%) and the lowest against pertussis (4%) (p < .001). There were significant differences between patients with high risk (HR) and non-HR ALL regarding serology status for some vaccines. After revaccination, the levels of response to each booster dose were significantly different: 100% after booster dose for varicella and polio, and only 34% after pertussis booster. CONCLUSIONS: Loss of humoral protection for vaccine preventable diseases is a common finding among patients with ALL. Revaccination with one dose of vaccine after completion of chemotherapy achieved seroconversion in 34-100% of the patients depending on the type of vaccine. We recommend this revaccination schedule to all children who completed ALL therapy and were previously fully vaccinated.

EBV-driven lymphoid neoplasms associated with pediatric ALL maintenance therapy.

The development of a second malignancy after the diagnosis of childhood acute lymphoblastic leukemia (ALL) is a rare event. Certain second malignancies have been linked with specific elements of leukemia therapy, yet the etiology of most second neoplasms remains obscure and their optimal management strategies are unclear. This is a first comprehensive report of non-Hodgkin lymphomas (NHLs) following pediatric ALL therapy, excluding stem-cell transplantation. We analyzed data of patients who developed NHL following ALL diagnosis and were enrolled in 12 collaborative pediatric ALL trials between 1980-2018. Eighty-five patients developed NHL, with mature B-cell lymphoproliferations as the dominant subtype (56 of 85 cases). Forty-six of these 56 cases (82%) occurred during or within 6 months of maintenance therapy. The majority exhibited histopathological characteristics associated with immunodeficiency (65%), predominantly evidence of Epstein-Barr virus-driven lymphoproliferation. We investigated 66 cases of post-ALL immunodeficiency-associated lymphoid neoplasms, 52 from our study and 14 additional cases from a literature search. With a median follow-up of 4.9 years, the 5-year overall survival for the 66 patients with immunodeficiency-associated lymphoid neoplasms was 67.4% (95% confidence interval [CI], 56-81). Five-year cumulative risks of lymphoid neoplasm- and leukemia-related mortality were 20% (95% CI, 10.2-30) and 12.4% (95% CI, 2.7-22), respectively. Concurrent hemophagocytic lymphohistiocytosis was associated with increased mortality (hazard ratio, 7.32; 95% CI, 1.62-32.98; P = .01). A large proportion of post-ALL lymphoid neoplasms are associated with an immunodeficient state, likely precipitated by ALL maintenance therapy. Awareness of this underrecognized entity and pertinent diagnostic tests are crucial for early diagnosis and optimal therapy.

Invasive Fusariosis in Pediatric Hematology/Oncology and Stem Cell Transplant Patients: A Report from the Israeli Society of Pediatric Hematology-Oncology.

Invasive Fusarium species infections in immunocompromised patients occur predominantly in those with hematological malignancies. Survival rates of 20−40% were reported in adults, but data in children are limited. Our retrospective, nationwide multicenter study of invasive fusariosis in pediatric hematology/oncology and stem cell transplant (SCT) patients identified twenty-two cases. Underlying conditions included hematological malignancies (n = 16; 73%), solid tumors (n = 2), and non-malignant hematological conditions (n = 4). Nineteen patients (86%) were neutropenic, nine (41%) were SCT recipients, and seven (32%) received corticosteroids. Sixteen patients (73%) had disseminated fusariosis, five had local infection, and one had isolated fungemia. Fifteen patients (68%) had skin involvement and eight (36%) had a bloodstream infection. Four patients (18%) presented with osteoarticular involvement and four with pulmonary involvement. Nineteen patients (86%) received combination antifungal therapy upfront and three (14%) received single-agent treatment. Ninety-day probability of survival was 77%: four of the five deaths were attributed to fusariosis, all in patients with relapsed/refractory acute leukemias. Ninety-day probability of survival for patients with relapsed/refractory underlying malignancy was 33% vs. 94% in others (p < 0.001). Survival rates in this largest pediatric population-based study were strikingly higher than those reported in adults, demonstrating that invasive fusariosis is a life-threatening but salvageable condition in immunosuppressed children.

COVID-19 infection in pediatric patients treated for cancer.

BACKGROUND: COVID-19, the novel coronavirus, has caused a global pandemic affecting millions of people around the world. Risk factors for critical disease in adults are advanced age and underlying medical comorbidities, including cancer. Data are sparse on the effect of COVID-19 infection on pediatric patients with cancer during their active antineoplastic therapy. The optimal management of antineoplastic treatment during COVID-19 infection in this unique population is controversial. AIM: To describe the severity and clinical course of COVID-19 infection in pediatric patients with cancer during active antineoplastic treatment and to study their course of treatment. METHODS: Clinical and laboratory data were collected from medical files of patients diagnosed with COVID-19, confirmed by polymerase chain reaction (PCR), who received active antineoplastic treatment between March 2020 and May 2021 in a large tertiary pediatric medical center. RESULTS: Eighteen patients with diverse pediatric cancers are described. They were infected with COVID-19 at different stages of their antineoplastic treatment regimen. Eight had an asymptomatic COVID-19 infection, nine had mild symptoms, and one had severe disease. All of them recovered from COVID-19 infection. Two patients experienced delays in their antineoplastic treatment; none of the other patients had delays or interruptions, including patients who were symptomatic for COVID-19. CONCLUSION: In pediatric patients with cancer who test positive for COVID-19, yet are asymptomatic or have mild symptoms, the continuance of antineoplastic therapy may be considered.

Elevated intraocular pressure in children with acute lymphoblastic leukaemia: A prospective study.

Most childhood acute lymphoblastic leukaemia (ALL) protocols include high-dose steroid therapy. However, the known potential of high-dose steroids to significantly elevate intraocular pressure (IOP) and lead to glaucomatous optic neuropathy has not been intensively investigated in children with ALL. Moreover, as children with ALL do not routinely undergo IOP measurements, the need for IOP monitoring and therapy is unknown. We prospectively measured IOP in 90 children with newly diagnosed ALL attending a tertiary paediatric haematology/oncology centre, at diagnosis and at the middle and end of induction therapy. Ocular hypertension (IOP > 21 mm Hg) at any time point was documented in 64 children (71%), and the prevalence increased during induction. Thirty-six children (40%) had elevated IOP at ALL diagnosis before therapy initiation, and stratification to non-standard ALL was a risk factor. IOP reduction therapy was administered to 13 children (14%); none required surgery. Values normalised in all cases. On multivariate logistic regression analysis, dexamethasone therapy was a significant risk factor for ocular hypertension. High body mass index was an additional risk factor in children with elevated IOP at ALL diagnosis. Routine evaluation of IOP during steroid therapy is very important in children with ALL to ensure early intervention which may prevent permanent ocular damage.

Delayed diagnosis and treatment of children with cancer during the COVID-19 pandemic.

BACKGROUND: COVID-19, the novel coronavirus has caused a global pandemic affecting millions of people around the world. Although children, including children with cancer, have been found to be affected less commonly and less severely than adults, indirect effects of the pandemic on the diagnosis and treatment of children with cancer have been less described. METHODS: A survey was performed in the four largest tertiary pediatric hematology-oncology medical centers in Israel. Clinical and laboratory data were collected from the medical files of patients diagnosed or treated with cancer during April-October 2020. RESULTS: Seventeen patients are described, who had a significant delay in diagnosis or treatment of cancer. These represent approximately 10% of all pediatric cancer diagnosed during the study period in these centers. A main cause of delay was fear of exposure to COVID-19 (fears felt by the patient, parent, physician, or decision-makers at the institution; or the implementation of national guidelines). Delays also resulted from co-infection with COVID-19 and the attribution of the oncologic symptoms to the infection. In addition, treatment was delayed of patients already diagnosed with cancer, due to COVID-19 infection detected in the patient, a family member, or a bone marrow donor. CONCLUSION: Fear from the COVID-19 pandemic may result in delayed diagnosis and treatment of children with cancer, which may carry a risk to dismal prognosis. It is crucial that pediatricians and patients alike remember that other diseases still prevail and must be thought of and treated in a timely fashion.

Long-term ovarian reserve and fertility outcomes in female survivors of childhood acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy, yet data regarding long-term ovarian reserve of female survivors are limited. The aim of this study was to investigate whether there is a differential pattern of anti-Mullerian hormone (AMH) levels in female childhood ALL survivors compared with the normal age-matched population. In a cohort of 56 female childhood ALL survivors (median age 29 years; median follow-up 20.6 years), a negative correlation was found between age at leukemia diagnosis and age-adjusted anti-Mullerian hormone (AMH) levels (r = -0.334, p = .031). Despite alkylating agent therapy, AMH levels did not differ significantly from age-related nomograms (age < 30, p = .17; age ≥ 30, p = .94). The mean number of children per fertile woman adjusted for maternal age was similar to the national average (2.76 versus 3.11, p = .19). Our results imply that reproductive outcomes are not significantly hampered in female pediatric ALL survivors. Long-term surveillance of ovarian reserve may enable personalized survivorship counseling.

Bone pain at leukemia diagnosis and other risk factors for symptomatic osteonecrosis in children with acute lymphoblastic leukemia.

BACKGROUND: Osteonecrosis is a major cause of acute and long-lasting complications of acute lymphoblastic leukemia (ALL) therapy in children. Our study aimed to evaluate the prevalence, characteristics, risk factors, and outcome of osteonecrosis in children with ALL. PROCEDURE: The cohort included 559 children aged 1-20 years diagnosed with ALL between 2003 and 2018 at two tertiary medical centers in Israel and enrolled in two consecutive protocols: ALL-IC BFM 2002 and AIEOP-BFM ALL 2009. Symptomatic osteonecrosis was prospectively captured as an adverse event. RESULTS: Osteonecrosis occurred in 51 patients (9.1%). Ninety-four percent of the events were graded as moderate or severe (grades 3-4, Ponte di Legno Toxicity Working Group classification) and multiple bone involvement was common. Full resolution of osteonecrosis was documented in only 16% of the children (median follow-up 4.2 years). Stepwise logistic regression identified five risk factors for osteonecrosis, with a high predictive value (AUC = 0.88): older ageat ALL diagnosis, high-risk ALL group, T-cell immunophenotype, female gender, and a novel risk factor: bone pain at the time of leukemia diagnosis. In addition, osteonecrosis was less common among children of Arab ethnicity. Thrombophilia and an elevated age-adjusted body mass index were not confirmed as risk factors for osteonecrosis. CONCLUSION: Due to the low rates of osteonecrosis resolution and its debilitating long-term impact, the identification of patients at high risk for osteonecrosis is important for their inclusion in further studies evaluating potential therapeutic adjustments.

Disseminated Mucormycosis in Immunocompromised Children: Are New Antifungal Agents Making a Difference? A Multicenter Retrospective Study.

BACKGROUND: Mucormycosis is a life-threatening infection with a tendency for angioinvasion that may lead to progressive dissemination. Disseminated mucormycosis, defined as the involvement of two or more non-contiguous sites, is rare in children, and data concerning its management and outcome are scarce. The aim of this study was to assess the contemporary management strategies and outcomes of disseminated mucormycosis in the pediatric population. METHODS: We conducted a retrospective search in six large tertiary medical centers for all cases of disseminated mucormycosis that occurred between 2009-2020 in patients aged 1-20 years. RESULTS: Twelve cases were identified. Underlying conditions included hematological malignancies (n = 10), solid tumor (post-autologous hematopoietic stem cell transplantations; n = 1), and solid organ (liver) transplantation (n = 1). In all cases, amphotericin B formulations were administered as first-line therapy; in eight cases, they were also administered in combination with an echinocandin or triazole. Seven patients underwent surgical debridement procedures. The six-week mortality was 58%. Among the patients diagnosed between 2009-2015, one of the six survived, and of those diagnosed between 2016-2020, four of the six were salvaged. CONCLUSIONS: Disseminated mucormycosis is a life-threatening and often fatal disease, and improved diagnostic and therapeutic strategies are needed. Nevertheless, in this population-based study, five patients (42%) were salvaged through combined liposomal amphotericin/triazole treatment and extensive surgical interventions.

A Homozygous Mutation in 5' Untranslated Region of TNFRSF11A Leading to Molecular Diagnosis of Osteopetrosis Coinheritance With Wiskott-Aldrich Syndrome.

Wiskott-Aldrich syndrome (WAS) and osteopetrosis are 2 different, rare hereditary diseases. Here we report clinical and molecular genetics investigations on an infant patient with persistent thrombocytopenia and prolonged fever. He was clinical diagnosed as osteopetrosis according to clinical presentation, radiologic skeletal features, and bone biopsy results. Gene sequencing demonstrated a de novo homozygous mutation in 5'-untranslated region of TNFRSF11A, c.-45A>G, which is relating to osteopetrosis. Meanwhile, a hemizygous transition mutation in WAS gene, c.400G>A diagnosed the infant with WAS. This is the first clinical report for the diagnosis of osteopetrosis coinheritance with WAS in a single patient.

Venous Thromboembolism and Its Risk Factors in Children with Acute Lymphoblastic Leukemia in Israel: A Population-Based Study.

Venous thromboembolism (VTE) is a serious complication of acute lymphoblastic leukemia (ALL) therapy. The aim of this population-based study was to evaluate the rate, risk factors, and long-term sequelae of VTE in children treated for ALL. The cohort included 1191 children aged 1-19 years diagnosed with ALL between 2003-2018, prospectively enrolled in two consecutive protocols: ALL-IC BFM 2002 and AIEOP-BFM ALL 2009. VTEs occurred in 89 patients (7.5%). Long-term sequelae were uncommon. By univariate analysis, we identified four significant risk factors for VTEs: Severe hypertriglyceridemia (p = 0.005), inherited thrombophilia (p < 0.001), age >10 years (p = 0.015), and high-risk ALL group (p = 0.039). In addition, the incidence of VTE was significantly higher in patients enrolled in AIEOP-BFM ALL 2009 than in those enrolled in ALL-IC BFM 2002 (p = 0.001). Severe VTE occurred in 24 children (2%), all of whom had at least one risk factor. Elevated triglyceride levels at diagnosis did not predict hypertriglyceridemia during therapy. In a multivariate analysis of 388 children, severe hypertriglyceridemia and inherited thrombophilia were independent risk factors for VTE. Routine evaluation for these risk factors in children treated for ALL may help identify candidates for intervention.

Mucormycosis in children with haematological malignancies is a salvageable disease: a report from the Israeli Study Group of Childhood Leukemia.

Mucormycosis has emerged as an increasingly important cause of morbidity and mortality in immunocompromised patients, but contemporary data in children are lacking. We conducted a nationwide multicentre study to investigate the characteristics of mucormycosis in children with haematological malignancies. The cohort included 39 children with mucormycosis: 25 of 1136 children (incidence 2·2%) with acute leukaemias prospectively enrolled in a centralized clinical registry in 2004-2017, and an additional 14 children with haematological malignancies identified by retrospective search of the databases of seven paediatric haematology centres. Ninety-two percent of mucormycosis cases occurred in patients with acute leukaemias. Mucormycosis was significantly associated with high-risk acute lymphoblastic leukaemia (OR 3·75; 95% CI 1·51-9·37; P = 0·004) and with increasing age (OR 3·58; 95% CI 1·24-9·77; P = 0·01). Fifteen patients (38%) died of mucormycosis. Rhinocerebral pattern was independently associated with improved 12-week survival (OR 9·43; 95% CI 1·47-60·66; P = 0·02) and relapsed underlying malignancy was associated with increased 12-week mortality (OR 6·42; 95% CI, 1·01-40·94; P = 0·05). In patients receiving frontline therapy for their malignancy (n = 24), one-year cumulative mucormycosis-related mortality was 21 ± 8% and five-year overall survival was 70 ± 8%. This largest paediatric population-based study of mucormycosis demonstrates that children receiving frontline therapy for their haematological malignancy are often salvageable.

Blinatumomab as a bridge to further therapy in cases of overwhelming toxicity in pediatric B-cell precursor acute lymphoblastic leukemia: Report from the Israeli Study Group of Childhood Leukemia.

Tremendous progress in the therapy of pediatric acute lymphoblastic leukemia (ALL) has been achieved through combination cytotoxic chemotherapy, leading to high cure rates, at the cost of significant life-threatening toxicity. The bispecific T-cell engager blinatumomab, recently approved for relapsed/refractory ALL, has a unique nonmyelotoxic toxicity profile. As blinatumomab causes B-cell depletion, the safety of its use during severe chemotherapy-induced toxicity is unclear. We report 11 pediatric patients with ALL, treated with blinatumomab following overwhelming chemotherapy-associated toxicity, with recovery of all patients and successful bridging to further antileukemia therapy. Blinatumomab can be considered for rare patients who cannot tolerate cytotoxic therapy.

Thrombophilia screening and thromboprophylaxis may benefit specific ethnic subgroups with paediatric acute lymphoblastic leukaemia.

This study investigated the prevalence of inherited thrombophilia, risk of venous thromboembolism (VTE) and benefit of low molecular weight heparin prophylaxis in 476 Israeli children with acute lymphoblastic leukaemia (ALL) treated between 2004 and 2016. Thrombophilia was found in 15·5%. Arab children had a higher prevalence of F5 R506Q (factor V Leiden) than Jewish children (19·4% vs. 2·9%, P < 0·01). Patients with thrombophilia had higher VTE rates VTE (26·5% vs. 5·6%, P < 0·001). None of the thrombophilic children given prophylaxis had severe VTE. Routine evaluation for inherited thrombophilia followed by thromboprophylaxis when findings are positive may benefit at-risk patients with ALL.

Response of Symptomatic Persistent Chronic Disseminated Candidiasis to Corticosteroid Therapy in Immunosuppressed Pediatric Patients: Case Study and Review of the Literature.

BACKGROUND: Chronic disseminated candidiasis (CDC) is a severe invasive fungal infection principally observed during neutrophil recovery in patients with acute leukemia treated with intensive chemotherapy. Its pathophysiology remains unclear. We describe the management of 6 children with symptomatic CDC who did not respond to antifungal therapy. METHODS: The databases of the hematology-oncology departments of 2 tertiary pediatric medical centers were searched for all patients diagnosed with CDC from 2003 to 2015, who responded to corticosteroids after failing antifungal therapy. Clinical, laboratory and radiologic data were collected. RESULTS: Six patients (3 women, 3 men; 9-18 years of age) met the study criteria. Underlying diseases were acute lymphoblastic leukemia (n = 3) and large B-cell lymphoma, acute myeloid leukemia and severe aplastic anemia (n = 1 each). Presenting symptoms/signs of CDC were fever in all cases, with abdominal or chest pain, and/or mucositis. Candida infection was identified in blood cultures in 4 patients and in bronchoalveolar lavage fluid in one. In the absence of response to antifungal agents (4-50 days from CDC diagnosis), prednisone 2 mg/kg/day or equivalent was administered. CDC-attributable clinical symptoms resolved in 4 patients within 6-19 days; one patient required an additional nonsteroidal anti-inflammatory agent. Abnormalities on imaging decreased or disappeared within 5 months to 2 years in 4 patients. CONCLUSIONS: In children with persistent symptomatic CDC, despite adequate antifungal therapy, administration of corticosteroids may yield rapid resolution of symptoms and decreased inflammatory markers. In patients who do not respond to steroids, the addition of a nonsteroidal anti-inflammatory drug should be considered.

Growth and pubertal patterns in young survivors of childhood acute lymphoblastic leukemia.

BACKGROUND: Survivors of acute lymphoblastic leukemia (ALL) may experience endocrine dysfunction. This study evaluated growth and pubertal patterns in survivors of childhood ALL. METHODS: Longitudinal assessment of anthropometric measurements and pubertal status was performed in a retrospective cohort of survivors (n=183). Median age at last endocrine visit was 16.1 years (range 8.2-27.6); median follow-up time was 8.7 years (range 3-21.4). RESULTS: Treatment with chemotherapy+prophylactic cranial radiation (pCRT, n=29) was associated with lower mean height standard deviation score (SDS) than chemotherapy alone (n=154) (p=0.001) and higher prevalence of adult short stature (13% vs. 2.2%). Mean age at pubertal onset was normal (girls: 10.3±1.3 years; boys: 12.0±1.3 years). Precocious puberty, diagnosed in 8.7% of patients, was more prevalent in pCRT-treated girls. Rates of overweight and obesity were 22.9% and 9.3%, respectively. Predictors of endocrine disorders were pCRT (p=0.031) and female gender (p=0.041); of obesity, higher body mass index (BMI)-SDS at diagnosis (p=0.001); and of short stature, lower height-SDS at diagnosis (p=0.038). CONCLUSIONS: Most childhood ALL survivors given chemotherapy alone attain normal adult height and puberty. Childhood ALL survivors are at increased risk of overweight, especially those with increased BMI at diagnosis. Clinicians should screen for overweight early in survivorship and introduce early interventions.

miR expression profiling at diagnosis predicts relapse in pediatric precursor B-cell acute lymphoblastic leukemia.

Our aim was to identify miRNAs that can predict risk of relapse in pediatric patients with acute lymphoblastic leukemia (ALL). Following high-throughput miRNA expression analysis (48 samples), five miRs were selected for further confirmation performed by real time quantitative PCR on a cohort of precursor B-cell ALL patients (n = 138). The results were correlated with clinical parameters and outcome. Low expression of miR-151-5p, and miR-451, and high expression of miR-1290 or a combination of all three predicted inferior relapse free survival (P = 0.007, 0.042, 0.025, and <0.0001, respectively). Cox regression analysis identified aberrant expression of the three miRs as an independent prognostic marker with a 10.5-fold increased risk of relapse (P = 0.041) in PCR-MRD non-high risk patients. Furthermore, following exclusion of patients harboring IKZF1 deletion, the aberrant expression of all three miRs could identify patients with a 24.5-fold increased risk to relapse (P < 0.0001). The prognostic relevance of the three miRNAs was evaluated in a non-BFM treated precursor B-cell ALL cohort (n = 33). A significant correlation between an aberrant expression of at least one of the three miRs and poor outcome was maintained (P < 0.0001). Our results identify an expression profile of miR-151-5p, miR-451, and miR-1290 as a novel biomarker for outcome in pediatric precursor B-cell ALL patients, regardless of treatment protocol. The use of these markers may lead to improved risk stratification at diagnosis and allow early therapeutic interventions in an attempt to improve survival of high risk patients.

Difficulty in Distinguishing Posterior Reversible Encephalopathy Syndrome, Hypoxic-Ischemic Insult, and Acute Toxic Leukoencephalopathy in Children.

AIM: This study aims to describe our experience of unique pediatric neurological cases and associated difficulty in differentiating posterior reversible encephalopathy syndrome (PRES) from hypoxic-ischemic insult (HII), and acute toxic leukoencephalopathy (ATL). METHODS: The study included three children with a clinical picture suggestive of PRES, HII, and ATL of different etiologies who were diagnosed and treated at a tertiary pediatric medical center in 2011 to 2014. RESULTS: All patients presented with blindness following seizures with asphyxia/aspiration in a syndromatic child, too-rapid lipid infusion in a child with acute lymphoblastic leukemia, and repeated vomiting in a child with cerebral palsy, hydrocephalus, and malfunction of ventriculoperitoneal shunt. All patients had cortical blindness and high-signal foci in the cortical and subcortical regions on magnetic resonance imaging. All children improved. CONCLUSIONS: Familiarity with the clinical and radiological characteristics of neurological conditions leading to reversible cortical blindness is essential for diagnosis and management. Distinguishing PRES from HII and ATL can be challenging. Our cases most likely combined these etiologies, with the first patient diagnosed with PRES with HII, the second with PRES with ATL, and the third with focal HII. Given the diversity of the findings and the unclear prognostic significance, studies of the pathophysiology of PRES are warranted.