Donor Lymphocyte Infusions After Allogeneic Stem Cell Transplantation in Acute Leukemia: A Survey From the Gruppo Italiano Trapianto Midollo Osseo (GITMO)

We conducted a retrospective multicenter study including pediatric and adult patients with acute leukemia (AL) who received donor lymphocyte infusions (DLIs) after allogeneic hematopoietic stem cell transplantation (HCT) between January 1, 2010 and December 31, 2015, in order to determine the efficacy and toxicity of the immune treatment. Two hundred fifty-two patients, median age 45.1 years (1.6\u201373.4), were enrolled from 34 Italian transplant centers. The underlying disease was acute myeloid leukemia in 180 cases (71%). Donors were HLA identical or 1 locus mismatched sibling (40%), unrelated (40%), or haploidentical (20%). The first DLI was administered at a median time of 258 days (55\u20133,784) after HCT. The main indication for DLI was leukemia relapse (73%), followed by mixed chimerism (17%), and pre-emptive/prophylactic use (10%). Ninety-six patients (38%) received one single infusion, whereas 65 (26%), 42 (17%), and 49 patients (19%) received 2, 3, or 654 infusions, respectively, with a median of 31 days between two subsequent DLIs. Forty percent of evaluable patients received no treatment before the first DLI, whereas radiotherapy, conventional chemotherapy or targeted treatments were administered in 3, 39, and 18%, respectively. In informative patients, a few severe adverse events were reported: grade III\u2013IV graft versus host disease (GVHD) (3%), grade III\u2013IV hematological toxicity (11%), and DLI-related mortality (9%). Forty-six patients (18%) received a second HCT after a median of 232 days (32\u20131,390) from the first DLI. With a median follow-up of 461 days (2\u20133,255) after the first DLI, 1-, 3-, and 5- year overall survival (OS) of the whole group from start of DLI treatment was 55, 39, and 33%, respectively. In multivariate analysis, older recipient age, and transplants from haploidentical donors significantly reduced OS, whereas DLI for mixed chimerism or as pre-emptive/prophylactic treatment compared to DLI for AL relapse and a schedule including more than one DLI significantly prolonged OS. This GITMO survey confirms that DLI administration in absence of overt hematological relapse and multiple infusions are associated with a favorable outcome in AL patients. DLI from haploidentical donors had a poor outcome and may represent an area of further investigation

Multicenter Experience Using Total Lymphoid Irradiation and Antithymocyte Globulin as Conditioning for Allografting in Hematological Malignancies

A non myeloablative conditioning with total lymphoid irradiation (TLI) and antithymocyte globulin (ATG) was shown to protect against graft-versus-host disease (GVHD). To evaluate the effects of TLI-ATG in a multicenter study, 45 heavily pretreated patients, median age 51, with lymphoid (n = 38) and myeloid (n = 7) malignancies were enrolled at 9 centers. Twenty-eight patients (62%) received at least 3 lines of treatment before allografting, and 13 (29%) had refractory/relapsed disease at the time of transplantation. Peripheral blood hematopoietic cells were from HLA identical sibling (n = 30), HLA-matched (n = 9), or 1 antigen HLA-mismatched (n = 6) unrelated donors. A cumulative TLI dose of 8 Gy was administered from day -11 through -1 with ATG at the dose of 1.5 mg/kg/day (from day -11 through -7). GVHD prophylaxis consisted of cyclosporine and mycophenolate mofetil. Donor engraftment was reached in 95% of patients. Grade II to IV acute GVHD (aGVHD) developed in 6 patients (13.3%), and in 2 of these patients, it developed beyond day 100. Incidence of chronic GVHD (cGVHD) was 35.8%. One-year nonrelapse mortality was 9.1%. After a median follow-up of 28 months (range, 3-57 months) from transplantation, median overall survival was not reached, whereas median event-free survival was 20 months. This multicenter experience confirms that TLI-ATG protects against GVHD and maintains graft-vs-tumor effects

Busulfan or Treosulfan Conditioning Platform for Allogeneic Stem Cell Transplantation in Patients Aged >60 y with Acute Myeloid Leukemia/Myelodysplastic Syndrome: A Subanalysis of the GITMO AlloEld Study

Background. The conditioning regimens with different alkylators at different doses can influence the outcome of allogeneic stem cell transplantation (SCT), but conclusive data are missing. Methods. With the aim to analyze real-life allogeneic SCTs performed in Italy between 2006 and 2017 in elderly patients (aged >60 y) with acute myeloid leukemia or myelodysplastic syndrome, we collected 780 first transplants data. For analysis purposes, patients were grouped according to the type of alkylator included in the conditioning (busulfan [BU]-based; n = 618; 79%; treosulfan [TREO]-based; n=162; 21%). Results. No significant differences were observed in nonrelapse mortality, cumulative incidence of relapse, and overall survival, although in the TREO-based group, we observed a greater proportion of elderly patients (P < 0.001); more active diseases at the time of SCT (P < 0.001); a higher prevalence of patients with either hematopoietic cell transplantation-comorbidity index ≥3 (P < 0.001) or a good Karnofsky performance status (P = 0.025); increased use of peripheral blood stem cells as graft sources (P < 0.001); and greater use of reduced intensity conditioning regimens (P = 0.013) and of haploidentical donors (P < 0.001). Moreover, the 2-y cumulative incidence of relapse with myeloablative doses of BU was significantly lower than that registered with reduced intensity conditioning (21% versus 31%; P = 0.0003). This was not observed in the TREO-based group. Conclusions. Despite a higher number of risk factors in the TREO group, no significant differences were observed in nonrelapse mortality, cumulative incidence of relapse, and overall survival according to the type of alkylator, suggesting that TREO has no advantage over BU in terms of efficacy and toxicity in acute myeloid leukemia and myelodysplastic syndrome

Ni/SiO2-Al2O3 catalysts for CO2 methanation: Effect of La2O3 addition

Ni-based catalysts, 13.5 Ni wt.%, with enhanced thermal stability and catalytic performance for CO2 methanation have been synthesized with different La2O3 loadings. Catalysts have been extensively characterised by: XRD, IR, H2-TPR, IPA-TPD, UV\u2013vis-NIR, FE-SEM and tested in CO2 methanation. SiO2 addition to Al2O3 support decreases the activity for CO2 methanation, while lanthanum acts as suitable promoter by strongly increasing catalytic performances. Silica presence successfully inhibits the formation of crystalline perovskites phases, stabilizes support morphology, and allows the introduction of high La2O3 loadings, allowing a better control of acid-base properties. 37 % wt. La2O3 addition gives rise to even higher performances than those previously observed, i.e. 83 % CH4 yield at 573 K. Reaction orders for CO2 and H2 have been determined; La- addition is confirmed to be responsible for a reduction in the CO2 reaction order, suggesting a stronger CO2 adsorption and the possible role of these species as a reactant reservoirs

QuantiFERON (R)-CMV for immune-monitoring after allogeneic stem cell transplantation: preliminary data

We studied the application of Quantiferon CMV as monitoring of CMV riactivation after bone marrow transplantatio

Human Anti Cancer Cytokine Induced Killer Cells and TheirInteraction With the Host Immune System

Cytokine-induced killer cells are in vitro expanded cells used in adoptive therapy for the treatment of solid and hematopoietic tumors. They express the T cell markers CD3 and CD56 and lack the cytotoxicity machinery of natural killer (NK) cells. Several papers have described the interactions between cytokine-induced killer cells and tumor targets. We focused our attention on the specific interplay between cytokine-induced killer cells and peripheral blood mononuclear cells in order to elucidate the possible consequences of this interaction. Cytokine induced killer cells were generated from peripheral blood mononuclear cells of 5 healthy donors by 21 days ex vivo expansion after priming with interferon gamma and monoclonal anti-CD3 antibody in medium supplemented with interleukin-2. After the expansion, cells were stained with CFSE and co-cultured with autologous peripheral blood mononuclear cells for 5 hours. The co-cultures were then stained with anti-CD14 antibody for monocytes, anti-CD19 antibody for B lymphocytes, anti-CD56 antibody as activation marker, anti-CD3, anti-CD4 and anti-CD8 for lymphocytes subpopulations, and analyzed by means of Imagestream and cytofluorimetric techniques. We observed that after the 5 hours incubation, the percentage of CFSE-CD14 double positive cells increased in a ratio dependent manner. The physical interaction was confirmed by Imagestream technique. We detected a small number of double positive CFSE-CD19 cells and we noticed a decrease in the total number of CD19 cells suggesting a possible specific cytotoxic activity against B cells. We confirmed this in vivo noticing that two patients undergoing CIK therapy showed a transient reduction in number of circulating CD19. The direct toxicity versus healthy circulating B cells could explain why this therapy leads to the maximum therapeutic benefit in the treatment of hematological malignancies. We noticed as well in vitro a CD56 increased expression on CIK cells that could be explained by the increased activation after monocyte contact. Further investigation is required to elucidate whether this activation could be different in the presence of suppressive monocytes. Our results could be of crucial relevance especially in the setting of solid tumor where the strong immunosuppressive context could negatively influence the activation status of the adoptively infused cells