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.

Measurable residual disease (MRD) evaluation by multiparameter flow cytometry (MFC) or quantitative polymerase chain reaction methods is an established standard of care for assessing risk of relapse before or after hematopoietic cell transplantation (HCT) for acute lymphoblastic leukemia (ALL). Next-generation sequencing (NGS)–MRD has emerged as a highly effective approach that allows for the detection of lymphoblasts at a level of <1 in 106 nucleated cells, increasing sensitivity of ALL detection by 2 to 3 logs. Early studies have shown superior results compared with MFC and suggest that NGS-MRD may allow for the determination of patients in whom reduced toxicity transplant preparative approaches could be deployed without sacrificing outcomes. Many centers/study groups have implemented immune modulation approaches based on MRD measurements that have resulted in improved outcomes. Challenges remain with NGS-MRD, because it is not commercially available in many countries, and interpretation of results can be complex. Through patient case review, discussion of relevant studies, and detailed expert opinion, we share our approach to NGS-MRD testing before and after HCT in pediatric and adult ALL. Improved pre-HCT risk classification and post-HCT monitoring for relapse in bone marrow and less invasive peripheral blood monitoring by NGS-MRD may lead to alternative approaches to prevent relapse in patients undergoing this challenging procedure.

CD19 chimeric antigen receptor T cells (CD19-CAR) are effective at eradicating bone marrow (BM) B-cell acute lymphoblastic leukemia (B-ALL), but efficacy data for the treatment of extramedullary leukemia are lacking. We conducted a multisite, retrospective review of 308 children and young adults who received CD19-CAR and report efficacy in patients with active central nervous system (CNS) disease (CNS cohort, n = 36), active non-CNS extramedullary disease (EMD; n = 21), or isolated BM disease (iBM; n = 251) at infusion. The overall survival (OS) at 24 months in the iBM, EMD, and CNS cohorts was 71.5% (95% confidence interval [CI], 66.0-77.6), 66.7% (95% CI, 49.3-90.2), and 57.0% (95% CI, 42.6-76.3), respectively (P = .032); the corresponding event-free survival (EFS) was 51.8% (95% CI, 45.8-58.6), 45.8% (95% CI, 28.2-74.4), and 35.2% (95% CI, 22.4-55.3) (P = .035). All patients with isolated EMD (n = 5) achieved complete response and did not relapse. Eight patients (80%) with isolated CNS disease (n = 10) had clearing of the CNS, and 3 (37.5%) subsequently relapsed. Concurrent EMD or CNS disease with high BM disease burden (HD) was associated with inferior outcomes when compared with low BM disease burden (LD) in terms of OS (EMD-HD, 41.7% vs EMD-LD, 100%; P = .005; CNS-HD, 33.3% vs CNS-LD, 92.3%; P = .001) and EFS (EMD-HD, 8.3% vs EMD-LD, 100%; P< .001; CNS-HD, 14.3% vs CNS-LD, 63.6%; P< .001). In summary, CD19-CAR may be an effective option for relapsed/refractory B-ALL with active EMD or CNS disease, but concurrent HD predicts inferior outcomes, prompting consideration of enhanced preinfusion evaluation and treatment.

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a life-threatening monogenic inborn error of immunity caused by pathogenic variants in the FOXP3 gene. In this report, we describe the clinical and immunologic consequences of a novel FOXP3 variant in an infant with refractory IPEX syndrome. Rapid whole-genome sequencing revealed a missense variant c.1050C>G (p.Ile350Met) in the forkhead domain of FOXP3. FOXP3 expression was abrogated in the regulatory T cell (Treg) subset but was maintained at low levels in activated effector T cells. The frequency of Treg-specific demethylated region (TSDR)–demethylated T cells was within normal range at birth, but it increased to pathologically high levels at 2 wk of age, prior to manifestation of disease symptoms. These results support the clinical relevance of the TSDR-demethylated cell percentage in evaluation of disease activity in IPEX. This case highlights a severe form of IPEX syndrome refractory to multiple immunosuppressive agents and the importance of early immunological studies to verify the clinical significance of novel genetic findings.