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.

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.

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.

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.

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.

Pooled safety analysis of tisagenlecleucel in children and young adults with B cell acute lymphoblastic leukemia.

BACKGROUND: Tisagenlecleucel, an anti-CD19 chimeric antigen receptor T cell therapy, has demonstrated efficacy in children and young adults with relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL) in two multicenter phase 2 trials (ClinicalTrials.gov, NCT02435849 (ELIANA) and NCT02228096 (ENSIGN)), leading to commercialization of tisagenlecleucel for the treatment of patients up to age 25 years with B-ALL that is refractory or in second or greater relapse. METHODS: A pooled analysis of 137 patients from these trials (ELIANA: n=79; ENSIGN: n=58) was performed to provide a comprehensive safety profile for tisagenlecleucel. RESULTS: Grade 3/4 tisagenlecleucel-related adverse events (AEs) were reported in 77% of patients. Specific AEs of interest that occurred ≤8 weeks postinfusion included cytokine-release syndrome (CRS; 79% (grade 4: 22%)), infections (42%; grade 3/4: 19%), prolonged (not resolved by day 28) cytopenias (40%; grade 3/4: 34%), neurologic events (36%; grade 3: 10%; no grade 4 events), and tumor lysis syndrome (4%; all grade 3). Treatment for CRS included tocilizumab (40%) and corticosteroids (23%). The frequency of neurologic events increased with CRS severity (p<0.001). Median time to resolution of grade 3/4 cytopenias to grade ≤2 was 2.0 (95% CI 1.87 to 2.23) months for neutropenia, 2.4 (95% CI 1.97 to 3.68) months for lymphopenia, 2.0 (95% CI 1.87 to 2.27) months for leukopenia, 1.9 (95% CI 1.74 to 2.10) months for thrombocytopenia, and 1.0 (95% CI 0.95 to 1.87) month for anemia. All patients who achieved complete remission (CR)/CR with incomplete hematologic recovery experienced B cell aplasia; however, as nearly all responders also received immunoglobulin replacement, few grade 3/4 infections occurred >1 year postinfusion. CONCLUSIONS: This pooled analysis provides a detailed safety profile for tisagenlecleucel during the course of clinical trials, and AE management guidance, with a longer follow-up duration compared with previous reports.

Tisagenlecleucel immunogenicity in relapsed/refractory acute lymphoblastic leukemia and diffuse large B-cell lymphoma.

Tisagenlecleucel is indicated for pediatric and young adult patients with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL) and adult patients with r/r diffuse large B-cell lymphoma (DLBCL). The tisagenlecleucel chimeric antigen receptor (CAR) contains a murine single-chain variable fragment domain; we examined the effects of humoral and cellular immune responses to tisagenlecleucel on clinical outcomes using 2 validated assays. Data were pooled from the ELIANA (registered at www.clinicaltrials.gov as #NCT02435849) and ENSIGN (#NCT02228096) trials in r/r B-ALL (N = 143) and the JULIET trial (#NCT02445248) in r/r DLBCL (N = 115). Humoral responses were determined by flow cytometric measurement of anti-murine CAR19 (mCAR19) antibodies in serum. Cellular responses were determined using T-cell production of interferon-γ in response to 2 different pools of mCAR19 peptides. Pretreatment anti-mCAR19 antibodies were detected in 81% of patients with r/r B-ALL and 94% of patients with r/r DLBCL. Posttreatment anti-mCAR19 antibodies were higher than patient-specific baseline in 42% of r/r B-ALL and 9% of r/r DLBCL patients. Pretreatment and posttreatment anti-mCAR19 antibodies did not affect tisagenlecleucel cellular kinetics, including maximum concentration and persistence (r2 < 0.05), clinical response (day-28 response, duration of response, and event-free survival), and safety. T-cell responses were consistent over time, with net responses <1% at baseline and posttreatment time points in a majority of patients and no effect on transgene expansion or persistence or outcomes. Presence of baseline and/or posttreatment anti-mCAR19 antibodies or T-cell responses did not alter the activity of tisagenlecleucel in patients with r/r B-ALL or r/r DLBCL.

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).

Tisagenlecleucel infusion in patients with relapsed/refractory ALL and concurrent serious infection.

BACKGROUND: Tisagenlecleucel, an anti-CD19 chimeric antigen receptor T (CAR-T) cell therapy, has demonstrated durable efficacy and a manageable safety profile in pediatric and young adult patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) in the ELIANA pivotal trial and real-world experience. Experience from investigator-led studies prior to ELIANA suggests that infections and inflammatory conditions may exacerbate the severity of cytokine release syndrome (CRS) associated with CAR-T cell therapy, leading to extreme caution and strong restrictions for on-study and commercial infusion of tisagenlecleucel in patients with active infection. CRS intervention with interleukin (IL)-6 blockade and/or steroid therapy was introduced late in the course during clinical trials due to concern for potential negative effect on efficacy and persistence. However, earlier CRS intervention is now viewed more favorably. Earlier intervention and consistency in management between providers may promote broader use of tisagenlecleucel, including potential curative therapy in patients who require remission and recovery of hematopoiesis for management of severe infection. MAIN BODY: Patient 1 was diagnosed with B-ALL at 23 years old. Fourteen days before tisagenlecleucel infusion, the patient developed fever and neutropenia and was diagnosed with invasive Mucorales infection and BK virus hemorrhagic cystitis. Aggressive measures were instituted to control infection and to manage prolonged cytopenias during CAR-T cell manufacturing. Adverse events, including CRS, were manageable despite elevated inflammatory markers and active infection. The patient attained remission and recovered hematopoiesis, and infections resolved. The patient remains in remission ≥1 year postinfusion.Patient 2 was diagnosed with pre-B-ALL at preschool age. She developed severe septic shock 3 days postinitiation of lymphodepleting chemotherapy. After receiving tisagenlecleucel, she experienced CRS with cardiac dysfunction and extensive lymphadenopathy leading to renovascular compromise. The patient attained remission and was discharged in good condition to her country of origin. She remained in remission but expired on day 208 postinfusion due to cardiac arrest of unclear etiology. CONCLUSIONS: Infusion was feasible, and toxicity related to tisagenlecleucel was manageable despite active infections and concurrent inflammation, allowing attainment of remission in otherwise refractory pediatric/young adult ALL. This may lead to consideration of tisagenlecleucel as a potential curative therapy in patients with managed active infections.

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.

Overcoming Wnt-ß-catenin dependent anticancer therapy resistance in leukaemia stem cells.

Leukaemia stem cells (LSCs) underlie cancer therapy resistance but targeting these cells remains difficult. The Wnt-ß-catenin and PI3K-Akt pathways cooperate to promote tumorigenesis and resistance to therapy. In a mouse model in which both pathways are activated in stem and progenitor cells, LSCs expanded under chemotherapy-induced stress. Since Akt can activate ß-catenin, inhibiting this interaction might target therapy-resistant LSCs. High-throughput screening identified doxorubicin (DXR) as an inhibitor of the Akt-ß-catenin interaction at low doses. Here we repurposed DXR as a targeted inhibitor rather than a broadly cytotoxic chemotherapy. Targeted DXR reduced Akt-activated ß-catenin levels in chemoresistant LSCs and reduced LSC tumorigenic activity. Mechanistically, ß-catenin binds multiple immune-checkpoint gene loci, and targeted DXR treatment inhibited expression of multiple immune checkpoints specifically in LSCs, including PD-L1, TIM3 and CD24. Overall, LSCs exhibit distinct properties of immune resistance that are reduced by inhibiting Akt-activated ß-catenin. These findings suggest a strategy for overcoming cancer therapy resistance and immune escape.

Microfluidic Device for On-Chip Immunophenotyping and Cytogenetic Analysis of Rare Biological Cells.

The role of circulating plasma cells (CPCs) and circulating leukemic cells (CLCs) as biomarkers for several blood cancers, such as multiple myeloma and leukemia, respectively, have recently been reported. These markers can be attractive due to the minimally invasive nature of their acquisition through a blood draw (i.e., liquid biopsy), negating the need for painful bone marrow biopsies. CPCs or CLCs can be used for cellular/molecular analyses as well, such as immunophenotyping or fluorescence in situ hybridization (FISH). FISH, which is typically carried out on slides involving complex workflows, becomes problematic when operating on CLCs or CPCs due to their relatively modest numbers. Here, we present a microfluidic device for characterizing CPCs and CLCs using immunofluorescence or FISH that have been enriched from peripheral blood using a different microfluidic device. The microfluidic possessed an array of cross-channels (2-4 µm in depth and width) that interconnected a series of input and output fluidic channels. Placing a cover plate over the device formed microtraps, the size of which was defined by the width and depth of the cross-channels. This microfluidic chip allowed for automation of immunofluorescence and FISH, requiring the use of small volumes of reagents, such as antibodies and probes, as compared to slide-based immunophenotyping and FISH. In addition, the device could secure FISH results in <4 h compared to 2-3 days for conventional FISH.

Application of 2016 WHO classification in the diagnosis of paediatric high-grade MYC-negative mature B-cell lymphoma with Burkitt-like morphological features.

AIMS: Historically, there has been no consensus on the diagnostic classification of high-grade B-cell lymphoma (HGBCL) with morphological features of Burkitt lymphoma (BL) but no MYC gene rearrangement (MYC-negative). The 2016 WHO classification of tumours of haematopoietic and lymphoid tissues has shed some light on this field with the modification of the grey-zone lymphoma with features intermediate between BL and diffuse large B-cell lymphoma, and the creation of several new entities. The aim of this study was to investigate how the revised WHO classification affects our practice in diagnosing these lymphomas in children. METHODS: We retrospectively reviewed cases of mature HGBCL diagnosed at our hospital between 2015 and 2018. RESULTS: Among 14 mature HGBCL cases with BL morphological features, 11 showed MYC rearrangement consistent with BL and 3 were MYC-negative. Two MYC-negative cases showed regions of 11q gain and loss by microarray consistent with Burkitt-like lymphoma with 11q aberration (BLL-11q). The third MYC-negative case showed diffuse and strong MUM1 expression, translocation involving 6p25 by chromosome analysis and IRF4 rearrangement by fluorescence in situ hybridisation analysis consistent with large B-cell lymphoma with IRF4 rearrangement (LBL-IRF4). All patients were treated according to applicable chemotherapeutic protocols and achieved remission. CONCLUSIONS: BLL-11q and LBL-IRF4, two newly defined entities, should be considered in paediatric MYC-negative mature HGBCL cases. Accurate diagnosis needs careful histopathological examination and proper cytogenetic testing. Since they have unique cytogenetic features, specific treatments for them may emerge in the future. Therefore, accurate diagnosis based on the 2016 WHO classification is clinically significant.

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.

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.

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.

Correction: Inotuzumab ozogamicin in pediatric patients with relapsed/refractory acute lymphoblastic leukemia.

We thank the research coordinators and following physicians at pediatric cancer centers for contributing data to this project: Prashant Hiwarkar and Jayashree Motwani, Birmingham Women's and Children's Hospital, UK; Kelly Malone, Children's Hospital of Colorado, USA; Mylene Bassal, Children's Hospital of Eastern Ontario, Canada; Yoav Messinger and Joanna Perkins, Children's Hospital of Minnesota, USA; Van Huynh, Children's Hospital of Orange County, USA; Richard Ho, Children's Hospital at Vanderbilt, USA; Joanne Chuah and Jessa Morales, Children's Hospital at Westmead, Australia; Donald Wells, Dell Children's Hospital, USA; Nicolas Boissel, Hospital Saint-Louis, France; Tannie Huang, Kaiser Permanente, USA; Stacey Marjerrison, McMaster Children's Hospital, Canada; William Carroll and Joanna Pierro, New York University Langone Medical Center, USA; Ajay Vora, Sheffield Children's Hospital, UK; Donna Lancaster, The Royal Marsden Hospital, UK; Lucie Srámková, University Hospital Motol, Czech Republic; Chatchawin Assanasen, University of Texas Health Science Center, San Antonio, USA; Rupert Handgretinger, University of Tübingen, Germany.

Tisagenlecleucel Model-Based Cellular Kinetic Analysis of Chimeric Antigen Receptor-T Cells.

Tisagenlecleucel is a chimeric antigen receptor-T cell therapy that facilitates the killing of CD19+ B cells. A model was developed for the kinetics of tisagenlecleucel and the impact of therapies for treating cytokine release syndrome (tocilizumab and corticosteroids) on expansion. Data from two phase II studies in pediatric and young adult relapsed/refractory B cell acute lymphoblastic leukemia were pooled to evaluate this model and evaluate extrinsic and intrinsic factors that may impact the extent of tisagenlecleucel expansion. The doubling time, initial decline half-life, and terminal half-life for tisagenlecleucel were 0.78, 4.3, and 220 days, respectively. No impact of tocilizumab or corticosteroids on the expansion rate was observed. This work represents the first mixed-effect model-based analysis of chimeric antigen receptor-T cell therapy and may be clinically impactful as future studies examine prophylactic interventions in patients at risk of higher grade cytokine release syndrome and the effects of these interventions on chimeric antigen receptor-T cell expansion.

Inotuzumab ozogamicin in pediatric patients with relapsed/refractory acute lymphoblastic leukemia.

Although inotuzumab ozogamicin (InO) is recognized as an effective agent in relapsed acute lymphoblastic leukemia (ALL) in adults, data on safety and efficacy in pediatric patients are scarce. We report the use of InO in 51 children with relapsed/refractory ALL treated in the compassionate use program. In this heavily pretreated cohort, complete remission was achieved in 67% of patients with overt marrow disease. The majority (71%) of responders were negative for minimal residual disease. Responses were observed irrespective of cytogenetic subtype or number or type of prior treatment regimens. InO was well-tolerated; grade 3 hepatic transaminitis or hyperbilirubinemia were noted in 6 (12%) and grade 3/4 infections in 11 (22%) patients. No patient developed sinusoidal obstruction syndrome (SOS) during InO therapy; however, 11 of 21 (52%) patients who underwent hematopoietic stem cell transplantation (HSCT) following InO developed SOS. Downregulation of surface CD22 was detected as a possible escape mechanism in three patients who developed a subsequent relapse after InO. We conclude that InO is a well-tolerated, effective therapy for children with relapsed ALL and prospective studies are warranted. Identification of risk factors for developing post-HSCT SOS and strategies to mitigate this risk are ongoing.