In October 2017, the FDA granted regular approval to axicabtagene ciloleucel, a CD19-directed chimeric antigen receptor (CAR) T-cell therapy, for treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy. Efficacy was based on complete remission (CR) rate and duration of response (DOR) in 101 adult patients with relapsed or refractory large B-cell lymphoma (median 3 prior systemic regimens) treated on a single-arm trial. Patients received a single infusion of axicabtagene ciloleucel, preceded by lymphodepleting chemotherapy with cyclophosphamide and fludarabine. The objective response rate per independent review committee was 72% [95% confidence interval (CI), 62-81], with a CR rate of 51% (95% CI, 41-62). With a median follow-up of 7.9 months, the median DOR was not reached in patients achieving CR (95% CI, 8.1 months; not estimable, NE), whereas patients with partial remission had an estimated median DOR of 2.1 months (95% CI, 1.3-5.3). Among 108 patients evaluated for safety, serious adverse reactions occurred in 52%. Cytokine release syndrome and neurologic toxicities occurred in 94% and 87% of patients, respectively, leading to implementation of a risk evaluation and mitigation strategy.

Pediatric patient-reported outcome (PRO) data can help inform the U.S. Food and Drug Administration’s (FDA) benefit-risk assessment of cancer therapeutics by quantifying symptom and functional outcomes from the patient’s perspective. This study assessed use of PROs in commercial pediatric oncology trials submitted to FDA for regulatory review. FDA databases were searched to identify pediatric oncology product applications approved between 1997 and 2020. Sponsor-submitted documents were reviewed to determine whether PRO data were collected, which instruments were used, and the quality of collected data (sample size, completion rates, and use of fit-for-purpose instruments). The role of PROs in each trial (endpoint hierarchy) was also recorded, along with whether any PRO endpoints were included in product labeling. Seventeen pediatric oncology applications were reviewed, 4 included PRO data: Denosumab, Tisagenlecleucel, Larotrectinib, and Selumetinib. In these 4 instances, PROs served as exploratory endpoints and were not incorporated in product labeling. Trials collecting PRO data were Phase II or Phase I/II single-arm studies with sample sizes of 28 to 88 patients. Symptomatic Adverse Events were characterized using clinician-reported Common Terminology Criteria for Adverse Events (CTCAE) without additional patient self-report. PROs were infrequently utilized in pediatric cancer registration trials. When used, PRO data were limited by lack of a clear research objective and corresponding prospective statistical analysis plan. Contemporary PRO symptom libraries such as the National Cancer Institute’s Pediatric PRO-CTCAE may provide an opportunity to better evaluate the occurrence and impact of symptomatic Adverse Events, from the patient’s perspective, in pediatric oncology trials.

Current multimodality therapy consisting of surgery, chemotherapy and radiation will fail in approximately 40% of patients with pediatric sarcomas and results in substantial long-term morbidity in those who are cured. Immunotherapeutic regimens for the treatment of solid tumors typically generate antigen-specific responses too weak to overcome considerable tumor burden and tumor suppressive mechanisms and are in need of adjuvant assistance. Previous work suggests that inhibitors of DASH (Dipeptidyl peptidase IV activity and/or structural homologues) enzymes can mediate tumor regression via immune-mediated mechanisms. Here we demonstrate that the DASH inhibitor, ARI-4175, can induce regression and eradication of well-established solid tumors, both as a single agent and as an adjuvant to a dendritic cell (DC) vaccine and adoptive cell therapy (ACT) in mice implanted with the M3-9-M rhabdomyosarcoma (RMS) cell line. Treatment with effective doses of ARI-4175 correlated with recruitment of myeloid (CD11b+) cells, particularly myeloid dendritic cells (DCs), to secondary lymphoid tissues and with reduced frequency of intratumoral monocytic (CD11b+Ly6-ChiLy6-Glo) myeloid-derived suppressor cells. In immunocompetent mice, combining ARI-4175 with a DC vaccine or ACT with tumor-primed T cells produced significant improvements in tumor responses against well-established M3-9-M tumors. In M3-9-M-bearing immunodeficient (Rag1-/-) mice, ACT combined with ARI-4175 produced greater tumor responses and significantly improved survival compared to either treatment alone. These studies warrant the clinical investigation of ARI-4175 for treatment of sarcomas and other malignancies particularly as an adjuvant to tumor vaccines and ACT.

Twenty-seven pediatric residents were assessed for knowledge, attitudes, and behaviors regarding rights of immigrant families. A program documenting immigrant rights was reinforced in the clinic with posters and individual consultations on immigrant children's needs. This brief program was effective in instructing residents on health and nutritional services for immigrant patients.

The seventh multi-stakeholder Paediatric Strategy Forum focused on chimeric antigen receptor (CAR) T-cells for children and adolescents with cancer. The development of CAR T-cells for patients with haematological malignancies, especially B-cell precursor acute lymphoblastic leukaemia (BCP-ALL), has been spectacular. However, currently, there are scientific, clinical and logistical challenges for use of CAR T-cells in BCP-ALL and other paediatric malignancies, particularly in acute myeloid leukaemia (AML), lymphomas and solid tumours. The aims of the Forum were to summarise the current landscape of CAR T-cell therapy development in paediatrics, too identify current challenges and future directions, with consideration of other immune effector modalities and ascertain the best strategies to accelerate their development and availability to children.Although the effect is of limited duration in about half of the patients, anti-CD19 CAR Tcells produce high response rates in relapsed/refractory BCP-ALL and this has highlighted previously unknown mechanisms of relapse. CAR T-cell treatment as first-or second-line

In October 2021, the FDA approved brexucabtagene autoleucel (brexu-cel), a CD19-directed chimeric antigen receptor (CAR) T-cell therapy, for the treatment of adult patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (B-ALL). Approval was based on the phase II portion of ZUMA-3, a single-arm, open-label, multicenter trial that evaluated a single infusion of brexu-cel, preceded by lymphodepleting chemotherapy with cyclophosphamide and fludarabine, in this population. Efficacy was established on the basis of complete remission (CR) within 3 months after infusion and the duration of CR (DOCR). Among 54 patients in the efficacy analysis population, the CR rate was 52% (95% CI: 38, 66) with a median time-to-response of 56 days. With a median follow-up for responders of 7.1 months, the median DOCR was not reached. For all leukapheresed patients in the phase II portion of this trial (n = 71), the CR rate was 41% (95% CI: 29, 53). Among the 78 patients treated with the approved dose of brexu-cel, serious adverse reactions occurred in 79% and fatal adverse reactions occurred in 5% and included cerebral edema and infections. Cytokine release syndrome occurred in 92% (grade ≥3, 26%) and neurologic toxicities occurred in 87% (grade ≥3, 35%), leading to implementation of a risk evaluation and mitigation strategy (REMS). Postmarketing study with 15 years of follow-up will further evaluate long-term safety in adult patients with relapsed or refractory B-ALL.

Background: With recent FDA approvals of CAR T cell therapy for the treatment of relapsed/refractory aggressive B cell non-Hodgkin lymphoma, an increasing number of older adults will be treated with this therapy. An improved understanding of the safety of CAR T cell therapy in this population is important to inform clinical decision making for the treatment of older subjects. Methods: Data from two prospective single arm studies (n=214) of two approved CART cell products for the treatment of relapsed/refractory lymphoma were pooled and analyzed. Rates of cytokine release syndrome (CRS), as well as severity and treatment modalities (oxygen, vasopressor support, tocilizumab and steroids) were pooled and analyzed by age. Selected neuropsychiatric events were pooled and analyzed by age. Results: Age was balanced between the two studies. The median age of subjects was 58 years (range 22-76 years). Of the 214 total subjects, 24% were 65 years of age and older. CRS and neurotoxicity were evaluated in the subjects who received treatment with CAR T cell therapy. (Table 1). *Two studies employed different grading methods for CRS; Lee's criteria (Lee DW et al, Blood 2014) and U Penn criteria (Porter DL et al, Blood 2014) Conclusions: This exploratory analysis suggests overall similar rates of CRS and grade 2 and higher CRS in subjects less than 65 years as compared to 65 years of age and older. There appears to be an overall higher rate of encephalopathy and grade 3 and higher delirium/encephalopathy in adults 65 years and older compared to less than 65 years of age. The inclusion of greater numbers of patients ≥ 65 years of age in clinical trials will further inform clinicians about the safety and efficacy of CAR T cell therapy in older adults. Table 1: Adverse Events by Age in subjects treated with CART cell therapy Disclosures No relevant conflicts of interest to declare.

Introduction: In recent years, there has been increased interest in patient experience data, including PROs. To determine how and where PRO data are being assessed and communicated as part of approval of a marketing application, we examined approvals in the Center of Drugs Evaluation and Research in the Office of Hematology and Oncology Products as well as the Center for Biologics Evaluation and Research. Here we report on PRO data from malignant and benign hematology indications. Method: New Molecular Entity (NME) and Supplemental applications with new indications approved between 2017 and 2018 were examined. We reviewed sponsor's clinical study reports (CSRs) for inclusion of PRO data. We assessed FDA review of this data by determining how often PRO data were incorporated in the Prescribing Information (label) and/or final FDA Clinical Reviews. Results: From 2017 to 2018 a total of 31 NMEs and 33 supplemental applications were approved for benign and malignant hematology indications (Figure 1). Of the 10 benign hematology NMEs and BLAs approved, 3 (30%) contained PRO data in the sponsor's CSR, and FDA included the PRO data in all three FDA clinical reviews with one application (Emicizumab) having PRO data incorporated in the FDA product labeling. Emicizumab's label captured disease symptoms and physical functioning, prespecified secondary endpoints in the trial. Of the 15 malignant hematology NMEs and BLAs approved, 7 (47%) contained PRO data in the sponsor's CSR. Of the 7 submissions that contained PRO data, 6 (86%) included PRO data in the FDA clinical review and PRO data were incorporated into the label for one application. Rituxan Hycela's label captured patient preference supported by a large randomized clinical trial with preference as the primary objective. Of the 8 supplemental indications for benign hematology, 3 (38%) of the applications contained PRO data in the sponsor's CSR and FDA included the PRO in all three FDA clinical reviews with one application (Feraheme) having PRO data incorporated in the FDA product labeling. Feraheme captured descriptive disease symptom data. Of the 20 applications submitted for supplemental indications for hematologic malignancies, 13 (65%) contained PRO data in the sponsor's CSR. Twelve of the 13 applications that contained PRO data (92%) had this data discussed in the FDA clinical review, and one application (ibrutinib) incorporated PRO data in FDA product labeling. Ibrutinib captured descriptive disease symptom data. Discussion: When PRO data were included in efficacy submissions to FDA, a large portion of FDA clinical reviews included discussion of this information. PRO data were included in the label more frequently for benign indications compared to malignant indications. When in the label, PRO data tended to refer to disease symptoms and physical function, both of which have been specified as being part of FDA's proposed core outcome set for cancer. Figure 1 Disclosures No relevant conflicts of interest to declare.