Giorgia Mancini

Low-dose Gemtuzumab-Ozogamicin as post-consolidation therapy in elderly patients with acute myeloid leukaemia: a pilot study

T., Heldmann, K., Carmi, R., Parvari, R., Beit-Or, H., Goldman, B., Peleg, L., Levy-Lahad, E., Renbaum, P., Legum, S., Shomrat, R., Yeger, H., Benbenisti, D., Navon, R., Dror, V., Shohat, M., Magal, N., Navot, N. & Eyal, N. (1998) Prevalence of glucocerebrosidase mutations in the Israeli Askenazi Jewish poulation. Human Mutations, 12, 240–244. Pocovi, M., Cenarro, A., Civeira, F., Torralba, M.A., Perez-Calvo, J.I., Mozas, P., Giraldo, P., Girait, M., Myers, R.H., Cupples, L.A. & Ordovas, J.M. (1998) Beta –glucocerebrosidase gene locus as a link for Gaucher’s disease and familial hypo-alfa-lipoproteinaemia. Lancet, 351, 1919–1923.

Conditioning regimen with BCNU, etoposide, cytarabine and melphalan plus amifostine for outpatient autologous stem cell transplant: feasibility and outcome in 97 patients with lymphoma.

BEAM (BCNU, etoposide, cytarabine, melphalan) is standard conditioning for autologous stem cell transplant (ASCT) in Hodgkin disease (HD) and in non-Hodgkin lymphoma (NHL) [1]. Growth factors (GFs)...

Immunomodulatory Effects of Tyrosine Kinase Inhibitors (TKIs) in Vitro and in Vivo Study.

Pathogenesis of chronic graft-versus-host disease (cGVHD) is incompletely defined, involving donor-derived CD4 and CD8-positive T lymphocytes as well as B cells. Standard treatment is lacking for steroid-dependent/refractory cases; therefore, the potential usefulness of tyrosine kinase inhibitors (TKIs) has been suggested, based on their potent antifibrotic effect. However, TKIs seem to have pleiotropic activity. We sought to evaluate the in vitro and in vivo impact of different TKIs on lymphocyte phenotype and function. Peripheral blood mononuclear cells (PBMCs) from healthy donors were cultured in the presence of increasing concentrations of nilotinib, imatinib, dasatinib, and ponatinib; in parallel, 44 PBMC samples from 15 patients with steroid-dependent/refractory cGVHD treated with nilotinib in the setting of a phase I/II trial were analyzed at baseline, after 90, and after 180 days of therapy. Flow cytometry was performed after labeling lymphocytes with a panel of monoclonal antibodies (CD3, CD4, CD16, CD56, CD25, CD19, CD45RA, FoxP3, CD127, and 7-amino actinomycin D). Cytokine production was assessed in supernatants of purified CD3+ T cells and in plasma samples from nilotinib-treated patients. Main T lymphocyte subpopulations were not significantly affected by therapeutic concentrations of TKIs in vitro, whereas proinflammatory cytokine (in particular, IL-2, IFN-γ, tumor necrosis factor-α, and IL-10) and IL-17 production showed a sharp decline. Frequency of T regulatory, B, and natural killer (NK) cells decreased progressively in presence of therapeutic concentrations of all TKIs tested in vitro, except for nilotinib, which showed little effect on these subsets. Of note, naive T regulatory cell (Treg) subset accumulated after exposure to TKIs. Results obtained in vivo on nilotinib-treated patients were largely comparable, both on lymphocyte subset kinetics and on cytokine production by CD3-positive cells. This study underlines the anti-inflammatory and immunomodulatory effects of TKIs and supports their potential usefulness as treatment for patients with steroid-dependent/refractory cGVHD. In addition, both in vitro and in vivo data point out that compared with other TKIs, nilotinib could better preserve the integrity of some important regulatory subsets, such as Treg and NK cells.

Reversal of poor graft function with iron-chelating therapy after allogeneic transplantation for severe aplastic anemia

Graft failure (GF) after allogeneic stem cell transplantation (SCT) is a serious complication with high mortality. Graft rejection and poor graft function (PGF) are common causes of GF and they can be distinguished by chimerism analysis: in rejection, chimerism status is mixed, with the presence of recipient cells, whereas full donor chimerism is present in PGF. [1] PGF is defined as severe cytopenia of at least two cell lines (Hb510 g/dl, neutrophil count51 10/ml, platelet count530 10/ml) for at least two consecutive weeks beyond d + 14 posttransplant, with transfusion requirements, associated with hypoplastic-aplastic BM, in the presence of complete donor chimerism and in the absence of severe GVHD and relapse. [2] About 5–27% of transplanted patients will develop PGF; [2,3] several factors have been shown to influence its incidence, such as donor type, HLA matching, ABO incompatibility, cell dose, stem cell source, graft-versus-host disease (GVHD), viral infections, intensity of conditioning regimen, and the use of myelotoxic agents, such as ganciclovir. [4,5] The pathogenesis of PGF is probably multifactorial and includes immunologic issues as well as abnormalities in the bone marrow (BM) microenvironment, number of progenitor cells, and type of the underlying disease. [3] We report of a 27-year-old woman presenting to our clinic in September 2013 because of severe pancytopenia, following an episode of acute cryptogenetic hepatitis in March 2013. She had concomitant autoimmune hypothyroidism treated with L-thyroxine. She had hyporegenerative anemia (Hb 6.6 g/dl, reticulocyte count 2.7% reticulocyte index 0.6), severe thrombocytopenia (Platelets 3 10/l) and moderate neutropenia (840/mmc). Findings of BM aspirate and biopsy (marrow cellularity55%, presence of a lymphoplasmocytic infiltrate 15–20%) were consistent with aplastic anemia (AA). BM colony-forming unit assays showed absent growth for all three hematopoietic lineages. Serologic analyses for viral (HAV, HBV, HCV) and autoimmune (antinuclear, anti-ENA, anti-DNA antibodies) diseases resulted negative. Physical examination was notable for oral petechiae and several bruises at lower limbs. While waiting for availability of horse anti-lymphocyte globulin (h-ALG), she was started on Cyclosporine (150 mg bid) but, after 1 month, she had no hematologic improvement. H-ALG (ATGAM) 40 mg/kg/d was then administered for 4 days. Due to high transfusion requirements (6.4 RBC units/ month) and laboratory evidence of iron overload (serum ferritin 1787 ng/ml [normal value 20–200 ng/ml], transferrin saturation 87.6%) deferasirox 750 mg bid was started in December 2013 (72 days before transplant). Follow-up CBC counts did not show response to hALG (Table I). Due to lack of a matched related donor, she was referred for allogeneic transplantation from matched unrelated donor (UD). Search on the International Bone Marrow Donor Registry (IBMDR) identified a 10/12 male donor with major AB0 incompatibility. The BM was preferred over the peripheral source; the delivered graft contained 2.8 10/kg total nucleated cells; the donor was A Rh-positive, while the patient 0 Rh-positive, with a titre anti-A of 1:64. Therefore an erythrodepletion was planned before reinfusion. She underwent immunosuppressive conditioning with TBI (200 cGy), Cyclophosphamide (300 mg/m) and Fludarabine (30 mg/m). [6] GVHD prophylaxis included antithymocyte globulin 7.5 mg/kg (3.75 mg/kg on days 4 and 3), Cyclosporine 2 mg/kg starting on day 3, Methotrexate 15 mg on d + 2, and 13 mg on days +4, +7. Due to insufficient recovery of mononuclear cells after erythrodepletion of the marrow graft, the whole graft content was reinfused at day 0, after reducing the anti-A titre (to 1:4) with plasma-exchange. [7] She achieved full donor chimerism at d + 14; hematologic recovery was slightly delayed (neutrophils