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Summary:We measured glomerular filtration rate (GFR), effective renal plasma flow (ERPF) and the concentrating capacity of the kidneys in children after autologous BMT. Twenty-six patients had received TBI in their conditioning regimen and 14 patients had received chemotherapy only. Median follow-up was 10 years. Mean After this initial decrease, GFR and ERPF remained essentially unchanged in both groups. The mean concentrating capacity of the kidneys was normal before and after BMT. In seven patients chronic renal impairment developed after BMT (GFR Ͻ70 ml/min/1.73 m 2 ). All had received TBI. They had also received more nephrotoxic antibiotics than the other patients. We conclude that TBI was the principal cause of deterioration of renal function after BMT, possibly by limiting compensatory hyperperfusion and resulting in a fall in GFR. Antibiotic treatment may have contributed.

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After SCT in childhood, survivors may develop disorders of glucose metabolism. The role of obesity is controversial. We measured insulin sensitivity using the homeostasis model assessment (HOMA) and the frequently sampled i.v. glucose tolerance test (FSIVGTT), as well as body composition using dual-energy X-ray absorptiometry in 18 young adults median 18.2 years after SCT and compared them with matched controls. We also measured growth hormone (GH) secretion, and levels of leptin and adiponectin. HOMA showed insulin resistance in eight patients (44%), as opposed to none of the controls (P=0.008) and FSIVGTT showed a decreased sensitivity index in the patients (2.98 vs 4.54 mU/L/min, P=0.042). Dual energy X-ray absorptiometry showed a higher percentage fat mass in the patients (34.9 vs 24.3%, P=0.011), which correlated inversely with the sensitivity index (r=-0.52, P=0.032). The patients had a lower peak value of GH (GH(max) 9 vs 20.7 mU/L, P=0.002). Time post SCT correlated with percentage fat mass and inversely with GH(max). The patients had higher levels of leptin and lower levels of adiponectin, even after adjustment for fat mass. We propose that the decreased insulin sensitivity may primarily be explained by the adverse body composition, which may owe to long-standing GH deficiency.

B-cell malignancies upregulate the B-cell lymphoma 2 (Bcl-2) family inhibitors of the intrinsic apoptosis pathway, making them therapy resistant. However, small-molecule inhibitors of Bcl-2 family members such as ABT-737 restore a functional apoptosis pathway in cancer cells, and its oral analog ABT-263 (Navitoclax) has entered clinical trials. Gene engineered chimeric antigen receptor (CAR) T cells also show promise in B-cell malignancy, and as they induce apoptosis via the extrinsic pathway, we hypothesized that small-molecule inhibitors of the Bcl-2 family may potentiate the efficacy of CAR T cells by engaging both apoptosis pathways. CAR T cells targeting CD19 were generated from healthy donors as well as from pre-B-ALL (precursor-B acute lymphoblastic leukemia) patients and tested together with ABT-737 to evaluate apoptosis induction in five B-cell tumor cell lines. The CAR T cells were effective even if the cell lines exhibited different apoptosis resistance profiles, as shown by analyzing the expression of apoptosis inhibitors by PCR and western blot. When combining T-cell and ABT-737 therapy simultaneously, or with ABT-737 as a presensitizer, tumor cell apoptosis was significantly increased. In conclusion, the apoptosis inducer ABT-737 enhanced the efficacy of CAR T cells and could be an interesting drug candidate to potentiate T-cell therapy.