Genotype, oxidase status, and preceding infection or autoinflammation do not affect allogeneic HCT outcomes for CGD.

Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by life-threatening infections and inflammatory conditions. Hematopoietic cell transplantation (HCT) is the definitive treatment for CGD, but questions remain regarding patient selection and impact of active disease on transplant outcomes. We performed a multi-institutional retrospective and prospective study of 391 patients with CGD treated either conventionally (non-HCT) enrolled from 2004 to 2018 or with HCT from 1996 to 2018. Median follow-up after HCT was 3.7 years with a 3-year overall survival of 82% and event-free survival of 69%. In a multivariate analysis, a Lansky/Karnofsky score <90 and use of HLA-mismatched donors negatively affected survival. Age, genotype, and oxidase status did not affect outcomes. Before HCT, patients had higher infection density, higher frequency of noninfectious lung and liver diseases, and more steroid use than conventionally treated patients; however, these issues did not adversely affect HCT survival. Presence of pre-HCT inflammatory conditions was associated with chronic graft-versus-host disease. Graft failure or receipt of a second HCT occurred in 17.6% of the patients and was associated with melphalan-based conditioning and/or early mixed chimerism. At 3 to 5 years after HCT, patients had improved growth and nutrition, resolved infections and inflammatory disease, and lower rates of antimicrobial prophylaxis or corticosteroid use compared with both their baseline and those of conventionally treated patients. HCT leads to durable resolution of CGD symptoms and lowers the burden of the disease. Patients with active infection or inflammation are candidates for transplants; HCT should be considered before the development of comorbidities that could affect performance status. This trial was registered at www.clinicaltrials.gov as #NCT02082353.

How I treat newly diagnosed and refractory T-cell acute lymphoblastic lymphoma in children and young adults.

T-cell lymphoblastic lymphoma (T-LLy) and T-cell acute lymphoblastic leukemia (T-ALL) have historically been considered a spectrum of the same disease. However, recent evidence demonstrating differential responses to chemotherapy raise the possibility that T-LLy and T-ALL are distinct clinical and biologic entities. Here, we examine differences between the 2 diseases and use illustrative cases to highlight key recommendations on how to best treat patients with newly diagnosed and relapsed/refractory T-LLy. We discuss results of recent clinical trials incorporating use of nelarabine and bortezomib, choice of induction steroid, role of cranial radiotherapy, and risk stratification markers to identify patients at highest risk of relapse and to further refine current treatment strategies. Because prognosis for relapsed or refractory T-LLy patients is poor, we discuss ongoing investigations incorporating novel therapies, including immunotherapeutics, into upfront and salvage regimens and the role of hematopoietic stem cell transplantation.

HLH-like toxicities predict poor survival after the use of tisagenlecleucel in children and young adults with B-ALL.

Chimeric antigen receptor-associated hemophagocytic lymphohistiocytosis (HLH)-like toxicities (LTs) involving hyperferritinemia, multiorgan dysfunction, coagulopathy, and/or hemophagocytosis are described as occurring in a subset of patients with cytokine release syndrome (CRS). Case series report poor outcomes for those with B-cell acute lymphoblastic leukemia (B-ALL) who develop HLH-LTs, although larger outcomes analyses of children and young adults (CAYAs) with B-ALL who develop these toxicities after the administration of commercially available tisagenlecleucel are not described. Using a multi-institutional database of 185 CAYAs with B-ALL, we conducted a retrospective cohort study including groups that developed HLH-LTs, high-grade (HG) CRS without HLH-LTs, or no to low-grade (NLG) CRS without HLH-LTs. Primary objectives included characterizing the incidence, outcomes, and preinfusion factors associated with HLH-LTs. Among 185 CAYAs infused with tisagenlecleucel, 26 (14.1%) met the criteria for HLH-LTs. One-year overall survival and relapse-free survival were 25.7% and 4.7%, respectively, in those with HLH-LTs compared with 80.1% and 57.6%, respectively, in those without. In multivariable analysis for death, meeting criteria for HLH-LTs carried a hazard ratio of 4.61 (95% confidence interval, 2.41-8.83), controlling for disease burden, age, and sex. Patients who developed HLH-LTs had higher pretisagenlecleucel disease burden, ferritin, and C-reactive protein levels and lower platelet and absolute neutrophil counts than patients with HG- or NLG-CRS without HLH-LTs. Overall, CAYAs with B-ALL who developed HLH-LTs after tisagenlecleucel experienced high rates of relapse and nonrelapse mortality, indicating the urgent need for further investigations into prevention and optimal management of patients who develop HLH-LTs after tisagenlecleucel.

Tisagenlecleucel for treatment of children and young adults with relapsed/refractory B-cell acute lymphoblastic leukemia.

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.