Undergoing Maintenance Chemotherapy Research Articles

Compromised antibody responses and memory lymphocyte formation to COVID-19 mRNA vaccination in children with acute lymphoblastic leukemia undergoing maintenance chemotherapy

Abstract COVID-19 mRNA vaccines, with 95% efficacy in the general population, have been shown to exhibit suboptimal effectiveness in hematological malignancy patients. Our previous published study revealed that COVID-19 vaccine responses were related to innate immune responses. In this study, we investigated the innate and adaptive immune responses to COVID-19 mRNA vaccines in children with acute lymphoblastic leukemia (ALL). We longitudinally investigated the innate immune responses to PRR-agonists stimulation and after vaccine injection, along with vaccine-induced anti-S antibodies, S-specific memory B and T cell responses in 13 ALL children who completed or were undergoing maintenance chemotherapy and 24 healthy controls. We found that both ALL groups had impaired dsDNA-induced cytotoxic NK cell activation while patients in maintenance therapy also showed decreased dsRNA-induced activation in those cells. After vaccination, ALL children with completed therapy demonstrated similar S-specific antibody responses and memory B cells as healthy controls. In patients with maintenance therapy, these responses were notably reduced, especially cross-protective antibodies. Both ALL groups exhibited lower S-specific CD8+ T cells, which correlated with weaker TLR9 responses. In conclusion, we discovered the compromised vaccine responses in ALL children, especially those in maintenance chemotherapy, highlighting the importance of improved COVID-19 vaccines for this special group of patients.

Ledipasvir/Sofosbuvir in Hepatitis C Virus–Infected Children With Hematological Malignancies: A Pharmacokinetic Study

Children with hematological malignancies and chronic hepatitis C virus (HCV) infection are at a higher risk for rapid progression of liver disease and malignancy relapse due to multiple hepatitis flares and chemotherapy interruption. They are therefore potential candidates for microelimination of HCV infection. This study aimed to assess the effect of acute lymphoblastic leukemia (ALL) on the pharmacokinetic (PK) profile of direct-acting antivirals, namely ledipasvir/sofosbuvir (LDV/SOF) and the SOF major metabolite GS-331007. This was a 24-week, prospective, controlled, open-label, 2-arm PK study of patients receiving 45/200 mg once-daily LDV/SOF orally for 12 weeks. Eligible patients were HCV-RNA-positive, treatment-naive children aged 6 to <12 years and/or weighing 17 to <35 kg with genotype 4 chronic HCV infection without cirrhosis. The primary efficacy and safety end points were the achievement of sustained virologic response for all patients with absence of any adverse events leading to permanent discontinuation of the study drug. Steady-state noncompartmental analysis was performed to determine the PK parameters of SOF, GS-331007, and LDV as the primary PK outcome. Dose suitability was based on the 90% CI of exposure geometric mean ratio percentage within 50% to 200% compared with adults. Ten HCV-infected children with ALL (chemotherapy treatment group) and 12 eligible children with no malignancy (control group) were enrolled and completed the study period. All 22 patients achieved the sustained virologic response with no adverse events leading to interruption or permanent discontinuation of the study drug. Compared with the control group, the ALL group patients had similar SOF, GS-331007, and LDV exposure. Compared with adults, the AUCτ of GS-331007 was lower and the AUCτ and Cmax,ss of SOF and the Cmax,ss of LDV were modestly higher in the ALL group (acceptance limit, 50%-200%). However, the observed efficacy and favorable safety profile made these changes not clinically significant. Weight-based dosing of LDV/SOF (45/200 mg) is highly effective and safe among genotype 4 HCV-infected children weighing 17 to <35 kg and diagnosed with ALL undergoing maintenance chemotherapy. The similarity in the drug exposure, efficacy, and safety clinical end points between patients with and without hematological malignancy support their therapeutic equivalence. Further studies with a larger sample size may be required to confirm the safety of LDV/SOF in patients with ALL and to recommend appropriate dosing in children with hematological malignancies, if needed. gov identifier: NCT03903185.

Cytomegalovirus Retinitis in a Child with Acute Lymphoblastic Leukemia

BACKGROUND: Due to the reduced immune response following chemotherapy, cytomegalovirus (CMV) retinitis is the most prevalent opportunistic intraocular infection in HIV-infected adults. It can also affect children with acute lymphoblastic leukemia (ALL). CASE PRESENTATION: We describe an 11.5-year-old female who is undergoing maintenance chemotherapy for B-lineage ALL. She had vision loss in her right eye and began to have hazy vision in her left eye. Bilateral active retinitis lesions were discovered during the retinal examination. The diagnosis of bilateral CMVR was made based on clinical symptoms, retinal examination findings, and a blood sample for CMV DNA detection using the polymerase chain reaction (PCR) technique. She was given ganciclovir intravenously and intravitreally, followed by oral valganciclovir prophylaxis. Patients who received a solid organ or hematopoietic stem cell transplant were infected with CMVR, although patients with ALL who received less immunosuppressive chemotherapy were also affected (maintenance phase therapy). Intravenous and intravitreal ganciclovir injections are effective treatments, the patient had significant clinical improvement. CMV retinitis is frequent in children with ALL who are in the maintenance phase of the treatment. CONCLUSION: The importance of early detection and treatment cannot be overstated. CMV retinitis: Key prognostic variables. CMV retinitis should be considered as cause of blurred vision in patients with ALL.

Suspected Case of Multisystem Inflammatory Syndrome in Children Associated With SARS-CoV-2 Infection Presenting as Acute Pancreatitis in a Child With Leukemia

Multisystem inflammatory syndrome in children (MIS-C) associated with SARS-CoV-2 may present with fever, elevated inflammatory markers, and multiorgan involvement. Although the gastrointestinal system is commonly affected in MIS-C patients, associated necrotizing pancreatitis is rare. We present an 11-year-old boy with B-cell acute lymphoblastic leukemia in remission undergoing maintenance chemotherapy presenting with acute necrotizing pancreatitis. He developed fevers, fluid and electrolyte imbalance, respiratory distress, cytopenias, and coagulopathy, and was found to have markedly elevated inflammatory markers and positive SARS-CoV-2 antibodies. The patient met criteria for MIS-C and was treated with intravenous immunoglobulin with significant clinical improvement. This is the first known reported case of a child with B-cell acute lymphoblastic leukemia who met criteria for MIS-C presenting as acute pancreatitis, and highlights the importance of considering a broader differential for pancreatitis in children given the current SARS-CoV-2 pandemic.

Akut Lenfoblastik Lösemili Çocuklarda İdame Tedavisinin Nadir Bir Komplikasyonu: Folik Asit Eksikliği

Vitamin B12 (cobalamin) and folic acid play a crucial role in DNA synthesis, cell division and proliferation. Their deficiency may cause serious disorders of hematopoietic, gastrointestinal and neurologic system. A 14-year-old girl, undergoing maintenance chemotherapy (methotrexate, 6-mercaptopurine) for acute lymphoblastic leukemia (ALL), presented with the complaints of pallor and nose bleeding. At admission, white blood cells (WBC) was 2230/mm3, hemoglobin 6.2 gr/dL, mean corpuscular volume (MCV) 122 fL and thrombocytes 26700/mm3. Peripheral blood smear revealed hypersegmented neutrophils, macrocytosis, anisocytosis, rare normoblasts and 4-5 platelet per field. Bone marrow aspiration and biopsy did not confirm the pre-diagnoses of relapsed ALL, hemophagocytic lymphohistiocytosis (HLH) and myelodysplastic syndrome (MDS). Vitamin B12 and folic acid were prescribed after obtaining the results of vitamin B12 (587 pg/mL), folic acid (1.3 ng/mL) and homocystein (21 µmol/L). Folic acid deficiency must be kept in mind in childrenwith ALL receiving maintenance therapy. Serum cobalamin and folic acid levels must be checked in case of unexplained pancytopenia.

Individual prediction of non-adherence to oral mercaptopurine (6MP) in children with acute lymphoblastic leukemia (ALL): Results from COG AALL03N1 study.

10530 Background: Poor adherence to 6MP (measured electronically [MEMS]) increases relapse risk in children with ALL (Bhatia et al. JAMA Oncol 2015). Adherence is difficult to assess clinically and non-adherers are more likely to over-report 6MP intake (Landier et al. Blood 2017). Key sociodemographic/clinical factors (Bhatia et al. JCO 2012) and red cell methyl-mercaptopurine (MMP, a 6MP metabolite) levels (Hoppmann et al. ASCO 2017) are associated with non-adherence and could potentially identify non-adherers. Methods: We developed a prediction model for 6MP non-adherence (MEMS adherence rate &lt; 90%), using receiver operating characteristic (ROC) analyses in 407 children with ALL receiving 6MP (mean age 7.7±4.4y; 68% males; 35% Caucasians, 34% Hispanics, 16% African Americans, 15% Asians). The cohort was divided into a training set (n = 250) and test set (n = 157) using stratified random sampling (stratified by race/ethnicity, gender, age and 6MP non-adherence). We used logistic regression with backward variable elimination, guided by change in area under ROC (AUC), to create a prediction model in the training set, using only clinical and sociodemographic variables (Clinical Model). We then generated a model that added 6MP dose-intensity (6MPDI)-adjusted red cell MMP levels to the Clinical Model (Final Model). All models were validated in the test set. Results: Predictors retained in the Training Clinical Model included: age, race/ethnicity, absolute neutrophil count, 6MPDI, family structure, and taking 6MP at the same vs varied time of day (AUC = 0.79; 95%CI 0.72-0.85). The Training Final Model (adding 6MPDI-adjusted MMP to the Clinical Model) yielded an AUC = 0.79 (95%CI 0.72-0.86). The Test Final Model (AUC = 0.79, 95%CI 0.69-0.88) showed significantly superior discrimination compared to the Test Clinical Model (AUC = 0.74, 95%CI 0.63-0.85; P = 0.002). Using a binary classifier with predicted probability of non-adherence ≥0.5, the Test Final Model had an accuracy of 79%, and positive and negative predictive values of 71% and 80%, respectively. Conclusions: We created, validated, and compared 2 risk-prediction models for 6MP non-adherence in children undergoing maintenance chemotherapy. While inclusion of red cell MMP levels provided superior discrimination in identifying non-adherent patients, the Clinical Model (without MMP levels) performed adequately well, and could be used in the clinical setting.

Impact of IgG Monitoring and IVIG Supplementation on the Frequency of Febrile Illnesses in Pediatric Acute Lymphoblastic Leukemia Patients Undergoing Maintenance Chemotherapy.

Monitoring serum immunoglobulin G (IgG) levels in pediatric oncology patients and treating subtherapeutic levels with intravenous immunoglobulin (IVIG) may prevent infections; however, evidence is limited. This retrospective study assessed pediatric acute lymphoblastic leukemia patients diagnosed 2006 to 2011 to evaluate if monitoring/supplementing IgG would reduce febrile illnesses during maintenance chemotherapy. A subject was categorized as "ever IgG monitored" if they had ≥1 IgG levels checked and their risk days were stratified into not IgG monitored days and IgG monitored days. IgG monitored days were further stratified into IgG monitored with IVIG supplementation, monitored with no IVIG supplementation (IgG level >500 mg/dL) and monitored with no IVIG supplementation days (IgG level <500 mg/dL). Generalized linear mixed effects poisson models were used to compare events (febrile episode, positive blood culture, and febrile upper respiratory infection rates among these groups. In 136 patients, the febrile episode rate was higher in the ever IgG monitored cohort than the never monitored cohort (5.26 vs. 3.78 episodes/1000 d). Among monitored patients, IVIG monitoring and supplementation did not significantly impact the febrile episode, febrile upper respiratory infection, or the positive blood culture rates. These data suggest that monitoring/supplementing low IgG is not indicated for infection prophylaxis in acute lymphoblastic leukemia patients during maintenance chemotherapy.

2448 The effect of allopurinol on pediatric patients undergoing maintenance chemotherapy for acute lymphoblastic leukemia or lymphoblastic lymphoma

OBJECTIVES/SPECIFIC AIMS: This study aims to assess the safety, feasibility, clinical benefits and pharmacodynamics of adding allopurinol to standard maintenance therapy that includes 6-mecaptopurine (6-MP) in pediatric patients with acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma. Our goal is to investigate if allopurinol improves hepatotoxicity and GI toxicity, if it safely decreases acute neutrophil count (ANC), if it reduces the 6-MP dose required during chemotherapy, and if it works through our hypothesized mechanism by lowering the levels of the toxic metabolite, 6-methylmecaptopurine (6-MMP) and by raising the levels of the active metabolite, 6-thioguanine (6-TGN). METHODS/STUDY POPULATION: This is a single arm, nonblinded pilot study of patients under age 30 years who were being treated in the maintenance phase of therapy for ALL or lymphoblastic lymphoma, and had adverse effects such as high 6-MMP:6-TGN ratio, high ANC, and high liver enzymes. Patients enrolled were started with allopurinol in addition to ongoing oral chemotherapy. Data from beginning maintenance to end of chemotherapy was collected in the electronic medical record, EPIC for the 13 patients enrolled at Johns Hopkins, and data analysis was conducted using STATA and Excel. RESULTS/ANTICIPATED RESULTS: Initial data analysis reveals that the required dose of 6-MP after addition of allopurinol to the chemotherapy regimen was significantly lower compared with that before the addition of allopurinol in 11 out of the 12 patients assessed (p&lt;0.05). Among the 10 patients that were assessed for 6MMP:6TG ratio, all had lower average 6MMP:6TGN ratios after allopurinol compared to before allopurinol; the percentage of weeks that goal 6MMP:6TGN ratio (&lt;40) were maintained were statistically significant in 6 patients (p&lt;0.05) and close to significance in 2 other patients (p=0.057). The percentage of weeks that patients maintained alanine aminotransferase levels below 120 was significantly greater after addition of allopurinol compared to before the addition of allopurinol in 9 out of 13 patients assessed, suggesting that allopurinol may be associated with reduced hepatotoxicity. Further data analysis is ongoing to assess the percentage of weeks that patients maintained goal total bilirubin, direct bilirubin, and ANC, as well as average number of admissions for infections and average number of therapy holds after allopurinol addition compared to before allopurinol addition. DISCUSSION/SIGNIFICANCE OF IMPACT: Allopurinol is associated with reduction in required 6-MP dose, decrease in the percentage of weeks that patients have hepatotoxicity, and reduction in the ratio of toxic metabolite to active anti-leukemic metabolite in several patients. We hope that the results of this study can be used for further research and for guiding clinical practice since there are no established guidelines in pediatric oncology regarding addressing side effects of oral chemotherapy using 6-MP. If allopurinol indeed is safe and effective, adding it to the standard chemotherapy regimen can lead to better tolerance and compliance to oral maintenance chemotherapy, and hopefully improved outcomes for children with ALL and lymphoblastic leukemia.

Folate deficiency in north Indian children undergoing maintenance chemotherapy for acute lymphoblastic leukemia-Implications and outcome.

Treatment-related toxicity and mortality are not uncommon during maintenance chemotherapy for childhood acute lymphoblastic leukemia (ALL), especially in the low- and middle-income countries (LMIC). Undernutrition and micronutrient deficiencies are commonly seen in children from LMICs undergoing treatment for ALL. The present study examines the prevalence and clinical implications of folate deficiency in north Indian children with ALL during the maintenance phase of treatment in view of prolonged antifolate treatment and high population prevalence of folate deficiency. Pre-cycle folate levels/deficiency as well as weight for age z-score and serum albumin level were determined and correlated with complications of treatment and mortality encountered during the maintenance phase of treatment. Twenty-nine of 52 children enrolled in the study had folate deficiency at some point during maintenance chemotherapy. Neutropenia (18 of 29 vs. 4 of 23; P = 0.002), thrombocytopenia (17 of 29 vs. 4 of 23; P = 0.005), febrile neutropenia (17 of 29 vs. 4 of 23; P = 0.005), and need for chemotherapy dose reduction (20 of 29 vs. 7 of 21; P = 0.01) were more common in folate-deficient children. Maintenance deaths were higher (8 of 29 vs. 1 of 23; P = 0.03) and survival lower (P = 0.02) in deficient children. In multivariate analysis, hypoalbuminemia (P = 0.02) and folate deficiency (P = 0.01) were associated with febrile neutropenia, and folate deficiency with maintenance deaths (P = 0.03). Folate deficiency was associated with treatment-related complications and adverse outcome in our patients. The risks and benefits of folate supplementation in deficient children during maintenance chemotherapy need to be explored with properly designed randomized studies in similar settings.

A Sleep Hygiene and Relaxation Intervention for Children With Acute Lymphoblastic Leukemia: A Pilot Randomized Controlled Trial.

Background:Sleep disturbance and fatigue are common and distressing pediatric cancer-related outcomes. Sleep hygiene education and relaxation techniques are recommended to improve sleep in healthy children and adult cancer survivors. No studies have tested these interventions to improve sleep and fatigue for children with acute lymphoblastic leukemia (ALL) in the home setting.Objectives:The aim of this study is to establish the feasibility and acceptability of a sleep hygiene and relaxation intervention to improve sleep and fatigue for children receiving maintenance chemotherapy for ALL. The child's fatigue and sleep data were collected to inform sample size calculations for a future trial.Methods:In this pilot randomized controlled trial, 20 children were allocated randomly to the sleep intervention or control group. The sleep intervention group received a 60-minute educational session to discuss sleep and fatigue in children with cancer and strategies to improve sleep, including use of 2 storybooks to teach deep breathing and progressive muscle relaxation. Objective sleep data were collected using actigraphy and fatigue was measured using the Childhood Cancer Fatigue Scale.Results:The intervention was acceptable to families, and feasibility of the intervention and data collection was clearly established. Although not statistically significant, increases in mean nighttime sleep and decreases in mean wake time after sleep onset in the sleep intervention group represented clinically important improvements.Conclusions:This pilot study demonstrated the feasibility and acceptability of a sleep hygiene and relaxation intervention for children undergoing maintenance chemotherapy for ALL.Implications for practice:Given the clinically important improvements in sleep observed, replication in a larger, adequately powered randomized controlled trial is merited.

The Association of Plasma and Cerebral Spinal Fluid Cytokines with Daytime Sleepiness Among Children with Acute Lymphoblastic Leukemia

Introduction:Fatigue and daytime sleepiness (DS) are understudied among children with acute lymphoblastic leukemia (ALL). Past studies have identified pro-inflammatory cytokines, such as TNFα and interferon-inducible protein measured in serum as potential mediators of fatigue and sleep disturbances in other populations. Cytokines measured in cerebral spinal fluid (CSF) may correlate more closely with DS than those measured in serum. Yet, CSF measurements of cytokines are rare because they are difficult to obtain. ALL patients undergo lumbar puncture as part of routine exams, thus presenting an opportunity to measure CSF levels of cytokines without additional procedures. The aim of our study was to examine the associations of plasma and CSF cytokines with patient-reported fatigue among children with ALL. Our hypothesis was that higher levels of cytokines and soluble cytokine receptors would be associated with greater patient-reported DS.Patients and Methods:This study included 16 children aged 4-11 years with ALL who had cytokine and DS measures available. The cytokine IL-6, and cytokine receptors IL-1 R1 & R2, TNF R1 & R2 were measured in plasma and/or cerebral spinal fluid at up to three time points during maintenance chemotherapy regimens, approximately 3 months apart. DS was assessed at each of these same time points using the Pediatric Daytime Sleepiness Scale (PDSS), which is completed by the child and has possible values between 0 and 32 points. Higher scores on this scale indicate greater DS, with a score of 17 or greater indicating clinically relevant DS. We used repeated measures linear regression models to examine the association of each cytokine with PDSS scores, adjusting for age at each visit.Results:The mean age at study entry was 6.1 years (SD=2.4), and 47% of patients were male. The mean PDSS score was 20.4 points (SD=6.1, range 4 to 29), and 79% of the patients had a PDSS score ≥17. Table 1 shows the age-adjusted associations of each cytokine with PDSS score. Each 100 pg/mL increase in CSF TNF R2 was associated with a 2.13 (SE=0.76) point higher score on the PDSS (p=0.01). In general, higher cytokine levels in both plasma and CSF were associated with higher PDSS scores, although no other associations reached statistical significance.Conclusions:We found that the majority of ALL patients undergoing maintenance chemotherapy experienced clinically relevant DS. Higher CSF levels of TNF R2 were associated with greater patient-reported DS, which supports results from past studies that measured TNFα in plasma. This association is biologically plausible because TNF R2 mediates the many metabolic effects of TNF that can include fatigue and sleep. We are in the process of evaluating other cytokines and cytokine-receptors on sleep. Our findings suggest that the complex relation of fatigue, daytime-sleepiness, and CSF cytokines should be evaluated in a larger patient population, and that targeting chronic stimulation of the TNFα pathway may help to mitigate daytime sleepiness in ALL patients.Table 1Age-adjusted associations of IL-1 R1 & R2, IL-6, and TNF R1 & R2 withPediatric Daytime Sleepiness Scale (PDSS) scores among pediatric acute lymphoblastic leukemia (ALL) patientsCytokine or Cytokine ReceptorBeta (SE)aper 100 pg/mL unit increasep-valueaIL-1R1Plasma1.74 (3.1)0.59CSF––IL-1R2Plasma0.01 (0.02)0.39CSF0.05 (0.08)0.55IL-6Plasma0.02 (0.02)0.29CSF0.28 (0.38)0.47TNF R1Plasma0.29 (0.28)0.31CSF0.77 (0.74)0.31TNF R2Plasma0.04 (0.07)0.56CSF2.13 (0.76)0.01a Estimates are from repeated linear regression models, adjusted for age at each visit. DisclosuresNo relevant conflicts of interest to declare.

Lymphoproliferative disorder that resembles heptosplenic lymphoma during maintenance treatment for T‐cell acute lymphoblastic leukemia

A 6-year-old male presented with a testicular mass, hepatosplenomegaly, and a pleural effusion while undergoing maintenance chemotherapy for treatment of T-cell acute lymphoblastic leukemia (T-ALL). He was subsequently diagnosed with a lymphoproliferative disorder that resembled hepatosplenic lymphoma (HSL). While the extranodal presentation and the protracted yet aggressive clinical course are consistent with HSL, the findings of monosomy 8 and polymorphic cell populations are unique and have not been previously described in this type of lymphoma.

Pandemic H1N1 Influenza Infection in Children With Acute Leukemia

In English literature, there are only 2 specific series of pandemic H1N1 influenza infection in children with leukemia. To increase knowledge about pandemic influenza in children with leukemia and better understand the risk factors for severe disease, we have presented the clinical characteristics of 8 children with acute leukemia and pandemic influenza treated at our center. The mean age of the children (4 girls and 4 boys) was 6.7±2.0 years (range, 4 to 10 y). All these children [3 acute lymphoblastic leukemia and 5 acute myeloid leukemia (AML) cases] were receiving chemotherapy during the course of infection, except 1 who was found to be H1N1 positive at the same time that she was diagnosed with AML. Among the other 7 patients undergoing chemotherapy, 4 were receiving induction, 1 was receiving consolidation, and 2 were undergoing maintenance chemotherapy. In our series, 1 patient with AML had a fatal course. She had recently received a chemotherapy bloc. Her neutrophil count was 0 during the course of H1N1 infection. She developed acute respiratory distress syndrome within a short time after the symptoms commenced and she died within 4 days. In conclusion, the clinical course of H1N1 infection may be fatal in rare cases of leukemic children receiving chemotherapy. Thus, vaccination is advisable for all leukemic children, especially for those under maintenance chemotherapy, as it might be life saving during such pandemics.

A Pilot Study to Examine the Feasibility and Effects of a Home-Based Aerobic Program on Reducing Fatigue in Children With Acute Lymphoblastic Leukemia

Fatigue is one of the most frequent symptoms experienced by children with cancer during treatment. Effective management of fatigue is essential for improving children's quality of life. The aim of this study was to examine the feasibility of a home-based aerobic exercise intervention to reduce fatigue in children with acute lymphoblastic leukemia (ALL). A 6-week home-based aerobic exercise intervention was implemented for children who were in the intervention group, whereas patients in the control group received routine care. Multivariate analysis was used to examine the effects of the aerobic exercise intervention on the children's self-reported levels of fatigue at posttest and 1-month follow-up. Two types of analysis were used: intent-to-treat analysis and per-protocol analysis. This study was conducted with 22 children with ALL: 12 in the intervention group and 10 in the control group who were matched by age and sex. For per-protocol analysis, the finding indicated that children who received the exercise intervention reported significantly lower "general fatigue" subscale than those in the control group at the 1-month follow-up measurement. For intent-to-treat analysis, the findings indicated that there were no intervention and time effect for any of the 3 fatigue subscales at either posttest or 1-month follow-up. The finding indicated that the exercise program is feasible and warrants being tested in a clinical trial with a much larger sample of children for ALL. It suggests that a home-based exercise program may reduce fatigue for ALL children who are undergoing maintenance chemotherapy.

A case of adult medulloblastoma onset during maintenance chemotherapy for anaplastic astrocytoma one year after radiotherapy

Multiple primitive intracranial tumors with different histological characteristics are uncommon. Although coexistence of a medulloblastoma with glial tumors has been reported in children, medulloblastoma is rarely found in adults, especially those older than 40 years of age. We present an extremely rare case of a medulloblastoma developing in a 40-year-old male undergoing maintenance chemotherapy for anaplastic astrocytoma for 21 months after radiotherapy. Initially, he complained of intractable epilepsy characterized by complex partial seizures. Magnetic resonance imaging (MRI) revealed a slightly enhanced mass lesion in the left insula region. He underwent subtotal removal of the tumor and it was histologically diagnosed as anaplastic astrocytoma. After 19 months of treatment with temozolomide (TMZ) and radiotherapy, he presented with vertigo and headache. A homogeneously enhanced mass had developed in the left cerebellar hemisphere. He received gross total resection of the second tumor, pathologically diagnosed as medulloblastoma. In conclusion, this is the first case report of an adult medulloblastoma coexisting with anaplastic astrocytoma.

Average Absolute Neutrophil Count During Maintenance Chemotherapy In Latino Versus Non-Latino Caucasian Patients with Childhood Acute Lymphoblastic Leukemia

AbstractAbstract 3237Despite recent advances in the treatment of childhood acute lymphoblastic leukemia (ALL), Latino children consistently have survival rates approximately 10% lower than among Caucasians. The thiopurine, 6-mercaptopurine (6MP), is an essential component of ALL maintenance therapy; therefore differences in adherence, absorption, and/or the pharmacogenomics of 6MP metabolism may play a role in explaining their survival difference. The presence of one or more polymorphism of the enzyme thiopurine methyltransferase (TPMT) affects TPMT enzyme activity, and therefore sensitivity to 6MP. Genotype is commonly evaluated prior to initiating 6MP therapy, to identify patients at risk for significant myelosuppression who will require dose reductions, allowing patients to maintain targeted neutrophil counts while forming adequate concentrations of the metabolite thioguanine nucleotide (TGN). The TPMT phenotype reflects actual enzyme activity level, but it is less commonly measured prior to 6MP therapy, since results may be obscured by recent packed cell transfusions frequently given to patients at diagnosis. Most individuals (89%) inherit a normal TPMT genotype (wild type); however, there is significant heterogeneity of TPMT enzyme activity within this group. Recent data suggest that ALL patients who are genotypically normal, and have higher TPMT enzyme activity may have inferior survival compared to patients with lower TPMT enzyme activity. Higher activity may be associated clinically with a higher absolute neutrophil count (ANC) as higher TPMT enzyme activity is associated with the formation of more methylated metabolite and less TGN. Thus, we hypothesized that our Latino patients with wild type TPMT activity would have a skewed distribution of TPMT activity with higher activity than our non-Latino Caucasian population and that the absolute neutrophil count (ANC), which is used to dose adjust 6MP, would serve as a surrogate marker of TPMT enzyme activity.We conducted a retrospective analysis of all patients with ALL undergoing maintenance chemotherapy between 2005–2009 at Children's Medical Center of Dallas. All patients diagnosed with ALL between January 1, 2005 to August 1, 2009, who were self-described Latino and non-Latino Caucasian, and treated per a current COG treatment protocol, were included in this analysis. We recorded demographic information, diagnostic and risk stratification characteristics, all complete blood counts during maintenance therapy, 6MP and methotrexate dosing, and all coinciding infections and medications which could affect neutrophil counts. 134 patient records were analyzed. The nine patients known to have a heterozygous TPMT genotype were excluded; however, the 31 (25%) patients who had not been genotyped were included. Of those 125 patients, 68 (54%) were self-described Latino and 57 (46%) were non-Latino Caucasian. There was no significant difference in the average dose of 6-MP prescribed during maintenance therapy among Latino versus non-Latino Caucasians (445 mg/m2/week vs 426 mg/m2/week, p = 0.4), nor was there a significant difference in the average ANC for Latinos versus non-Latino Caucasians (2,199 vs 2,134, p = 0.6, by the Wilcoxon rank sum test). There was a wide range of enzyme activity in both Latino and non-Latinos Caucasian patients (17.4 - 60.6 EU/mL and 16.9 – 50.6 EU/mL, n = 32), with 3 Latino patients having activity levels > 50 EU/mL. In conclusion, this study did not demonstrate a difference in average ANC during maintenance therapy between Latino and non-Latino Caucasians in our Dallas population. Thus, if there were significant differences in either adherence or metabolism of 6MP secondary to a skew in TPMT activity, it was not detectable through an analysis of the average ANC during maintenance therapy. Enzyme activity was widely distributed in patients with wild type genetics, in both populations. Our study has many limitations, including small sample size, use of average ANC as a surrogate rather than direct measurements of TPMT enzyme activity, reliance on the medical record for definition of ethnicity, and possible inclusion of non-wild type patients who had not been genotyped. A larger prospective study is needed to directly evaluate TPMT enzyme activity in patients with known wild type genetics in order to elucidate the role of TPMT phenotypic variation in TPMT wild-type Latino patients. Disclosures:No relevant conflicts of interest to declare.

Sleep Habits and Fatigue of Children Receiving Maintenance Chemotherapy for ALL and Their Parents

The study of potential contributors to fatigue, such as sleep disturbance, has been identified as a research priority in pediatric cancer. The primary objective of this descriptive study was to explore relationships between sleep habits, sleep disturbance, and fatigue for children receiving maintenance chemotherapy for acute lymphoblastic leukemia (ALL). This study also described sleep habits, sleep disturbance, and fatigue of parents of children and adolescents with ALL and determined if relationships existed between parent and child sleep disturbance and fatigue. Using a descriptive, cross-sectional design, children aged 4-18 years receiving maintenance chemotherapy for ALL and their parents completed questionnaires about their sleep and fatigue. Sleep disturbance was common in both children (87%) and parents (48%) and sleep disturbance scores were positively correlated with fatigue scores. From qualitative written responses to open-ended questions, 9 themes emerged related to sleep for children undergoing maintenance chemotherapy for ALL. Sleep differences noted since diagnosis included (1) sleep is disturbed, (2) sleep habits have changed, and (3) sleep is unchanged or improved. Things that got in the way of children sleeping well included (4) side effects of medication, especially dexamethasone; and (5) medication schedules. Things that helped children get sleep at night were (6) sleeping with someone, (7) comforting activities or routine, (8) medications, and (9) food and drink. Sleep disturbance in children on ALL maintenance and their parents is common and likely contributes to increased fatigue and is a potential target for nursing interventions.

Safety of live‐virus vaccines for children with immune deficiency

Conduct an integrative literature review to evaluate the safety and effectiveness of live-virus vaccines, namely, the measles, mumps, rubella, and varicella vaccines, in children who are immune compromised by exogenous medication either posttransplant or while undergoing maintenance chemotherapy for leukemia. Medline, MedlinePlus, EBSCO, PubMed, MD Consult, CINAHL, Clinical Pharmacology, ERIC, Biomedical Reference Collection-Basic, Health Source-Consumer Edition, Health Source-Nursing/Academic Edition, Ovid, CANCERLIT, and the Cochrane Library Online. Because measles infection has a low incidence rate in the United States, it may be advisable not to vaccinate children who are immunocompromised and risk side effects of the vaccine. In contrast to measles infection, varicella has a higher incidence rate and poses a more imminent threat to those who are immunocompromised. Children who are immunosuppressed can receive the varicella vaccination; however, they should have regular titers drawn to confirm adequate protection against the disease and should receive boosters as deemed appropriate. The number of solid organ transplant recipients is steadily increasing with more than 600,000 solid organ transplantations worldwide since the first renal transplant in 1954. The steadily increasing numbers of pediatric patients surviving transplantation, coupled with increased life expectancy, accelerate the need for nurse practitioners to understand the management of these delicate patients following release from the transplant unit.

Vincristine-Induced Urinary Bladder Paralysis

The authors describe the development of bladder paralysis in a child with acute lymphoblastic leukemia undergoing maintenance chemotherapy. Immediately before the adverse clinical event, the child had received vincristine intravenously and triple therapy with hydrocortisone, cytosine arabinoside, and methotrexate intrathecally and had begun a 5-day pulse of prednisolone. The authors conclude that the ensuing reversible bladder paralysis was related to the vincristine. The clinical event resolved, and vincristine was deleted from the child's subsequent therapy until full recovery was achieved. The authors advise recognition of this problem and discontinuation of the vincristine if transient bladder paralysis develops until symptoms completely disappear.

Preponderance of methylenetetrahydrofolate reductase C677T homozygosity among leukemia patients intolerant to methotrexate

BackgroundMethylenetetrahydrofolate reductase (MTHFR) C677T polymorphism, a common mutation of the gene encoding the enzyme that catalyzes reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a carbon donor in the metabolism of folate, determines a striking reduction in the enzyme activity in carriers of mutation at homozygous status. Patients and methodsWe retrospectively analyzed the incidence of MTHFR C677T and the influence of genotype on methotrexate (MTX) toxicity in patients with acute leukemia undergoing maintenance chemotherapy. Seventy-eight patients were analyzed and 61 were evaluable for toxicity. MTX toxicity was assessed on bone marrow, liver and mucosae. ResultsThe incidence of the C677T mutation was as expected in the general Italian population with 23.08% of patients being TT, 38.46% of patients CT and 38.46% of patients CC. The TT genotype was significantly associated with an increase of toxicity during MTX administration. No specific pattern of toxicity was detected, although in TT patients myelosuppression and liver toxicity were more pronounced. ConclusionsTT genotype may indicate a need to reduce the dose of MTX during prolonged administration. Considering the high prevalence of homozygous individuals in the Italian population, pretreatment screening may be worthwhile.