Consensus of German Transplant Centers on Hematopoietic Stem Cell Transplantation in Fanconi Anemia

Allogeneic hematopoietic stem cell transplantation (HSCT) is currently the only curative therapy for the severe hematopoietic complications associated with Fanconi anemia (FA). In Germany, it is estimated that 10–15 transplants are performed annually for FA. However, because FA is a DNA repair disorder, standard conditioning regimens confer a high risk of excessive regimen-related toxicities and mortality, and reduced intensity regimens are linked with graft failure in some FA patients. Moreover, development of graft-versus-host disease is a major contributing factor for secondary solid tumors. The relative rarity of the disorder limits HSCT experience at any single center. Consensus meetings were convened to develop a national approach for HSCT in FA. This manuscript outlines current experience and knowledge about HSCT in FA and, based on this analysis, general recommendations reached at these meetings

Vaccination to improve the persistence of CD19CAR gene-modified T cells in relapsed pediatric acute lymphoblastic leukemia

Trials with 2nd generation CD19 chimeric antigen receptors (CAR) T-cells report unprecedented responses but associated with risk of Cytokine Release Syndrome (CRS). Instead, we studied use of donor Epstein Barr virus-specific T-cells (EBV CTL) transduced with a 1st generation CD19CAR, relying on the endogenous T-cell receptor for proliferation. We conducted a multi- center phase I/II study of donor CD19CAR transduced EBV CTL in pediatric ALL. Patients were eligible pre-emptively if they developed molecular relapse (>5 × 10-4) post-1st SCT, or prophylactically post-2nd SCT. An initial cohort showed poor expansion/persistence. We next investigated EBV-directed vaccination to enhance expansion/persistence. 11 patients were treated. No CRS, neurotoxicity or GVHD was observed. At 1 month, 5 patients were in CR (4 continuing, 1 de-novo), 1 PR, 3 had stable disease and 3 no response. At a median follow-up of 12 months, 10 of 11 have relapsed, 2 are alive with disease and 1 alive in CR 3 years. Whilst CD19CAR CTL expansion was poor, persistence was enhanced by vaccination. Median persistence was 0 (range 0-28) days without vaccination compared to 56 (range 0-221) days with vaccination (P=0.06). This study demonstrates feasibility of such multi-center studies and the potential for enhancing persistence with vaccination.Leukemia accepted article preview online, 27 January 2017. doi:10.1038/leu.2017.39

Reduced intensity conditioning in unrelated donor transplantation for refractory cytopenia in childhood

Myelodysplastic syndromes (MDS) are a heterogenous group of acquired hematopoietic stem cell disorders. Refractory cytopenia (RC) is the most common subtype of childhood MDS and hematopoietic stem cell transplantation (HSCT) is the only curative treatment. HSCT following a myeloablative preparative regimen is associated with a low probability of relapse and considerable transplant-related mortality. In the present European Working Groups of MDS pilot study, we investigated whether a reduced intensity conditioning regimen (RIC) is able to offer reduced toxicity without increased rates of graft failure or relapse. Nineteen children with RC were transplanted from an unrelated donor following RIC consisting of fludarabine, thiotepa and anti-thymocyte globulin. Three patients experienced graft failure. Neutrophil and platelet engraftment occurred at a median time of 23 and 30 days, respectively. Cumulative incidence of grade II-IV and grade III and IV acute graft-versus-host disease (GVHD) was 0.48 and 0.13, respectively; three patients developed extensive chronic GVHD. Although infections were the predominant complications, only one patient with extensive chronic GVHD died from infectious complications. Overall and event-free survival at 3 years were 0.84 and 0.74, respectively. In conclusion, our results were comparable to those of patients treated with myeloablative HSCT. Long-term follow-up is needed to demonstrate the expected reduction in long-term sequelae

Charged-coupled devices for charged-particle spectroscopy on OMEGA and NOVA

Charge-coupled devices (CCDs) are to be utilized as charged-particle detectors for rho R and implosion symmetry diagnostics on OMEGA and NOVA. Using a large range of MeV charged particles, comprehensive studies have been performed on several back-illuminated CCDs in order to establish their utility for determining particle energy and identity (e.g., H, D, or T). Issues of signal and noise (i.e., especially from neutrons and gammas interacting with the CCDs) are also being investigated

Design of an electronic charged particle spectrometer to measure <rho R> on inertial fusion experiments

The design and fabrication of a new diagnostic that measures the energy spectra of charged particles from targets on the Omega Upgrade are actively underway. Using seven 512x512 charge coupled devices (CCDs) and a 7.5 kG permanent magnet, this instrument will uniquely determine particle identities and measure particle energies from 1 MeV up to the maximum charged particle energies of interest for rho R measurements (10.6 MeV knock-on tritons, 12.5 MeV knock-on deuterons and 30.8 MeV tertiary protons). The resolution of the diagnostic will be better than 5%. We have tested the response of SITe back-illuminated CCDs to 1.2-13.6 MeV protons from our Cockcroft-Walton accelerator and to alpha particles from an Am-241 source, and the results agree extremely well with predictions. With its high density picture elements, each CCD has 10(5) single-hit detectors. In the case of a low DT yield of 10(9) neutrons, about 100 knock-on charged particles will be detected when the spectrometer aperture is 60 cm from the implosion. Measurements of pR up to 150 mg/cm(2) can be obtained from knock-on D and T spectra, and values up to 300 mg/cm(2) can be determined from secondary proton spectra. The sensitivity of the CCDs to 14 and 2.5 MeV neutrons has been experimentally determined using our Cockcroft-Walton accelerator source and indicates that by incorporating neutron shielding, the signal to neutron noise ratio at a yield of 10(11) will be better than 100:1. Ln the development phases of this program, we plan to utilize CR-39 track detectors concurrently with the CCDs. (C) 1997 American Institute of Physics