Building blocks for institutional preparation of CTL019 delivery.

Chimeric antigen receptor (CAR) T-cell therapy is an investigational immunocellular therapy that reprograms a patient's cytotoxic T cells to engage and eliminate malignant cells. CAR T-cell therapies targeting the CD19 antigen have demonstrated high efficacy in clinical trials for patients with B-cell malignancies and may potentially be available on a broader scale in the future. CAR T-cell therapy begins with the collection of a sufficient number of T cells from a patient's peripheral blood through leukapheresis. Several factors must be considered when patients undergo leukapheresis for CAR T-cell therapy, including age and prior therapies. The leukapheresis material is shipped to a manufacturing facility, followed by return of the CAR T cells to the treatment center. Careful coordination of a multidisciplinary team composed of physicians, nurses, pharmacists and other hospital personnel is critical for the proper care of the patient before, during and after CAR T-cell therapy. CAR T-cell therapy has been associated with adverse events (AEs) such as cytokine release syndrome, which requires rapid attention by the emergency department, intensive care unit and hospital pharmacy. In this review, we discuss several aspects of institutional preparation for leukapheresis, CAR T-cell infusion and AE management based on our experience with clinical trials of the CD19 CAR T-cell therapy CTL019.

Pooled safety analysis of tisagenlecleucel in children and young adults with B cell acute lymphoblastic leukemia.

BACKGROUND: Tisagenlecleucel, an anti-CD19 chimeric antigen receptor T cell therapy, has demonstrated efficacy in children and young adults with relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL) in two multicenter phase 2 trials (ClinicalTrials.gov, NCT02435849 (ELIANA) and NCT02228096 (ENSIGN)), leading to commercialization of tisagenlecleucel for the treatment of patients up to age 25 years with B-ALL that is refractory or in second or greater relapse. METHODS: A pooled analysis of 137 patients from these trials (ELIANA: n=79; ENSIGN: n=58) was performed to provide a comprehensive safety profile for tisagenlecleucel. RESULTS: Grade 3/4 tisagenlecleucel-related adverse events (AEs) were reported in 77% of patients. Specific AEs of interest that occurred ≤8 weeks postinfusion included cytokine-release syndrome (CRS; 79% (grade 4: 22%)), infections (42%; grade 3/4: 19%), prolonged (not resolved by day 28) cytopenias (40%; grade 3/4: 34%), neurologic events (36%; grade 3: 10%; no grade 4 events), and tumor lysis syndrome (4%; all grade 3). Treatment for CRS included tocilizumab (40%) and corticosteroids (23%). The frequency of neurologic events increased with CRS severity (p<0.001). Median time to resolution of grade 3/4 cytopenias to grade ≤2 was 2.0 (95% CI 1.87 to 2.23) months for neutropenia, 2.4 (95% CI 1.97 to 3.68) months for lymphopenia, 2.0 (95% CI 1.87 to 2.27) months for leukopenia, 1.9 (95% CI 1.74 to 2.10) months for thrombocytopenia, and 1.0 (95% CI 0.95 to 1.87) month for anemia. All patients who achieved complete remission (CR)/CR with incomplete hematologic recovery experienced B cell aplasia; however, as nearly all responders also received immunoglobulin replacement, few grade 3/4 infections occurred >1 year postinfusion. CONCLUSIONS: This pooled analysis provides a detailed safety profile for tisagenlecleucel during the course of clinical trials, and AE management guidance, with a longer follow-up duration compared with previous reports.

Can Parents Refuse a Potentially Lifesaving Transplant for Severe Combined Immunodeficiency?

If untreated, most children with severe combined immunodeficiency disorder (SCID) will die of complications of infection within the first 2 years of life. Early hematopoietic stem cell transplant (HSCT) is the current standard of care for this disease. Although potentially lifesaving, prognosis of HSCT in SCID is variable depending on a number of host and donor factors. Of the survivors, many develop secondary problems such as chronic graft-versus-host disease or even second malignancies. Posttransplant care is complex and requires great effort from parents to adhere to difficult treatment regimens. In this article, we address the difficult ethical question of what to do if parents choose not to have their child with SCID undergo HSCT but prefer palliative care.

Liver transplantation for severe hepatic graft-versus-host disease: an analysis of aggregate survival data.

Graft-versus-host disease (GVHD) often occurs after bone marrow transplantation (BMT). GVHD may lead to cirrhosis or complete destruction of the bile ducts, and few effective treatment options exist for such cases. Orthotopic liver transplantation (OLT) has been described as an option, but to date the patient survival, graft survival, and GVHD recurrence rates after OLT have been unknown. Cases of OLT for GVHD were accumulated from several sources: (1) cases of OLT performed at a single institution, (2) the English-language medical literature, and (3) the United Network for Organ Sharing (UNOS) liver transplant registry. Descriptive data were derived from pre- and post-OLT information; survival analysis was performed using the Kaplan-Meier method. One case of OLT for GVHD after BMT was found at our institution, and another 6 cases were previously reported in the literature. Extrahepatic GVHD recurred in 2 cases, but no recurrence of hepatic GVHD was reported. The UNOS registry contained an additional 73 patients who underwent OLT for hepatic GVHD. The 1- and 5-year actuarial patient survival rates were 72.4% and 62.9%, respectively. Although 4 patients required retransplantation, no deaths or retransplants were attributed to the recurrence of hepatic GVHD. OLT is an effective treatment for hepatic GVHD after BMT or non-liver organ transplant. Long-term disease-free survival is obtainable in these cases, and recurrence of hepatic GVHD has not been reported. These findings suggest that OLT should be considered as an effective treatment option for cases of hepatic GVHD recalcitrant to medical treatment.