To prospectively evaluate the effectiveness of risk-adapted preemptive tocilizumab (PT) administration in preventing severe cytokine release syndrome (CRS) after CTL019, a CD19 chimeric antigen ...receptor T-cell therapy.
Children and young adults with CD19-positive relapsed or refractory B-cell acute lymphoblastic leukemia were assigned to high- (≥ 40%) or low- (< 40%) tumor burden cohorts (HTBC or LTBC) based on a bone marrow aspirate or biopsy before infusion. HTBC patients received a single dose of tocilizumab (8-12 mg/kg) after development of high, persistent fevers. LTBC patients received standard CRS management. The primary end point was the frequency of grade 4 CRS (Penn scale), with an observed rate of ≤ 5 of 15 patients in the HTBC pre-defined as clinically meaningful. In post hoc analyses, the HTBC was compared with a historical cohort of high-tumor burden patients from the initial phase I CTL019 trial.
The primary end point was met. Seventy patients were infused with CTL019, 15 in the HTBC and 55 in the LTBC. All HTBC patients received the PT intervention. The incidence of grade 4 CRS was 27% (95% CI, 8 to 55) in the HTBC and 3.6% (95% CI, 0.4 to 13) in the LTBC. The best overall response rate was 87% in the HTBC and 100% in the LTBC. Initial CTL019 expansion was greater in the HTBC than the LTBC (
< .001), but persistence was not different (
= .73). Event-free and overall survival were worse in the HTBC (
= .004,
< .001, respectively). In the post hoc analysis, grade 4 CRS was observed in 27% versus 50% of patients in the PT and prior phase I cohorts, respectively (
= .18).
Risk-adapted PT administration resulted in a decrease in the expected incidence of grade 4 CRS, meeting the study end point, without adversely impacting the antitumor efficacy or safety of CTL019.
The treatment landscape for cancer therapy has changed drastically over the past decade. Tisagenlecleucel, the first genetically engineered adoptive cellular therapy approved by the United States ...Food and Drug Administration, has revolutionized this field by demonstrating impressive clinical success in children and young adults with relapsed/refractory B‐cell acute lymphoblastic leukemia (r/r B‐ALL). Now 3 years since its approval, we have gained a deeper understanding on the basic immunobiology and clinical efficacy of this drug. This review will provide an updated summary of tisagenlecleucel in childhood and young adults with r/r B‐ALL, common side effects and their associated management strategies, as well as barriers that remain to be addressed in order to realize the maximum potential of this drug.
To study the biology and identify markers of severe cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) in children after chimeric antigen receptor ...T-cell (CAR T) treatment.
We used comprehensive proteomic profiling to measure over 1,400 serum proteins at multiple serial timepoints in a cohort of patients with B-cell acute lymphoblastic leukemia treated with the CD19-targeted CAR T CTL019 on two clinical trials.
We identified fms-like tyrosine kinase 3 (FLT3) and mast cell immunoglobulin-like receptor 1 (MILR1) as preinfusion predictive biomarkers of severe CRS. We demonstrated that CRS is an IFNγ-driven process with a protein signature overlapping with hemophagocytic lymphohistiocytosis (HLH). We identified IL18 as a potentially targetable cytokine associated with the development of ICANS.
We identified preinfusion biomarkers that can be used to predict severe CRS with a sensitivity, specificity, and accuracy superior to the current gold standard of disease burden. We demonstrated the fundamental role of the IFNγ pathway in driving CRS, suggesting CRS and carHLH are overlapping rather than distinct phenomena, an observation with important treatment implications. We identified IL18 as a possible targetable cytokine in ICANS, providing rationale for IL18 blocking therapies to be translated into clinical trials in ICANS.
Chimeric antigen receptor (CAR)‐modified T‐cell therapy has revolutionized the care of patients with relapsed and refractory B‐cell acute lymphoblastic leukemia (B‐ALL). Results from clinical trials ...across multiple institutions report remarkable remission rates with CD19‐directed CAR‐modified T‐cell therapy. These remissions are also proving to be durable in many patients with a relapse‐free survival (RFS) of approximately 50% to 60% at 1 year across several trials and institutions in this population that has been historically very difficult to treat. In addition, new products are being developed to enhance upon the original CAR T‐cell products, which include a humanized CAR, allogeneic CARs, and both CD22 and biallelic CD19 and CD22 constructs. Toxicity after CAR‐modified T‐cell therapy is characterized by cytokine release syndrome (CRS) and neurotoxicity in the acute post‐infusion period and B‐cell aplasia as a long‐term consequence of treatment. This review will summarize the published data thus far on the use of CAR‐modified T‐cell therapy in pediatric B‐ALL and outline the various CAR products now being developed for this population. Delivery of this therapy and the decision to pursue hematopoietic stem cell transplant (HSCT) after treatment will be discussed.
Twenty‐eight patients were maintained on subcutaneous immunoglobulin replacement for persistent B‐cell aplasia and agammaglobulinemia following CD19‐targeted chimeric antigen receptor T‐cell therapy ...for B‐cell lymphoblastic leukemia. Patients were transitioned from intravenous to subcutaneous immunoglobulin replacement at a median of 11.5 months (range, 4‐20). Increasing serum IgG level was significantly associated with a lower rate of sinopulmonary infection (P = 0.0072). The median serum IgG level during infection‐free periods was 1000 mg/dL (range, 720‐1430), which was significantly higher than IgG levels in patients with sinopulmonary infections. As such, we recommend maintaining a goal IgG level > 1000 mg/dL to provide optimal protection.
Tisagenlecleucel, a chimeric antigen receptor (CAR) T-cell product targeting CD19 is approved for relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). However, the impact of pretreatment ...variables, such as CD19 expression level, on leukemic blasts, the presence of CD19– subpopulations, and especially prior CD19-targeted therapy, on the response to CAR T-cell therapy has not been determined. We analyzed 166 patients treated with CAR T-cell therapy at our institution. Eleven patients did not achieve a minimal residual disease (MRD)– deep remission, whereas 67 patients had a recurrence after achieving a MRD– deep remission: 28 patients with CD19+ leukemia and 39 patients with CD19– leukemia. Return of CD19+ leukemia was associated with loss of CAR T-cell function, whereas CD19– leukemia was associated with continued CAR T-cell function. There were no significant differences in efficacy of CAR T cells in CD19-dim B-ALL, compared with CD19-normal or -bright B-ALL. Consistent with this, CAR T cells recognized and lysed cells with very low levels of CD19 expression in vitro. The presence of dim CD19 or rare CD19– events by flow cytometry did not predict nonresponse or recurrence after CAR T-cell therapy. However, prior therapy with the CD19-directed, bispecific T-cell engager blinatumomab was associated with a significantly higher rate of failure to achieve MRD– remission or subsequent loss of remission with antigen escape. Finally, immunophenotypic heterogeneity and lineage plasticity were independent of underlying clonotype and cytogenetic abnormalities.
•Preinfusion dim CD19 expression and rare CD19– events in B-ALL do not affect relapses or responses to CD19-directed CAR T-cells.•Prior blinatumomab treatment increases the rate of failure to achieve MRD– remission and CD19– MRD and relapse.
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This study is a pharmacoepidemiologic description of pediatric bortezomib use. Exposure was identified through billing codes in patients admitted to US children's hospitals that participated with the ...Pediatric Health Information System between 2004 and 2013. Associated information on underlying diseases, demographics, institutional use, mortality, and physician type was collected. Exposure to bortezomib was identified in 314 patients. Hematologist/Oncologists prescribed half of the bortezomib used. Use increased during the study period. Inpatient volume was positively correlated with bortezomib utilization. Bortezomib use in pediatrics is increasing for a variety of diseases. Variation in use exists across institutions. Further studies are needed to characterize bortezomib's efficacy in pediatric diseases.
Background
Infertility can be the result of some common cancer treatments and can significantly impact quality of life. Semen cryopreservation allows for fertility preservation. We analyzed the semen ...parameters of specimens collected from pubertal males from the Children's Hospital of Philadelphia (CHOP) in order to expand current knowledge on the quality of these specimens and inform a standard clinical practice.
Procedure
Males who were at least Tanner stage III and newly diagnosed with cancer at CHOP were approached regarding sperm banking. The success and quality of the samples collected were analyzed and compared in relation to prior treatment, age, and diagnosis.
Results
From 399 patients approached for semen collection, 339 (85%) attempted to bank sperm, of which 265 (78%) were successful and 60 (15%) refused to participate. Therapy prior to sperm banking significantly impacted a successful collection (P < 0.01). Only 16.9% of the untreated patients were azoospermic, whereas 84.0% of the treated subjects were azoospermic. Older patients were less likely to be azoospermic and have a greater quality collection when compared with younger patients (P < 0.01). However, 65% of our youngest patients still were able to cryopreserve semen. There was no difference in azoospermia across diagnostic groups (P = 0.35), though there were differences in quality of semen parameters across diagnoses.
Conclusion
Our data support that sperm banking pubertal males prior to the initiation of therapy is feasible. While there were differences in quality of semen parameters across age and diagnostic groups, most males, regardless of age or diagnosis, had adequate specimens for cryopreservation.
Introduction
Our objectives were to design and validate methods to identify relapse and hematopoietic stem cell transplantation (HSCT) in children with acute lymphoblastic leukemia (ALL) using ...administrative data representing hospitalizations at US pediatric institutions.
Methods
We developed daily billing and ICD‐9 code definitions to identify relapses and HSCTs within a cohort of children with newly diagnosed ALL between January 1, 2004, and December 31, 2013, previously assembled from the Pediatric Health Information System (PHIS) database. Chart review for children with ALL at the Children's Hospital of Philadelphia (CHOP) and Texas Children's Hospital (TCH) was performed to establish relapse and HSCT gold standards for sensitivity and positive predictive value (PPV) calculations. We estimated incidences of relapse and HSCT in the PHIS ALL cohort.
Results
We identified 362 CHOP and 314 TCH ALL patients in PHIS and established true positives by chart review. Sensitivity and PPV for identifying both relapse and HSCT in PHIS were > 90% at both hospitals. Five‐year relapse incidence in the 10 150‐patient PHIS cohort was 10.3% (95% CI 9.8%‐10.9%) with 7.1% (6.6%‐7.6%) of children underwent HSCTs. Patients in higher‐risk demographic groups had higher relapse and HSCT rates. Our analysis also identified differences in incidences of relapse and HSCT by race, ethnicity, and insurance status.
Conclusions
Administrative data can be used to identify relapse and HSCT accurately in children with ALL whether they occur on‐ or off‐therapy, in contrast with published approaches. This method has wide potential applicability for estimating these incidences in pediatric ALL, including patients not enrolled on clinical trials.
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