In 2017, an autologous chimeric antigen receptor (CAR) T cell therapy indicated for children and young adults with relapsed and/or refractory CD19⁺ acute lymphoblastic leukaemia became the first gene therapy to be approved in the USA. This innovative form of cellular immunotherapy has been associated with remarkable response rates but is also associated with unique and often severe toxicities, which can lead to rapid cardiorespiratory and/or neurological deterioration. Multidisciplinary medical vigilance and the requisite health-care infrastructure are imperative to ensuring optimal patient outcomes, especially as these therapies transition from research protocols to standard care. Herein, authors representing the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network Hematopoietic Stem Cell Transplantation (HSCT) Subgroup and the MD Anderson Cancer Center CAR T Cell Therapy-Associated Toxicity (CARTOX) Program have collaborated to provide comprehensive consensus guidelines on the care of children receiving CAR T cell therapy.

Minimal residual disease (MRD) refers to a chemotherapy/radiotherapy-surviving leukemia cell population that gives rise to relapse of the disease. The detection of MRD is critical for predicting the outcome and for selecting the intensity of further treatment strategies. The development of various new diagnostic platforms, including next-generation sequencing (NGS), has introduced significant advances in the sensitivity of MRD diagnostics. Here, we review current methods to diagnose MRD through phenotypic marker patterns or differential gene patterns through analysis by flow cytometry (FCM), polymerase chain reaction (PCR), real-time quantitative polymerase chain reaction (RQ-PCR), reverse transcription polymerase chain reaction (RT-PCR) or NGS. Future advances in clinical procedures will be molded by practical feasibility and patient needs regarding greater diagnostic sensitivity.

Patients with B-lineage acute lymphoblastic leukemia (ALL) are at high-risk for relapse after allogeneic hematopoietic cell transplantation (HCT). We conducted a single-center phase 2 study evaluating the feasibility of 4 cycles of blinatumomab administered every 3 months during the first year after HCT in an effort to mitigate relapse in high-risk ALL patients. Twenty-one of 23 enrolled patients received at least 1 cycle of blinatumomab and were included in the analysis. The median time from HCT to the first cycle of blinatumomab was 78 days (range, 44 to 105). Twelve patients (57%) completed all 4 treatment cycles. Neutropenia was the only grade 4 adverse event (19%). Rates of cytokine release (5% G1) and neurotoxicity (5% G2) were minimal. The cumulative incidence of acute graft-versus-host disease (GVHD) grades 2 to 4 and 3 to 4 were 33% and 5%, respectively; 2 cases of mild (10%) and 1 case of moderate (5%) chronic GVHD were noted. With a median follow-up of 14.3 months, the 1-year overall survival (OS), progression-free survival (PFS), and nonrelapse mortality (NRM) rates were 85%, 71%, and 0%, respectively. In a matched analysis with a contemporary cohort of 57 patients, we found no significant difference between groups regarding blinatumomab’s efficacy. Correlative studies of baseline and posttreatment samples identified patients with specific T-cell profiles as “responders” or “nonresponders” to therapy. Responders had higher proportions of effector memory CD8 T-cell subsets. Nonresponders were T-cell deficient and expressed more inhibitory checkpoint molecules, including T-cell immunoglobulin and mucin domain 3 (TIM3). We found that blinatumomab postallogeneic HCT is feasible, and its benefit is dependent on the immune milieu at time of treatment. This paper is posted on ClinicalTrials.gov, study ID: NCT02807883.

Transplant-associated thrombotic microangiopathy (TA-TMA) is a severe complication of hematopoietic stem cell transplantation (HSCT). A single-center prospective screening study has shown that the incidence of TA-TMA is much higher than prior retrospective studies that did not systematically screen. These data have not been replicated in a multicenter study. Our objective was to determine the incidence and risk factors for TA-TMA and compare outcomes of pediatric HSCT patients with and without TA-TMA. Patients were prospectively screened for TA-TMA at participating centers using a simple to implement and inexpensive strategy from the start of the preparative regimen through day +100. TA-TMA was diagnosed if ≥4 of 7 laboratory/clinical markers diagnostic for TA-TMA were present concurrently or if tissue histology showed TA-TMA. A total of 614 patients (359 males; 58%) received prospective TA-TMA screening at 13 pediatric centers. TA-TMA was diagnosed in 98 patients (16%) at a median of 22 days (interquartile range, 14-44) posttransplant. Patients with TA-TMA had significantly increased bloodstream infections (38% [37/98] vs 21% [107/51], P ≤ .001), mean total hospitalization days (68; 95% confidence interval [CI], 63-74 vs 43; 95% CI, 41-45; P ≤ .001), and number of days spent in the intensive care unit (10.1; 95% CI, 6.4-14; vs 1.6; 95% CI, 1.1-2.2; P ≤ .001) in the first 100 days after HSCT compared with patients without TA-TMA. Overall survival was significantly higher in patients without TA-TMA (93%; 490/516) compared with patients with TA-TMA (78%; 76/98) (P ≤ .001). These data support the need for systematic screening for TA-TMA and demonstrate the feasibility and efficacy of an easy to implement strategy to do so.

Hodgkin lymphoma, a hematological malignancy of lymphoid origin that typically arises from germinal-center B cells, has an excellent overall prognosis. However, the treatment of patients who relapse or develop resistant disease still poses a substantial clinical and research challenge, even though current risk-adapted and response-based treatment techniques produce overall survival rates of over 95%. The appearance of late malignancies after the successful cure of primary or relapsed disease continues to be a major concern, mostly because of high survival rates. Particularly in pediatric HL patients, the chance of developing secondary leukemia is manifold compared to that in the general pediatric population, and the prognosis for patients with secondary leukemia is much worse than that for patients with other hematological malignancies. Therefore, it is crucial to develop clinically useful biomarkers to stratify patients according to their risk of late malignancies and determine which require intense treatment regimens to maintain the ideal balance between maximizing survival rates and avoiding late consequences. In this article, we review HL’s epidemiology, risk factors, staging, molecular and genetic biomarkers, and treatments for children and adults, as well as treatment-related adverse events and the late development of secondary malignancies in patients with the disease.