Correction of both immunodeficiency and hypoparathyroidism by thymus transplantation in complete DiGeorge syndrome.

Combined immune deficiency due to athymia in patients with complete DiGeorge syndrome can be corrected by allogeneic thymus transplantation. Hypoparathyroidism is a frequent concomitant clinical problem in these patients, which persists after thymus transplantation. Cotransplantation of allogeneic thymus and parental parathyroid tissue has been attempted but does not achieve durable correction of the patients' hypoparathyroidism due to parathyroid graft rejection. Surprisingly, we observed correction of hypoparathyroidism in one patient after thymus transplantation. Immunohistochemical analysis and fluorescence in situ hybridization confirmed the presence of allogeneic parathyroid tissue in the patient's thymus transplant biopsy. Despite a lack of HLA-matching between thymus donor and recipient, the reconstituted immune system displays tolerance toward the thymus donor. Therefore we expect this patient's hypoparathyroidism to be permanently cured. It is recognised that ectopic parathyroid tissue is not infrequently found in the thymus. If such thymuses could be identified, we propose that their use would offer a compelling approach to achieving lasting correction of both immunodeficiency and hypoparathyroidism.

Molecular remission of infant B-ALL after infusion of universal TALEN gene-edited CAR T cells.

Autologous T cells engineered to express chimeric antigen receptor against the B cell antigen CD19 (CAR19) are achieving marked leukemic remissions in early-phase trials but can be difficult to manufacture, especially in infants or heavily treated patients. We generated universal CAR19 (UCART19) T cells by lentiviral transduction of non-human leukocyte antigen-matched donor cells and simultaneous transcription activator-like effector nuclease (TALEN)-mediated gene editing of T cell receptor α chain and CD52 gene loci. Two infants with relapsed refractory CD19+ B cell acute lymphoblastic leukemia received lymphodepleting chemotherapy and anti-CD52 serotherapy, followed by a single-dose infusion of UCART19 cells. Molecular remissions were achieved within 28 days in both infants, and UCART19 cells persisted until conditioning ahead of successful allogeneic stem cell transplantation. This bridge-to-transplantation strategy demonstrates the therapeutic potential of gene-editing technology.

BCR/ABL amplification in chronic myelocytic leukemia blast crisis following imatinib mesylate administration.

The onset of accelerated phase or blast crisis of chronic myelocytic leukemia (CML) is usually associated with the acquisition of new chromosome abnormalities in addition to the t(9;22)(q34;q11) that is characteristic of the chronic phase CML. We describe the cytogenetic and molecular genetic findings in two cases of myelocytic blast crisis of CML, one occurring 6 months after commencing treatment with the ABL-specific tyrosine kinase inhibitor imatinib mesylate (STI571, Glivec, or Gleevec) and the second treated with imatinib mesylate for established blast crisis. In both cases, multiple secondary cytogenetic abnormalities were observed at transformation, with homogeneously staining regions that were shown to contain BCR/ABL amplification by fluorescence in situ hybridization appearing after imatinib mesylate administration. BCR/ABL amplification is emerging as an important mechanism of acquired resistance to imatinib mesylate.