Quadriparesis and paraparesis following chimeric antigen receptor T-cell (CART) therapy in children and adolescents.

Immune effector cell-associated neurotoxicity syndrome (ICANS) is a common but potentially severe adverse event associated with chimeric antigen receptor T-cell (CART) therapy characterized by the development of acute neurologic symptoms following CART infusion. ICANS encompasses a wide clinical spectrum typified by mild to severe encephalopathy, seizures and/or cerebral edema. As more patients have been treated with CART new ICANS phenomenology has emerged. We present the clinical course of five children who developed acute onset of quadriparesis or paraparesis associated with abnormal brain and/or spine neuroimaging after infusion of CD19 or CD22-directed CART, adverse events not previously reported in children. Orthogonal data from autopsy studies, cerebrospinal fluid (CSF) flow cytometry and CSF proteomics/cytokine profiling demonstrated chronic white matter destruction, but a notable lack of inflammatory pathologic changes and cell populations. Instead, children with quadriparesis or paraparesis post-CART therapy had lower levels of pro-inflammatory cytokines such as interferon gamma (IFN), CCL17, CCL23, and CXCL10 than those who did not develop quadriparesis or paraparesis. Taken together, these findings imply a non-inflammatory source of this newly described ICANS phenomenon in children. The pathophysiology of some neurologic symptoms following CART may therefore have a more complex etiology than exclusive T-cell activation and excessive cytokine production.

Reinfusion of CD19 CAR T cells for relapse prevention and treatment in children with acute lymphoblastic leukemia.

ABSTRACT: Relapse after CD19-directed chimeric antigen receptor (CAR)-modified T cells remains a substantial challenge. Short CAR T-cell persistence contributes to relapse risk, necessitating novel approaches to prolong durability. CAR T-cell reinfusion (CARTr) represents a potential strategy to reduce the risk of or treat relapsed disease after initial CAR T-cell infusion (CARTi). We conducted a retrospective review of reinfusion of murine (CTL019) or humanized (huCART19) anti-CD19/4-1BB CAR T cells across 3 clinical trials or commercial tisagenlecleucel for relapse prevention (peripheral B-cell recovery [BCR] or marrow hematogones ≤6 months after CARTi), minimal residual disease (MRD) or relapse, or nonresponse to CARTi. The primary endpoint was complete response (CR) at day 28 after CARTr, defined as complete remission with B-cell aplasia. Of 262 primary treatments, 81 were followed by ≥1 reinfusion (investigational CTL019, n = 44; huCART19, n = 26; tisagenlecleucel, n = 11), representing 79 patients. Of 63 reinfusions for relapse prevention, 52% achieved CR (BCR, 15/40 [38%]; hematogones, 18/23 [78%]). Lymphodepletion was associated with response to CARTr for BCR (odds ratio [OR], 33.57; P = .015) but not hematogones (OR, 0.30; P = .291). The cumulative incidence of relapse was 29% at 24 months for CR vs 61% for nonresponse to CARTr (P = .259). For MRD/relapse, CR rate to CARTr was 50% (5/10), but 0/8 for nonresponse to CARTi. Toxicity was generally mild, with the only grade ≥3 cytokine release syndrome (n = 6) or neurotoxicity (n = 1) observed in MRD/relapse treatment. Reinfusion of CTL019/tisagenlecleucel or huCART19 is safe, may reduce relapse risk in a subset of patients, and can reinduce remission in CD19+ relapse.

INSPIRED Symposium Part 4A: Access to CAR T Cell Therapy in Unique Populations with B Cell Acute Lymphoblastic Leukemia.

The approval of tisagenlecleucel (tisa-cel) for use in children with B cell acute lymphoblastic leukemia (B-ALL) was based on the phase 2 ELIANA trial, a global registration study. However, the ELIANA trial excluded specific subsets of patients facing unique challenges and did not include a sufficient number of patients to adequately evaluate outcomes in rare subpopulations. Since the commercialization of tisa-cel, data have become available that support therapeutic indications beyond the specific cohorts previously eligible for chimeric antigen receptor (CAR) T cells targeted to CD19 (CD19 CAR-T) therapy on the registration clinical trial. Substantial real-world data and aggregate clinical trial data have addressed gaps in our understanding of response rates, longer-term efficacy, and toxicities associated with CD19 CAR-T in special populations and rare clinical scenarios. These include patients with central nervous system relapsed disease, who were excluded from ELIANA and other early CAR-T trials owing to concerns about risk of neurotoxicity that have not been born out. There is also interest in the use of CD19 CAR-T for very-high-risk patients earlier in the course of therapy, such as patients with persistent minimal residual disease after 2 cycles of upfront chemotherapy and patients with first relapse of B-ALL. However, these indications are not specified on the label for tisa-cel and historically were not included in eligibility criteria for most clinical trials; data addressing these populations are needed. Populations at high risk of relapse, including patients with high-risk cytogenetic lesions, infants with B-ALL, patients with trisomy 21, and young adults with B-ALL, also may benefit from earlier treatment with CD19 CAR-T. It is important to prospectively study patient-reported outcomes given the differential toxicity expected between CD19 CAR-T and the historic standard of care, hematopoietic cell transplantation. Now that CD19 CAR-T therapy is commercially available, studies evaluating potential access disparities created by this very expensive novel therapy are increasingly pressing.

Chimeric Antigen Receptor T Cell Manufacturing on an Automated Cell Processor.

Chimeric antigen receptor (CAR)-T cells represent a promising immunotherapeutic approach for the treatment of various malignant and non-malignant diseases. CAR-T cells are genetically modified T cells that express a chimeric protein that recognizes and binds to a cell surface target, resulting in the killing of the target cell. Traditional CAR-T cell manufacturing methods are labor-intensive, expensive, and may carry the risk of contamination. The CliniMACS Prodigy, an automated cell processor, allows for manufacturing cell therapy products at a clinical scale in a closed system, minimizing the risk of contamination. Processing occurs semi-automatically under the control of a computer and thus minimizes human involvement in the process, which saves time and reduces variability and errors. This manuscript and video describes the T cell transduction (TCT) process for manufacturing CAR-T cells using this processor. The TCT process involves CD4+/CD8+ T cell enrichment, activation, transduction with a viral vector, expansion, and harvest. Using the Activity Matrix, a functionality that allows ordering and timing of these steps, the TCT process can be customized extensively. We provide a walk-through of CAR-T cell manufacturing in compliance with current Good Manufacturing Practice (cGMP) and discuss required release testing and preclinical experiments that will support an Investigational New Drug (IND) application. We demonstrate the feasibility and discuss the advantages and disadvantages of using a semi-automatic process for clinical CAR-T cell manufacturing. Finally, we describe an ongoing investigator-initiated clinical trial that targets pediatric B-cell malignancies [NCT05480449] as an example of how this manufacturing process can be applied in a clinical setting.

Outcome of chimeric antigen receptor T-cell therapy following treatment with inotuzumab ozogamicin in children with relapsed or refractory acute lymphoblastic leukemia.

Chimeric antigen receptor T cells targeting CD19 (CART-19) have shown remarkable efficacy for relapsed/refractory (R/R) B-cell precursor acute lymphoblastic leukemia (BCP-ALL). We investigated whether prior use of inotuzumab ozogamicin (InO), an anti-CD22 antibody conjugated to calicheamicin, may impact CAR T-cell manufacturing or efficacy via pre-CART-19 depletion of the B-cell compartment. In this international, retrospective analysis, 39 children and young adults receiving InO before (n = 12) and/or after (n = 27) T-cell apheresis as bridging therapy to CART-19 treatment were analyzed. Median age at infusion was 13 years (range 1.4-23 years). Thirty-four out of 39 patients (87.2%) obtained complete remission. With a median follow-up of 18.2 months after CART-19 infusion, 12-month event-free survival (EFS) was 53.3% (95% confidence interval (CI): 38.7-73.4) and overall survival (OS) was 77.8% (95% CI: 64.5-93.9). Seventeen patients (44%) relapsed with a median of 159 days (range 28-655) after CART-19 infusion. No difference in day 28 minimal residual disease negative complete response rate, 12-month OS/EFS, or incidence of CD19-positive or -negative relapses was observed among patients receiving InO before or after apheresis. Compared to published data for patients treated with CART-19 therapy without prior InO exposure, response and OS/EFS for patients treated with InO prior to CART-19 are similar.

Impact of poverty and neighborhood opportunity on outcomes for children treated with CD19-directed CAR T-cell therapy.

Children living in poverty experience excessive relapse and death from newly diagnosed acute lymphoblastic leukemia (ALL). The influence of household poverty and neighborhood social determinants on outcomes from chimeric antigen receptor (CAR) T-cell therapy for relapsed/refractory (r/r) leukemia is poorly described. We identified patients with r/r CD19+ ALL/lymphoblastic lymphoma treated on CD19-directed CAR T-cell clinical trials or with commercial tisagenlecleucel from 2012 to 2020. Socioeconomic status (SES) was proxied at the household level, with poverty exposure defined as Medicaid-only insurance. Low-neighborhood opportunity was defined by the Childhood Opportunity Index. Among 206 patients aged 1 to 29, 35.9% were exposed to household poverty, and 24.9% had low-neighborhood opportunity. Patients unexposed to household poverty or low-opportunity neighborhoods were more likely to receive CAR T-cell therapy with a high disease burden (>25%), a disease characteristic associated with inferior outcomes, as compared with less advantaged patients (38% vs 30%; 37% vs 26%). Complete remission (CR) rate was 93%, with no significant differences by household poverty (P = .334) or neighborhood opportunity (P = .504). In multivariate analysis, patients from low-opportunity neighborhoods experienced an increased hazard of relapse as compared with others (P = .006; adjusted hazard ratio [HR], 2.3; 95% confidence interval [CI], 1.3-4.1). There was no difference in hazard of death (P = .545; adjusted HR, 1.2; 95% CI, 0.6-2.4). Among children who successfully receive CAR T-cell therapy, CR and overall survival are equitable regardless of proxied SES and neighborhood opportunity. Children from more advantaged households and neighborhoods receive CAR T-cell therapy with a higher disease burden. Investigation of multicenter outcomes and access disparities outside of clinical trial settings is warranted.

Statistical Considerations for Analyses of Time-To-Event Endpoints in Oncology Clinical Trials: Illustrations with CAR-T Immunotherapy Studies.

Chimeric antigen receptor T-cell (CAR-T) therapy is an exciting development in the field of cancer immunology and has received a lot of interest in recent years. Many time-to-event (TTE) endpoints related to relapse, disease progression, and remission are analyzed in CAR-T studies to assess treatment efficacy. Definitions of these TTE endpoints are not always consistent, even for the same outcomes (e.g., progression-free survival), which often stems from analysis choices regarding which events to consider as part of the composite endpoint, censoring or competing risk in the analysis. Subsequent therapies such as hematopoietic stem cell transplantation are common but are not treated the same in different studies. Standard survival analysis methods are commonly applied to TTE analyses but often without full consideration of the assumptions inherent in the chosen analysis. We highlight two important issues of TTE analysis that arise in CAR-T studies, as well as in other settings in oncology: the handling of competing risks and assessing the association between a time-varying (post-infusion) exposure and the TTE outcome. We review existing analytical methods, including the cumulative incidence function and regression models for analysis of competing risks, and landmark and time-varying covariate analysis for analysis of post-infusion exposures. We clarify the scientific questions that the different analytical approaches address and illustrate how the application of an inappropriate method could lead to different results using data from multiple published CAR-T studies. Codes for implementing these methods in standard statistical software are provided.

Comprehensive Serum Proteome Profiling of Cytokine Release Syndrome and Immune Effector Cell-Associated Neurotoxicity Syndrome Patients with B-Cell ALL Receiving CAR T19.

PURPOSE: 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. EXPERIMENTAL DESIGN: 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. RESULTS: 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. CONCLUSIONS: 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.

Unrelated donor α/ß T cell- and B cell-depleted HSCT for the treatment of pediatric acute leukemia.

Unrelated donor (URD) hematopoietic stem cell transplant (HSCT) is associated with an increased risk of severe graft-versus-host disease (GVHD). TCRαß/CD19 depletion may reduce this risk, whereas maintaining graft-versus-leukemia. Outcome data with TCRαß/CD19 depletion generally describe haploidentical donors, with relatively few URDs. We hypothesized that TCRαß/CD19-depletion would attenuate the risks of GVHD and relapse for URD HSCT. Sixty pediatric and young adult (YA) patients with hematologic malignancies who lacked a matched-related donor were enrolled at 2 large pediatric transplantation centers between October 2014 and September 2019. All patients with acute leukemia had minimal residual disease testing, and DP typing was available for 77%. All patients received myeloablative total body irradiation- or busulfan-based conditioning with no posttransplant immune suppression. Engraftment occurred in 98%. Four-year overall survival was 69% (95% confidence interval [CI], 52%-81%), and leukemia-free survival was 64% (95% CI, 48%-76%), with no difference between lymphoid and myeloid malignancies (P = .6297 and P = .5441, respectively). One patient (1.7%) experienced primary graft failure. Relapse occurred in 11 patients (3-year cumulative incidence, 21%; 95% CI, 11-34), and 8 patients (cumulative incidence, 15%; 95% CI, 6.7-26) experienced nonrelapse mortality. Grade III to IV acute GVHD was seen in 8 patients (13%), and 14 patients (26%) developed chronic GVHD, of which 6 (11%) had extensive disease. Nonpermissive DP mismatch was associated with higher likelihood of acute GVHD (odds ratio, 16.50; 95% CI, 1.67-163.42; P = .0166) but not with the development of chronic GVHD. URD TCRαß/CD19-depleted peripheral HSCT is a safe and effective approach to transplantation for children/YAs with leukemia. This trial was registered at www.clinicaltrials.gov as #NCT02323867.

Impact of high-risk cytogenetics on outcomes for children and young adults receiving CD19-directed CAR T-cell therapy.

Chimeric antigen receptor (CAR) T-cell therapy can induce durable remissions of relapsed/refractory B-acute lymphoblastic leukemia (ALL). However, case reports suggested differential outcomes mediated by leukemia cytogenetics. We identified children and young adults with relapsed/refractory CD19+ ALL/lymphoblastic lymphoma treated on 5 CD19-directed CAR T-cell (CTL019 or humanized CART19) clinical trials or with commercial tisagenlecleucel from April 2012 to April 2019. Patients were hierarchically categorized according to leukemia cytogenetics: High-risk lesions were defined as KMT2A (MLL) rearrangements, Philadelphia chromosome (Ph+), Ph-like, hypodiploidy, or TCF3/HLF; favorable as hyperdiploidy or ETV6/RUNX1; and intermediate as iAMP21, IKZF1 deletion, or TCF3/PBX1. Of 231 patients aged 1 to 29, 74 (32%) were categorized as high risk, 28 (12%) as intermediate, 43 (19%) as favorable, and 86 (37%) as uninformative. Overall complete remission rate was 94%, with no difference between strata. There was no difference in relapse-free survival (RFS; P = .8112), with 2-year RFS for the high-risk group of 63% (95% confidence interval [CI], 52-77). There was similarly no difference seen in overall survival (OS) (P = .5488), with 2-year OS for the high-risk group of 70% (95% CI, 60-82). For patients with KMT2A-rearranged infant ALL (n = 13), 2-year RFS was 67% (95% CI, 45-99), and OS was 62% (95% CI, 40-95), with multivariable analysis demonstrating no increased risk of relapse (hazard ratio, 0.70; 95% CI, 0.21-2.90; P = .7040) but a higher proportion of relapses associated with myeloid lineage switch and a 3.6-fold increased risk of all-cause death (95% CI, 1.04-12.75; P = .0434). CTL019/huCART19/tisagenlecleucel are effective at achieving durable remissions across cytogenetic categories. Relapsed/refractory patients with high-risk cytogenetics, including KMT2A-rearranged infant ALL, demonstrated high RFS and OS probabilities at 2 years.

CD19-targeted chimeric antigen receptor T-cell therapy for CNS relapsed or refractory acute lymphocytic leukaemia: a post-hoc analysis of pooled data from five clinical trials.

BACKGROUND: CNS relapse of acute lymphocytic leukaemia is difficult to treat. Durable remissions of relapsed or refractory B-cell acute lymphocytic leukaemia have been observed following treatment with CD19-directed chimeric antigen receptor (CAR) T cells; however, most trials have excluded patients with active CNS disease. We aimed to assess the safety and activity of CAR T-cell therapy in patients with a history of CNS relapsed or refractory B-cell acute lymphocytic leukaemia. METHODS: In this post-hoc analysis, we included 195 patients (aged 1-29 years; 110 [56%] male and 85 [44%] female) with relapsed or refractory CD19-positive acute lymphocytic leukaemia or lymphocytic lymphoma from five clinical trials (Pedi CART19, 13BT022, ENSIGN, ELIANA, and 16CT022) done at the Children's Hospital of Philadelphia (Philadelphia, PA, USA), in which participants received CD19-directed CAR T-cell therapy between April 17, 2012, and April 16, 2019. The trials required control of CNS disease at enrolment and infusion and excluded treatment in the setting of acute neurological toxic effects (>grade 1 in severity) or parenchymal lesions deemed to increase the risk of neurotoxicity. 154 patients from Pedi CART19, ELIANA, ENSIGN, and 16CT022 received tisagenlecleucel and 41 patients from the 13BT022 trial received the humanised CD19-directed CAR, huCART19. We categorised patients into two strata on the basis of CNS status at relapse or within the 12 months preceding CAR T-cell infusion-either CNS-positive or CNS-negative disease. Patients with CNS-positive disease were further divided on the basis of morphological bone marrow involvement-either combined bone marrow and CNS involvement, or isolated CNS involvement. Endpoints were the proportion of patients with complete response at 28 days after infusion, Kaplan-Meier analysis of relapse-free survival and overall survival, and the incidence of cytokine release syndrome and neurotoxicity. FINDINGS: Of all 195 patients, 66 (34%) were categorised as having CNS-positive disease and 129 (66%) as having CNS-negative disease, and 43 (22%) were categorised as having isolated CNS involvement. The median length of follow-up was 39 months (IQR 25-49) in the CNS-positive stratum and 36 months (18-49) in the CNS-negative stratum. The proportion of patients in the CNS-positive stratum with a complete response at 28 days after infusion was similar to that in the CNS-negative stratum (64 [97%] of 66 vs 121 [94%] of 129; p=0·74), with no significant difference in relapse-free survival (60% [95% CI 49-74] vs 60% [51-71]; p=0·50) or overall survival (83% [75-93] vs 71% [64-79]; p=0·39) at 2 years between the two groups. Overall survival at 2 years was significantly higher in patients with isolated CNS involvement compared with those with bone marrow involvement (91% [82-100] vs 71% [64-78]; p=0·046). The incidence and severity of neurotoxicity (any grade, 53 [41%] vs 38 [58%]; grade 1, 24 [19%] vs 20 [30%]; grade 2, 14 [11%] vs 10 [15%]; grade 3, 12 [9%] vs 6 [9%], and grade 4, 3 [2%] vs 2 [3%]; p=0·20) and cytokine release syndrome (any grade, 110 [85%] vs 53 [80%]; grade 1, 12 [9%] vs 2 [3%]; grade 2, 61 [47%] vs 38 [58%]; grade 3, 18 [14%] vs 7 [11%] and grade 4, 19 [15%] vs 6 [9%]; p=0·26) did not differ between the CNS-negative and the CNS-positive disease strata. INTERPRETATION: Tisagenlecleucel and huCART19 are active at clearing CNS disease and maintaining durable remissions in children and young adults with CNS relapsed or refractory B-cell acute lymphocytic leukaemia or lymphocytic lymphoma, without increasing the risk of severe neurotoxicity; although care should be taken in the timing of therapy and disease control to mitigate this risk. These preliminary findings support the use of these CAR T-cell therapies for patients with CNS relapsed or refractory B-cell acute lymphocytic leukaemia. FUNDING: Children's Hospital of Philadelphia Frontier Program.

Humanized CD19-Targeted Chimeric Antigen Receptor (CAR) T Cells in CAR-Naive and CAR-Exposed Children and Young Adults With Relapsed or Refractory Acute Lymphoblastic Leukemia.

PURPOSE: CD19-targeted chimeric antigen receptor (CAR)-modified T cells demonstrate unprecedented responses in B-cell acute lymphoblastic leukemia (B-ALL); however, relapse remains a substantial challenge. Short CAR T-cell persistence contributes to this risk; therefore, strategies to improve persistence are needed. METHODS: We conducted a pilot clinical trial of a humanized CD19 CAR T-cell product (huCART19) in children and young adults with relapsed or refractory B-ALL (n = 72) or B-lymphoblastic lymphoma (n = 2), treated in two cohorts: with (retreatment, n = 33) or without (CAR-naive, n = 41) prior CAR exposure. Patients were monitored for toxicity, response, and persistence of huCART19. RESULTS: Seventy-four patients 1-29 years of age received huCART19. Cytokine release syndrome developed in 62 (84%) patients and was grade 4 in five (6.8%). Neurologic toxicities were reported in 29 (39%), three (4%) grade 3 or 4, and fully resolved in all cases. The overall response rate at 1 month after infusion was 98% (100% in B-ALL) in the CAR-naive cohort and 64% in the retreatment cohort. At 6 months, the probability of losing huCART19 persistence was 27% (95% CI, 14 to 41) for CAR-naive and 48% (95% CI, 30 to 64) for retreatment patients, whereas the incidence of B-cell recovery was 15% (95% CI, 6 to 28) and 58% (95% CI, 33 to 77), respectively. Relapse-free survival at 12 and 24 months, respectively, was 84% (95% CI, 72 to 97) and 74% (95% CI, 60 to 90) in CAR-naive and 74% (95% CI, 56 to 97) and 58% (95% CI, 37 to 90) in retreatment cohorts. CONCLUSION: HuCART19 achieved durable remissions with long-term persistence in children and young adults with relapsed or refractory B-ALL, including after failure of prior CAR T-cell therapy.

Electronic symptom monitoring in pediatric patients hospitalized for chemotherapy.

BACKGROUND: Using patient-reported outcomes for symptom monitoring in oncology has resulted in significant benefits for adult patients with cancer. The feasibility of this approach has not been established in the routine care of children with cancer. METHODS: The Pediatric Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (Ped-PRO-CTCAE) is an item library that enables children and caregivers to self-report symptoms. Ten symptom items from the Ped-PRO-CTCAE were uploaded to an online platform. Patients at least 7 years old and their caregivers were prompted by text/email message to electronically self-report daily during a planned hospitalization for chemotherapy administration. Symptom reports were emailed to the clinical team caring for the patient, but no instructions were given regarding the use of this information. Rates of patient participation and clinician responses to reports were systematically tracked. RESULTS: The median age of the participating patients (n = 52) was 11 years (range, 7-18 years). All patients and caregivers completed an initial login, with 92% of dyads completing at least 1 additional symptom assessment during hospitalization (median, 3 assessments; range, 0-40). Eighty-one percent of participating dyads submitted symptom reports on at least half of hospital days, and 54% submitted reports on all hospital days. Clinical actions were taken in response to symptom reports 21% of the time. Most patients felt that the system was easy (73%) and important (79%). Most clinicians found symptom reports easy to understand and useful (97%). CONCLUSIONS: Symptom monitoring using patient-reported outcome measures for hospitalized pediatric oncology patients is feasible and generates data valued by clinicians and patients.

Risk-Adapted Preemptive Tocilizumab to Prevent Severe Cytokine Release Syndrome After CTL019 for Pediatric B-Cell Acute Lymphoblastic Leukemia: A Prospective Clinical Trial.

PURPOSE: 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. METHODS: 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. RESULTS: 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 (P < .001), but persistence was not different (P = .73). Event-free and overall survival were worse in the HTBC (P = .004, P < .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 (P = .18). CONCLUSION: 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.

Beyond the storm - subacute toxicities and late effects in children receiving CAR T cells.

As clinical advances with chimeric antigen receptor (CAR) T cells are increasingly described and the potential for extending their therapeutic benefit grows, optimizing the implementation of this therapeutic modality is imperative. The recognition and management of cytokine release syndrome (CRS) marked a milestone in this field; however, beyond the understanding gained in treating CRS, a host of additional toxicities and/or potential late effects of CAR T cell therapy warrant further investigation. A multicentre initiative involving experts in paediatric cell therapy, supportive care and/or study of late effects from cancer and haematopoietic stem cell transplantation was convened to facilitate the comprehensive study of extended CAR T cell-mediated toxicities and establish a framework for new systematic investigations of CAR T cell-related adverse events. Together, this group identified six key focus areas: extended monitoring of neurotoxicity and neurocognitive function, psychosocial considerations, infection and immune reconstitution, other end organ toxicities, evaluation of subsequent neoplasms, and strategies to optimize remission durability. Herein, we present the current understanding, gaps in knowledge and future directions of research addressing these CAR T cell-related outcomes. This systematic framework to study extended toxicities and optimization strategies will facilitate the translation of acquired experience and knowledge for optimal application of CAR T cell therapies.

Use of Patient-Reported Outcomes to Understand & Measure the Patient Experience of Novel Cell and Gene Therapies.

Patient reported outcomes (PROs) are the gold standard for assessing patients' experience of treatment in oncology, defined in the 21st Century Cures Act as information about patients' experiences with a disease or condition, including the impact of a disease or condition, or a related therapy or clinical investigation on patients' lives; and patient preferences with respect to treatment of their disease or condition [1]. PROs provide a comprehensive assessment of the benefits and risks of new medical products, as well as essential data to inform real-world use. Although RCTs are the ultimate source for information for evaluating products in development, they are not always feasible for rare diseases with few or no effective treatment options available. Thus, it is important to consider other measures that can help to improve the strength of evidence for cell and gene therapies targeting rare indications. While collection of PROs and other patient experience endpoints does not resolve the difficulty of conducting trials in small populations, doing so contributes empirical evidence that informs both product development and patient access. Additionally, including routine collection of PROs in registries may provide supplemental data to further characterize the benefit:risk profile of cell and gene therapies at follow-up times that would be infeasible to operationalize in a clinical trial setting.

Mapping child and adolescent self-reported symptom data to clinician-reported adverse event grading to improve pediatric oncology care and research.

BACKGROUND: Clinicians are the standard source for adverse event (AE) reporting in oncology trials, despite the subjective nature of symptomatic AEs. The authors designed a pediatric patient-reported outcome (PRO) instrument for symptomatic AEs to support the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) (the Pediatric PRO-CTCAE). The current study developed a standardized algorithm that maps all possible Pediatric PRO-CTCAE response patterns to recommended CTCAE grades to improve the accuracy of AE reporting in pediatric oncology trials. METHODS: Two rounds of surveys were administered to experienced cancer clinicians across 9 pediatric hospitals. In round 1, pediatric oncologists assigned CTCAE grades to all 101 possible Pediatric PRO-CTCAE response patterns. The authors evaluated clinician agreement of CTCAE grades across response patterns and categorized each response pattern as having high or low agreement. In round 2, a survey was sent to a larger clinician group to examine clinician agreement among a select set of Pediatric PRO-CTCAE response patterns, and the authors examined how clinical context influenced grade assignment. RESULTS: A total of 10 pediatric oncologists participated in round 1. Of the 101 possible patterns, 89 (88%) had high agreement. The Light weighted kappa was averaged across the 10 oncologists (Light kappa = 0.73; 95% CI, 0.66-0.81). A total of 139 clinicians participated in round 2. High clinician agreement remained for the majority of generic response patterns and the clinical context did not typically change grades but rather improved agreement. CONCLUSIONS: The current study provides a framework for integrating child self-reported symptom data directly into mandated AE reporting in oncology trials. Translating Pediatric PRO-CTCAE responses into clinically meaningful metrics will guide future cancer care and toxicity grading.