MRD at the end of induction and EFS in T-cell lymphoblastic lymphoma: Children's Oncology Group trial AALL1231.

ABSTRACT: Defining prognostic variables in T-lymphoblastic lymphoma (T-LL) remains a challenge. AALL1231 was a Children's Oncology Group phase 3 clinical trial for newly diagnosed patients with T acute lymphoblastic leukemia or T-LL, randomizing children and young adults to a modified augmented Berlin-Frankfurt-Münster backbone to receive standard therapy (arm A) or with addition of bortezomib (arm B). Optional bone marrow samples to assess minimal residual disease (MRD) at the end of induction (EOI) were collected in T-LL analyzed to assess the correlation of MRD at the EOI to event-free survival (EFS). Eighty-six (41%) of the 209 patients with T-LL accrued to this trial submitted samples for MRD assessment. Patients with MRD <0.1% (n = 75) at EOI had a superior 4-year EFS vs those with MRD ≥0.1% (n = 11) (89.0% ± 4.4% vs 63.6% ± 17.2%; P = .025). Overall survival did not significantly differ between the 2 groups. Cox regression for EFS using arm A as a reference demonstrated that MRD EOI ≥0.1% was associated with a greater risk of inferior outcome (hazard ratio, 3.73; 95% confidence interval, 1.12-12.40; P = .032), which was independent of treatment arm assignment. Consideration to incorporate MRD at EOI into future trials will help establish its value in defining risk groups. CT# NCT02112916.

Caregiver perceptions of child heath behaviors and weight during treatment for acute lymphoblastic leukemia.

BACKGROUND: Changes in health behaviors and weight are common during the early phases of pediatric acute lymphoblastic leukemia treatment, and may negatively impact treatment tolerability. Given that ALL is most prevalent in children, caregivers play an essential role in shaping health behaviors during treatment. This study presents a qualitative analysis of semi-structured interviews with caregivers of youth in the early phases of ALL treatment. PROCEDURE: Caregivers (N = 17, 95% female) of a child (M age = 6.76 years) diagnosed with ALL and on treatment for less than 1 year (M = 8.7 months since diagnosis) completed a semi-structured interview about perceptions of their child's nutrition, physical activity, sedentary time, and weight during ALL treatment. Thematic analysis followed Braun and Clark's six-step framework (2006). Two coders established reliability (alpha = .88) and used a multi-pass coding system to extract themes. RESULTS: Caregivers' concerns around their child's weight during ALL treatment primarily centered around avoiding malnutrition. Weight gain during treatment was less of a concern and often viewed as protective. Caregivers reported encouraging their child to eat palatable, calorie-dense foods to mitigate risk for weight loss. Caregivers also expressed concern that children were less active and more sedentary due to treatment-related pain. Caregivers discussed health behaviors during treatment as being child-directed, rather than parent- or provider-directed. CONCLUSION: Future interventions may consider strategies to engage in joint parent-child decisions and caregiver education around risks of excessive weight gain during treatment. Interventions should include anticipatory guidance and aim to support parents in developing skills to support their child's health behaviors during treatment.

Family Rules and Routines During the Early Phases of Pediatric Cancer Treatment: Associations With Child Emotional and Behavioral Health.

OBJECTIVE: Consistent family rules and routines promote positive adaptation to stress and may be protective to child emotional and behavioral functioning. Few studies have quantified family engagement in these behaviors during pediatric cancer treatment or examined associations with child emotional and behavioral health. METHODS: In this cross-sectional observational study, 86 primary caregivers of youth ages 2-14 years (M = 7.9) with an initial diagnosis of cancer within 16 weeks reported on their frequency of engagement in family rules and routines (e.g., sleep, schoolwork, and meal routines) before their child's cancer diagnosis and their current frequency of engagement in the same routines. Caregivers also reported demographics, psychosocial distress, and child emotional and behavioral health outcomes. Analyses examined demographic and psychosocial factors associated with engagement in rules and routines during cancer treatment, and associations with child emotional and behavioral health. RESULTS: Families reported a lower frequency of engagement in rules and routines during cancer treatment, compared to before treatment (mean difference 0.8 SDs [95% confidence interval 0.7-1.1 SDs]). Caregiver factors associated with lower engagement in rules and routines during treatment included being married, having lower educational attainment, and higher levels of psychosocial distress. Families who engaged in higher levels of rules and routines during treatment reported fewer child externalizing and behavioral challenges. There was limited evidence of association between family rules and routines and child internalizing outcomes. CONCLUSIONS: Results found that engaging in family rules and routines during cancer treatment was associated with fewer child behavioral challenges during treatment. Future directions include longitudinal examinations of family rules, routines, and child emotional/behavioral outcomes to examine directional impact over time.

Chlorhexidine gluconate bathing in children with cancer or those undergoing hematopoietic stem cell transplantation: A double-blinded randomized controlled trial from the Children's Oncology Group.

BACKGROUND: To the authors' knowledge, information regarding whether daily bathing with chlorhexidine gluconate (CHG) reduces central line-associated bloodstream infection (CLABSI) in pediatric oncology patients and those undergoing hematopoietic stem cell transplantation (HCT) is limited. METHODS: In the current multicenter, randomized, double-blind, placebo-controlled trial, patients aged ≥2 months and <22 years with cancer or those undergoing allogeneic HCT were randomized 1:1 to once-daily bathing with 2% CHG-impregnated cloths or control cloths for 90 days. The primary outcome was CLABSI. Secondary endpoints included total positive blood cultures, acquisition of resistant organisms, and acquisition of cutaneous staphylococcal isolates with an elevated CHG mean inhibitory concentration. RESULTS: The study was stopped early because of poor accrual. Among the 177 enrolled patients, 174 were considered as evaluable (88 were randomized to the CHG group and 86 were randomized to the control group). The rate of CLABSI per 1000 central line days in the CHG group was 5.44 versus 3.10 in the control group (risk difference, 2.37; 95% confidence interval, 0.05-4.69 [P = .049]). Post hoc conditional power analysis demonstrated a 0.2% chance that the results would have favored CHG had the study fully enrolled. The rate of total positive blood cultures did not differ between groups (risk difference, 2.37; 95% confidence interval, -0.41 to 5.14 [P = .078]). The number of patients demonstrating the new acquisition of resistant organisms did not differ between groups (P = .54). Patients in the CHG group were found to be more likely to acquire cutaneous staphylococcal isolates with an elevated CHG mean inhibitory concentration (P = .032). CONCLUSIONS: The data from the current study do not support the use of routine CHG bathing in children with cancer or those undergoing allogeneic HCT.

Results of a phase 2, multicenter, single-arm, open-label study of lenalidomide in pediatric patients with relapsed or refractory acute myeloid leukemia.

BACKGROUND: Outcomes after relapse remain poor in pediatric patients with acute myeloid leukemia (AML), and new therapeutic approaches are needed. Lenalidomide has demonstrated activity in adults with lower risk myelodysplastic syndromes and older adults with relapsed or refractory (R/R) AML. METHODS: In this phase 2 study (NCT02538965), pediatric patients with R/R AML who received two or more prior therapies were treated with lenalidomide (starting dose 2 mg/kg/day on days 1-21 of each 28-day cycle) for a maximum of 12 cycles. The primary endpoint was rate of complete response (CR) and CR with incomplete blood count recovery (CRi) within the first four cycles. RESULTS: Seventeen patients enrolled and received one or more dose of lenalidomide. Median age was 12 years (range 5-18 years), median white blood cell count was 3.7 × 109 /L, and median peripheral blood blast count was 1.0 × 109 /L. One patient (5.9%) with a complex karyotype including del(5q) achieved CRi after two cycles of lenalidomide. This responder proceeded to a second hematopoietic stem cell transplantation and has remained without evidence of disease for 3 years. All patients experienced one or more of grades 3-4 treatment-emergent adverse event (TEAE). The most common grades 3-4 TEAEs were thrombocytopenia (58.8%), febrile neutropenia (47.1%), anemia (41.2%), and hypokalemia (41.2%). CONCLUSIONS: In this population of pediatric patients with R/R AML, safety data were consistent with the known safety profile of lenalidomide. As only one patient responded, further evaluation of lenalidomide at the dose and schedule studied is not warranted in pediatric AML, with the possible exception of patients with del(5q).

Treatment of children with relapsed and refractory acute lymphoblastic leukemia with mitoxantrone, vincristine, pegaspargase, dexamethasone, and bortezomib.

BACKGROUND: The treatment of relapsed or refractory acute lymphoblastic leukemia (ALL) in children is challenging and new treatment options are needed. Bortezomib is a proteasome inhibitor with activity in pediatric acute lymphoblastic leukemia. Adding bortezomib to standard reinduction chemotherapy in relapsed and refractory pediatric ALL has produced very good response rates in prior studies. METHODS: We evaluated bortezomib in combination with reinduction therapy (ALL R3) in 10 children with relapsed or refractory ALL. Bortezomib (1.3 mg/m2 /dose) was administered to patients on days 1, 4, 8, and 11. In addition, patients received mitoxantrone, dexamethasone, pegaspargase, vincristine, and intrathecal methotrexate over 4 weeks. RESULTS: Of the 10 patients, eight (80%) achieved a complete remission (CR) or complete remission with incomplete recovery (CRi). Of the patients in CR, two had undetectable minimal residual disease by flow cytometry (<0.01%). Five patients were subsequently treated with a stem cell transplant. All eight patients that achieved CR or CRi eventually relapsed. One patient remains alive following treatment with tisagenlecleucel after relapse. Grade 3 or higher infections occurred in four out of 10 patients, and other toxicities commonly associated with bortezomib were not seen. CONCLUSIONS: In children with relapsed or refractory ALL, the addition of bortezomib to reinduction chemotherapy that includes mitoxantrone produces a complete response in the majority of cases and does not lead to excessive toxicity.

Desensitization to pegaspargase in children with acute lymphoblastic leukemia and lymphoblastic lymphoma.

Hypersensitivity to pegaspargase is associated with inferior survival in pediatric patients with acute lymphoblastic leukemia and lymphoblastic lymphoma. In the past year, drug-supply shortages have led to the lack of an available alternative to pegaspargase. Rather than omit asparaginase from the treatment of acute lymphoblastic leukemia or lymphoblastic lymphoma patients with hypersensitivity to pegaspargase, we continued pegaspargase treatments for nine pediatric patients, utilizing a rapid desensitization protocol. There were no adverse events related to the pegaspargase during desensitization, and all patients who were checked had asparaginase serum levels above the threshold of 0.1 IU/mL at 7 to 14 days after pegaspargase therapy.

Results from an international phase 2 study of the anti-CD22 immunotoxin moxetumomab pasudotox in relapsed or refractory childhood B-lineage acute lymphoblastic leukemia.

BACKGROUND: In a multicenter phase 1 study of children with relapsed/refractory acute lymphoblastic leukemia (ALL), moxetumomab pasudotox, an anti-CD22 immunotoxin, demonstrated a manageable safety profile and preliminary evidence of clinical activity. A phase 2 study further evaluated efficacy. PROCEDURE: This international, multicenter, phase 2 study enrolled children with relapsed/refractory B-cell precursor ALL who received moxetumomab pasudotox 40 µg/kg intravenously every other day, for six doses per 21-day cycle. The primary objective was to evaluate the complete response (CR) rate. Secondary objectives included safety, pharmacokinetics, and immunogenicity evaluations. RESULTS: Thirty-two patients (median age, 10 years) were enrolled at 16 sites; 30 received study drug and were evaluable for safety; 28 were evaluable for response. The objective response rate was 28.6%, with three patients (10.7%) achieving morphologic CR, and five patients (17.9%) achieving partial response. Disease progression occurred in 11 patients (39.3%). Ten patients (33.3%) experienced at least one treatment-related serious adverse event, including capillary leak syndrome (CLS; n = 6), hemolytic uremic syndrome (HUS; n = 4), and treatment-related death (n = 1) from pulmonary edema. No differences were observed in inflammatory markers in patients who did or did not develop CLS or HUS. CONCLUSIONS: Despite a signal for clinical activity, this phase 2 study was terminated at interim analysis for a CR rate that did not reach the stage 1 target. Preclinical data suggest enhanced efficacy of moxetumomab pasudotox via continuous infusion or in combination regimens; thus, further studies designed to optimize the efficacy and safety of moxetumomab pasudotox in pediatric ALL may be warranted.

Pharmacokinetics of two 6-mercaptopurine liquid formulations in children with acute lymphoblastic leukemia.

BACKGROUND: A liquid formulation of 6-mercaptopurine (6-MP) was recently approved by the Food and Drug Administration (Purixan®) based on bioavailability (BA) data from healthy adults. We examined the pharmacokinetics (PK) and BA of 6-MP in children with acute lymphoblastic leukemia (ALL) comparing a marketed tablet, two extemporaneously prepared liquid formulations, and data from the approved liquid formulation. METHODS: Twenty-two children (6-17 years) participated in a randomized two-way, crossover study of two cohorts. Group 1 (n = 11; five males) received a 5 mg/ml liquid formulation and the marketed 50 mg 6-MP tablet on separate occasions, and Group 2 (n = 11; five males) received a 50 mg/ml liquid formulation and the marketed tablet. The usual prescribed 6-MP dose (25-115 mg/m2 ) was given after an 8-hr fast. Serial blood samples were collected over 8 hr postdose. Plasma 6-MP concentrations were determined using a good laboratory practice (GLP)-validated liquid chromatography-tandem mass spectrometry method. PK parameters were calculated using noncompartmental analysis and compared within and between cohorts, and thiopurine methyltransferase (TPMT) genotype was analyzed. RESULTS: No patient had a TPMT genotype reflective of a poor metabolizer phenotype. Comparison of PK parameters between 5 and 50 mg/ml treatments revealed significant differences (P <0.05) in AUCN (where AUC is area under the curve), CmaxN , and Tmax . Comparisons within each group revealed significant differences in AUC0-∞ and Tmax in the 5 mg/ml group. CONCLUSIONS: Pharmacokinetic profiles of 6-MP established in healthy adults with the approved liquid formulation may not reflect the PK profile in children with ALL. Formulation-specific differences in PK may significantly impact the dose-exposure profile in these children and must be considered.

A phase 1 study of the CXCR4 antagonist plerixafor in combination with high-dose cytarabine and etoposide in children with relapsed or refractory acute leukemias or myelodysplastic syndrome: A Pediatric Oncology Experimental Therapeutics Investigators' Consortium study (POE 10-03).

BACKGROUND: Plerixafor, a reversible CXCR4 antagonist, inhibits interactions between leukemic blasts and the bone marrow stromal microenvironment and may enhance chemosensitivity. A phase 1 trial of plerixafor in combination with intensive chemotherapy in children and young adults with relapsed or refractory acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and myelodysplastic syndrome (MDS) was performed to determine a tolerable and biologically active dose. PROCEDURE: Plerixafor was administered daily for 5 days at four dose levels (6, 9, 12, and 15 mg/m2 /dose) followed 4 hr later by high-dose cytarabine (every 12 hr) and etoposide (daily). RESULTS: Nineteen patients (13 with AML, 5 with ALL, 1 with MDS) were treated. The most common grade 3 or greater nonhematologic toxicities attributable to plerixafor were febrile neutropenia and hypokalemia. There were no dose-limiting toxicities (DLTs). Plerixafor exposure increased with increasing dose levels and clearance was similar on days 1 and 5. Eighteen patients were evaluable for response. Two patients achieved complete remission (CR) and one patient achieved CR with incomplete hematologic recovery (CRi): all three had AML. No responses were seen in patients with ALL or MDS. Plerixafor mobilized leukemic blasts into the peripheral blood in 14 of 16 evaluable patients (median 3.4-fold increase), and the degree of mobilization correlated with surface CXCR4 expression. CONCLUSIONS: Plerixafor, in combination with high-dose cytarabine and etoposide, was well tolerated in children and young adults with relapsed/refractory acute leukemias and MDS. While biologic responses were observed, clinical responses in this heavily pretreated cohort were modest.

Parental Perceptions of Obesity and Obesity Risk Associated With Childhood Acute Lymphoblastic Leukemia.

The prevalence of obesity and related comorbidities in survivors of childhood acute lymphoblastic leukemia (ALL) is well established and ranges anywhere from 29% to 69% depending on the study. We sought to explore the awareness of parents of survivors of childhood ALL regarding the increased risk of obesity and their perceptions regarding the overall health of their child. One hundred twenty-one parents of 99 survivors of pediatric ALL completed surveys regarding perceptions of obesity risk in survivors. Eighty percent of parents of overweight and obese survivors correctly identified their child as "a little overweight" or "overweight." Few parents recalled discussing weight gain (21%) or obesity risk (36%) with their practitioner. Parents that did recall having these discussions and/or reported a decreased level of posttherapy activity in their child were more likely to be concerned about their child's weight status. Improved awareness and education regarding the risk of obesity and associated comorbid conditions may provide an avenue for future prevention of obesity in survivors of pediatric ALL. Discussion and education regarding a healthy lifestyle, including proper diet and exercise, should be incorporated early in routine patient visits.

Early Discharge of Neutropenic Pediatric Oncology Patients Admitted With Fever.

BACKGROUND: Fever and neutropenia (FN) is a common complication of pediatric oncology therapy and accounts for a large number of hospital admissions. Standard therapy for FN includes hospital admission and empiric antibiotics. Strict adherence to this practice leads to prolonged hospitalizations that may be unnecessary for patients at low risk of having an underlying significant infection. PROCEDURE: Children admitted with FN could be discharged after a minimum of 48 hr with no further antibiotic therapy once they had been afebrile for 24 hr with negative blood cultures from initial presentation, regardless of their neutrophil count. We performed a retrospective review with regard to readmissions and subsequent documented infections in FN patients discharged with an ANC of ≤500 cells/mm(3) . RESULTS: There were 299 FN admissions in 188 patients who were discharged prior to achieving an ANC of ≥500 cells/mm(3) . Readmission to the hospital during the same period of neutropenia occurred in 50 cases (16.7%) with 27 infections diagnosed in 21 patients. Patients discharged with an ANC of ≤100 cells/mm(3) (odds ratio 3.7) and patients with acute lymphoblastic leukemia (odds ratio 2.6) were more likely to be readmitted for fever. All patients that developed a significant infection had an ANC of ≤100 cells/mm(3) at admission and discharge. In patients that developed a significant infection, only one required admission to the intensive care unit with no deaths. CONCLUSIONS: The practice of discharging patients with persistent neutropenia who are afebrile with negative blood cultures produces acceptable rates of readmission and subsequent infection and does not lead to increased morbidity and mortality.

Characteristics of Children With Cancer Discharged or Admitted From the Emergency Department.

BACKGROUND: Emergency department (ED) utilization by children with cancer is poorly understood. Among children with cancer, we explored reasons for ED visits and factors associated with admission within U.S. children's hospitals. METHODS: A retrospective study of the 2011-2013 Pediatric Health Information System (PHIS) was conducted. Eligible ED visits included those within 365 days from the first inpatient encounter with an International Classification of Diseases, Ninth Edition, Clinical Modification (ICD-9-CM) code for cancer. Patient characteristics and reasons for ED visits were assessed. Factors associated with admission from the ED were examined with multivariable regression. RESULTS: There were 26,770 ED visits by 17,943 children with cancer at 39 children's hospitals during the study period. Half of children with cancer visited the ED within 1 year after their first cancer hospitalization in PHIS. Fifty-six percent of ED visits resulted in admission. Fever or neutropenia accounted for the largest proportion of reasons for visits (34.6%). Risk factors for admission were as follows: "Other" race/ethnicity as compared to white, non-Hispanic (odds ratio [OR] = 1.4, 95% confidence interval [CI] 1.2-1.6), history of transplant (OR = 1.7, 95% CI 1.4-2.1), and ED visits reasons including neutropenia (OR = 43.4, 95% CI 36.0-52.3), blood stream infection (OR = 3.3, 95% CI 2.8-3.9), pancytopenia (OR = 28.8, 95% CI 18.1-45.9), dehydration (OR = 2.3, 95% CI 1.9-2.9), or pneumonia (OR = 3.8, 95% CI 2.8-5.1). CONCLUSIONS: Children with cancer have high ED usage within 1 year after their first cancer hospitalization. Age, demographic factors, and reasons for ED visits significantly impacted admission from the ED. Further research should focus on ED utilization among children with cancer.

Relative defects in mucosal immunity predict acute graft-versus-host disease.

Impairment of gut mucosal immunity by the transplant process could facilitate translocation of commensal bacteria and thereby augment the graft-versus-host response. To begin to assess the influence of gut mucosal immunity on the development of acute graft-versus-host disease (GVHD), we conducted a prospective study in 24 pediatric allogeneic hematopoietic cell transplant recipients, assessing 4 fecal markers of mucosal immunity: calprotectin, soluble CD8 (sCD8), soluble intracellular adhesion molecule 1, and ß-defensin-2. Stool samples were collected prospectively on transplant days 0, +5, +10, and +15 and analyzed by ELISA. Lower levels on day +5 (calprotectin and ß-defensin-2) and day +10 (calprotectin, ß-defensin-2, and sCD8) were associated with subsequent acute GVHD. The most striking difference was with calprotectin on day +10. Patients with levels below 424 mg/kg had an incidence of 77.8%, whereas those with levels above this threshold had a cumulative incidence of 0% (P = .002). Relative defects in gut mucosal immunity may be important in the pathogenesis of acute GVHD.

Caregiver survey results related to handling of oral chemotherapy for pediatric patients with acute lymphoblastic leukemia.

BACKGROUND: Oral chemotherapy is commonly administered in the home; however, there may be harmful effects on healthy individuals who handle these medications. Caregivers of pediatric patients were surveyed to establish educational needs for safe handling of oral chemotherapy agents. METHODS: An 11-question self-report survey was developed to characterize handling practices for patients in maintenance therapy for acute lymphoblastic leukemia related to caregiver education, use of protective gear, preparation, and disposal of oral chemotherapy agents. RESULTS: Fifty questionnaires were collected. Seventy-two percent of responders reported receiving instruction on safe handling of oral chemotherapy. Ninety percent of responders reported that they did not utilize protective gear during preparation of oral chemotherapy. Although tablet crushers were designated for use with oral chemotherapy by 61% of responders, 22% used the same device to crush other nonchemotherapy medications. The majority of responders disposed of medication waste with regular garbage or poured the remainder down the sink. CONCLUSIONS: Caregiver survey responses demonstrated that personal safeguards were not routinely utilized by pediatric caregivers while handling oral chemotherapy. Future educational efforts should be directed to improve caregiver understanding related to the use of protective equipment, designation of supplies for use with chemotherapy agents, and safe disposal.

Comparison of hypersensitivity reactions to PEG-asparaginase in children after intravenous and intramuscular administration.

INTRODUCTION: Polyethylene-glycolated (PEG)-asparaginase (PEG-ASP) is a crucial component of pediatric acute lymphoblastic leukemia therapy. Although hypersensitivity reactions to PEG-ASP occur less frequently than with other formulations, they are not uncommon and have an adverse impact on patient outcomes. Intravenous (IV) administration of PEG-ASP reduces patient pain and anxiety and is being used with increasing frequency in children. MATERIALS AND METHODS: A retrospective review was performed to compare the incidence of hypersensitivity reactions to PEG-ASP in children when administered either by intramuscular (IM) or IV routes between January 2006 and May 2008. RESULTS: Of 68 patients studied, 7 experienced a hypersensitivity reaction (10.3%). Two of 16 patients (12.5%) who received only IV PEG-ASP and 3 of 27 patients (11.1%) exposed to only IM PEG-ASP experienced a hypersensitivity reaction. Severe reactions (grade 3 or 4) occurred only once after 119 total doses (0.8%) of IV PEG-ASP and once after 215 total doses (0.5%) of IM PEG-ASP (P=1.0). Thrombosis or pancreatitis were rare and were not increased after IV PEG-ASP administration. DISCUSSION: IV PEG-ASP is well tolerated and does not result in a significant increase in the incidence of hypersensitivity reactions in children.

Rifaximin for preventing acute graft-versus-host disease: impact on plasma markers of inflammation and T-cell activation.

In murine allogeneic hematopoietic cell transplantation models, inhibiting bacterial translocation stemming from conditioning-induced damage to the gut mucosa abrogates inflammatory stimulation of donor T cells, preventing acute graft-versus-host disease (AGVHD). We conducted a phase I trial to begin testing the hypothesis that rifaximin, a broadly acting oral antibiotic, would reduce systemic inflammation and T-cell activation. We administered rifaximin to 20 adolescents and younger adults (day -10 through day +30) receiving intensive conditioning. We measured the plasma level of interleukin-6, as a marker of conditioning-induced inflammation, and the levels of soluble tumor necrosis factor receptor-1 and soluble interleukin-2 receptor, as surrogate markers of AGVHD. We formed a historical control group (n=24), from a previous study of biomarkers in AGVHD. The increase in the treatment group's mean interleukin-6 level from baseline to day 0 was 73% less than that in the control group (P=0.006). The increase from baseline to day 15 in the treatment group's mean soluble tumor necrosis factor-1 and soluble interleukin-2 receptor levels was similar to the control group. Incidences of grade 2 to 4 AGVHD also did not differ. This suggests that rifaximin may abrogate bacterial translocation and resultant inflammation, but in alternative donor transplants this does not prevent downstream activation of donor T cells.

Clinical predictors of invasive fungal rhinosinusitis in a tertiary pediatric hospital.

OBJECTIVES: Invasive fungal rhinosinusitis (IFRS) is a potentially fatal disease that affects the severely immunocompromised and requires aggressive treatment. The objective of this study is to better describe predictors of biopsy positivity in patients at high risk of IFRS at a pediatric hospital. METHODS: This was a single-center case-control study of 36 patients (37 total biopsies) ≤ 21 years old with one of five high-risk oncologic/hematologic diagnoses who underwent operative endoscopy for clinical suspicion for IFRS. IFRS positivity was defined histologically. Collected information included patient demographics, primary diagnosis, oncologic relapses, time from diagnosis to biopsy, clinical characteristics, and endoscopic findings. These data were used to create a simple predictive scoring system. RESULTS: 17 patients had biopsy-proven IFRS (IFRS(+)) for an overall incidence of 2.1% in the designated high-risk population. Average time from most recent oncologic development (diagnosis, relapse, or hematopoietic stem-cell transplant) to biopsy in the IFRS(+) group was 2.09 months (SD = 2.26), and 7.28 months in the IFRS(-) group (SD = 9.17) (p = 0.009). Clinical characteristics did not differentiate between IFRS(+) and IFRS(-). Bedside endoscopy performed poorly, as it was interpreted as normal in 42.8% of IFRS(+) and 53.8% of IFRS(-). In contrast, the presence of any positive endoscopic finding intra-operatively was highly specific for IFRS(+) (94%) with moderate sensitivity (70%), and the difference in rate of positivity between groups was statistically significant (p < 0.001). CONCLUSION: Operative endoscopy with biopsy remains the gold-standard to rule-out IFRS in the setting of high clinical suspicion. Time elapsed from most recent oncologic development to clinical concern for IFRS may influence the likelihood of disease, though this requires further study. Clinical symptoms and bedside endoscopy were not predictive and should be used with caution in decision-making.

Children's Oncology Group Trial AALL1231: A Phase III Clinical Trial Testing Bortezomib in Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia and Lymphoma.

PURPOSE: To improve the outcomes of patients with T-cell acute lymphoblastic leukemia (T-ALL) and lymphoblastic lymphoma (T-LL), the proteasome inhibitor bortezomib was examined in the Children's Oncology Group phase III clinical trial AALL1231, which also attempted to reduce the use of prophylactic cranial radiation (CRT) in newly diagnosed T-ALL. PATIENTS AND METHODS: Children and young adults with T-ALL/T-LL were randomly assigned to a modified augmented Berlin-Frankfurt-Münster chemotherapy regimen with/without bortezomib during induction and delayed intensification. Multiple modifications were made to the augmented Berlin-Frankfurt-Münster backbone used in the predecessor trial, AALL0434, including using dexamethasone instead of prednisone and adding two extra doses of pegaspargase in an attempt to eliminate CRT in most patients. RESULTS: AALL1231 accrued 824 eligible and evaluable patients from 2014 to 2017. The 4-year event-free survival (EFS) and overall survival (OS) for arm A (no bortezomib) versus arm B (bortezomib) were 80.1% ± 2.3% versus 83.8% ± 2.1% (EFS, P = .131) and 85.7% ± 2.0% versus 88.3% ± 1.8% (OS, P = .085). Patients with T-LL had improved EFS and OS with bortezomib: 4-year EFS (76.5% ± 5.1% v 86.4% ± 4.0%; P = .041); and 4-year OS (78.3% ± 4.9% v 89.5% ± 3.6%; P = .009). No excess toxicity was seen with bortezomib. In AALL0434, 90.8% of patients with T-ALL received CRT. In AALL1231, 9.5% of patients were scheduled to receive CRT. Evaluation of comparable AALL0434 patients who received CRT and AALL1231 patients who did not receive CRT demonstrated no statistical differences in EFS (P = .412) and OS (P = .600). CONCLUSION: Patients with T-LL had significantly improved EFS and OS with bortezomib on the AALL1231 backbone. Systemic therapy intensification allowed elimination of CRT in more than 90% of patients with T-ALL without excess relapse.