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K Perruccio,
F Topini,
A Tosti, A Carotti,
E Burchielli,
L Ruggeri,
A Mancusi,
E Urbani,
F Aversa,
M F Martelli,
A Velardi
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ABSTRACT: In adults, one-haplotype-mismatched haematopoietic SCT (haploidentical HSCT) is associated with slow immune recovery due to decaying thymic function and extensive T-cell depletion of the graft. Although essential for preventing GVHD, T-cell depletion underlies the major reasons for transplant failure: leukemia relapse and infections, with infection-related mortality accounting for about 40% of non-leukemic deaths. Adoptive T-cell therapy would be helpful for these patients but to administer it without causing GVHD, alloreactive T cells need to be eliminated from donor T lymphocytes before infusion. In a preclinical study, to address this problem, we determined the efficacy of photodynamic purging of alloreactive T cells, by investigating combinations of parameters in order to achieve maximum allodepletion, preservation of T-regulatory cells and of pathogen and leukemia-specific T-cell responses in donor-vs-recipient MLR. We also needed to identify an optimal method to quantify the Ag-specific T-cell repertoires. Optimal procedures were identified. In particular, we compared limiting-dilution analyses (LDA) of proliferating T cells with H(3)-thymidine incorporation by bulk T cells and with flow cytometry CD25 expression, which is accepted as a T-cell activation marker. This study demonstrated that LDA is a reliable, predictable and sensitive method for measuring alloreactive, pathogen- and leukemia-specific T-cell frequencies.
Bone marrow transplantation 12/2011; 47(9):1196-200. · 3.00 Impact Factor
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ABSTRACT: T helper (Th) 17 cells have emerged as important mediators in infectious and inflammatory diseases and, recently, in transplant rejection. We analyzed the associations between five common genetic variants in the IL-23/Th17 signaling pathway, namely in IL17A, IL17F and IL23R genes, and clinical outcome in T cell-depleted allogeneic SCT (allo-SCT). In the multivariate analysis, variants in IL23R and IL17A genes were the most important prognostic factors. Thus, patient GA genotype at rs11209026 in IL23R was associated with improved overall survival (hazard ratio (HR)=0.48; P=0.028) and, in donor, with decreased risk of fungal infections (P=0.05). In contrast, patient TC and CC genotypes at rs8193036 in IL17A gene were associated with increased risk of CMV infection (HR=3.68; P=0.011) and patient acute GVHD (HR=7.08; P=0.008), respectively. These results suggest that genetic variants in the IL-23/Th17 inflammatory pathway are important prognostic factors for the clinical outcome of allo-SCT. Although validation studies are ultimately required, our results would suggest the potential usefulness of IL-23/Th17 genotyping in donor selection and patient evaluation.
Bone marrow transplantation 02/2010; 45(11):1645-52. · 3.00 Impact Factor
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ABSTRACT: PREMISE: Since March 1993, 133 patients with high-risk acute leukemia (66 AML, 67 ALL) have received a megadose of T-cell depleted hematopoietic stem cells. The 1993-95 conditioning protocol included TBI, thiotepa, ATG and CY for 36 patients who received an inoculum made up of lectin-separated bone marrow and PBPCs. After 1995, to minimise the extra-hematological toxicity of the conditioning and eliminate GvHD, we substituted fludarabine for CY in the conditioning and PBPCs were depleted of T-cells by a positive selection of the CD34+ cells using CellPro (n=44 patients) or, since January 1999, CliniMacs (n = 53 patients). A later modification to the protocol in January 1999 was the suspension of post transplant G-CSF. WORK IN PROGRESS: We report here the results in the last 53 acute leukemia patients all of whom were transplanted under our modified protocol. Ages ranged from 9 to 62 years with a median of 38 years for the 33 patients with AML and 23 for the 20 with ALL. All were at high risk because 25 were actually in relapse at transplant, 16 were in second or later CR and even the 12 patients in CR1 were at high risk because of the unfavourable prognostic features. Overall 52/53 patients (98%) engrafted. The TBI-Fludarabine-based conditioning was well tolerated even in the 14 patients between 45 and 62 years of age. There was no veno-occlusive disease of the liver and the incidence of severe mucositis was low. Even though no post-transplant immunosuppressive therapy was given, acute GvHD grade > or = II occurred in only 4 cases and only one progressed to chronic GvHD. Overall, 16 patients (30%) have died of non-leukemic causes. Relapses occurred mainly in patients who were already in relapse at transplant (12/25). Only 3 of the 28 who were in any CR at transplant have so far relapsed. As our group has already shown, donor-vs-recipient NK cell alloreactivity exerts a specific graft-vs-AML effect in the absence of GvHD. In fact, leukemia relapse was largely controlled in AML recipients whose donor was NK alloreactive, with only 2 out of 16 relapsing. To date, 13 of 18 AML (72%) and 5 of 10 ALL (50%) who were in any CR at transplant, survive disease-free while 4 of the 15 patients (16%) in relapse at transplant survive. The probability of event-free survival for patients transplanted in CR is 60% in the 18 AML patients and 38% in the 10 ALL. The probability of EFS was significantly better in the 16 AML patients whose transplant included donor vs recipient NK cell alloreactivity than in those whose transplant did not (70% vs 7%). In conclusion, given our current results, the most suitable candidate for the full haplotype mismatched transplant should be in early stage disease and selection of an NK alloreactive donor is recommended.
International Journal of Hematology 08/2002; 76 Suppl 1:165-8. · 1.27 Impact Factor
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ABSTRACT: One hundred and ninety-three patients with hematological malignancies and a follow-up > or =1 year, treated with stem cell transplantation (45 autologous, 99 allogeneic T cell-depleted matched, 49 allogeneic T cell-depleted mismatched) from July 1985 to May 1998, were considered evaluable for the development of cataracts. Total body irradiation (TBI), administered either according to a hyperfractionated scheme (HTBI) or in a single dose (STBI), was employed in the conditioning regimens. HTBI was prescribed in 94% of patients undergoing allogeneic matched transplant, while STBI was used in 71% of patients receiving allogeneic mismatched and in all patients undergoing autologous transplant. The median follow-up was 7.56 years in the HTBI and 3.02 years in the STBI group. Among the different risk factors analyzed by univariate analysis only the TBI scheme and type of transplant reached statistical significance (P < 0.0001 and P < 0.001, respectively). By multivariate analysis only the TBI scheme was an independent factor for cataract development (STBI vs HTBI RR 7.2; P < 0.01). Our results showed that STBI is more cataractogenic than HTBI. The incidence of cataract we observed was among the lowest described in the literature. T cell depletion, because it prevents graft-versus-host disease and reduces the protracted use of post-transplant steroids, explains the results we obtained.
Bone Marrow Transplantation 03/2002; 29(6):503-7. · 3.75 Impact Factor
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ABSTRACT: Thirty-six sex-mismatched transplants were studied using fluorescence in situ hybridization (FISH) and polymerase chain reaction (PCR) methods. Molecular cytogenetics was performed using interphase FISH with a centromeric probe for chromosome Y, and PCR amplification was performed with a set of VNTR microsatellite loci. In addition, reverse transcriptase-PCR (RT-PCR) for BCR-ABL fusion was used to investigate cases of Philadelphia chromosome (Ph)-positive chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL). Our integrated approach of post-transplant monitoring was helpful in documenting successful transplants and in controlling the size of Ph-positive clones in CML. A striking overlap was found between results from FISH analysis and PCR for polymorphic loci.
Cancer Genetics and Cytogenetics 08/2000; 120(1):25-9. · 1.39 Impact Factor
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F Aversa,
A Terenzi, A Carotti,
R Felicini,
R Jacucci,
T Zei,
P Latini,
C Aristei,
A Santucci,
M P Martelli,
I Cunningham,
Y Reisner,
M F Martelli
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ABSTRACT: To eliminate the risk of rejection and lower the risk of relapse after T-cell-depleted bone marrow transplants in acute leukemia patients, we enhanced pretransplant immunosuppression and myeloablation.
Antithymocyte globulin and thiotepa were added to standard total-body irradiation/cyclophosphamide conditioning. Donor bone marrows were depleted ex vivo of T lymphocytes by soybean agglutination and E-rosetting. This approach was tested in 54 consecutive patients with acute leukemia who received transplants from HLA-identical sibling donors or, in two cases, from family donors mismatched at D-DR. No posttransplant immunosuppressive treatment was given as graft-versus-host disease (GVHD) prophylaxis.
Neither graft rejection nor GVHD occurred. Transplant-related deaths occurred in six (16.6%) of 36 patients in remission and in seven (38.8%) of 18 patients in relapse at the time of transplantation. The probability of relapse was .12 (95% confidence interval [CI], 0 to .19) for patients with acute myeloid leukemia and .28 (95% CI, .05 to .51) for patients with acute lymphoblastic leukemia who received transplants at the first or second remission. At a median follow-up of 6.9 years (minimum follow-up, 4.9 years), event-free survival for patients who received transplants while in remission was .74 (95% CI, .54 to .93) for acute myeloid leukemia patients and .59 (95% CI, .35 to .82) for acute lymphoblastic leukemia patients. All surviving patients have 100% performance status.
Adding antithymocyte globulin and thiotepa to the conditioning regimen prevents rejection of extensively T-cell-depleted bone marrow. Even in the complete absence of GVHD, the leukemia relapse rate is not higher than in unmanipulated transplants.
Journal of Clinical Oncology 06/1999; 17(5):1545-50. · 18.37 Impact Factor
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F Aversa,
A Terenzi,
R Felicini,
A Tabilio,
F Falzetti, A Carotti,
F Falcinelli,
P Sodani,
A Amici,
P Zucchetti,
I Mazzarino,
M F Martelli
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ABSTRACT: The aim of this study was to extend allogeneic hematopoietic stem cell transplantation to leukemia patients without a matched donor. To prevent graft failure, large doses of T cell-depleted hematopoietic stem cells were transplanted following a highly myeloablative and immunosuppressive conditioning regimen. Fifteen children with high-risk acute leukemia received T cell-depleted hematopoietic stem cells from full-haplotype mismatched family members after a conditioning regimen that included single-dose TBI, thiotepa, ATG and fludarabine. To prevent GVHD, marrow cells were T-depleted by soybean agglutinin and E-rosetting, peripheral blood cells by E-rosetting followed by positive selection of the CD34+ cells. No post-transplant prophylaxis for GVHD was administered. In all patients full donor-type engraftment was achieved. None of the evaluable patients developed either acute or chronic GVHD. Regimen-related toxicity was minimal. Five patients are alive and event-free at a median follow-up of 18 months (range 13-28). All surviving patients have a good quality of life. Seven patients have relapsed. This study shows that GVHD and graft failure, which limited the use of full-haplotype mismatched bone marrow transplants, have been overcome. Since almost all children have a mismatched relative, advances in this area should make mismatched transplants a routine consideration for patients with high-risk leukemia without a matched related or unrelated donor.
Bone Marrow Transplantation 01/1999; 22 Suppl 5:S29-32. · 3.75 Impact Factor
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Bone Marrow Transplantation 04/1996; 17 Suppl 2:S58-61. · 3.75 Impact Factor
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Bone Marrow Transplantation 02/1991; 7 Suppl 2:24. · 3.75 Impact Factor
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Bone Marrow Transplantation 01/1990; 4 Suppl 4:69-72. · 3.75 Impact Factor
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ABSTRACT: We report a case of 5q- syndrome that progressed to acute nonlymphocytic leukemia after 9 years of clinically and morphologically stable disease. The transition from the chronic to the leukemic phase was characterized by the appearance of an additional cytogenetic anomaly [inv(2)] in the cell carrying the 5q-, together with the expansion of a clone showing an apparently normal karyotype.
Cancer Genetics and Cytogenetics 07/1988; 32(2):205-9. · 1.39 Impact Factor
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ABSTRACT: A chronic myeloid leukemia (CML) patient who had presented a t(2;9;22) translocation during the chronic phase developed an unusual t(4;21) (p16;q22) translocation during the M2 type FAB classification blastic crisis. The role of these two recombinant chromosomes in the genesis of the terminal phase is discussed, particularly as the breakpoint on chromosome 21 near to the ets-2 oncogene locus, seems to be the same as that described in the t(8;21) (q22;q22) translocation specific of type M2 AML.
Leukemia Research 02/1986; 10(12):1487-91. · 2.92 Impact Factor
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ABSTRACT: Cytogenetic analysis of bone marrow from a chronic myeloid leukemia patient in chronic phase revealed a classical Philadelphia chromosome from a complex translocation t(2;9;22). The break points on 9 and 22 were, apparently, the same as for the standard translocation (9;22). However, whereas the terminal band of 9 (9q34) was translocated in the usual site, that is on 22q-, the tract deleted from 22 was present on band p13 of chromosome 2. The finding of this rare 22 translocation in classical CML would seem to support the hypothesis that the crucial event in the pathogenesis of CML is the translocation of band 9q34, that contains the c-abl oncogene, onto the Ph' chromosome, rather than the translocation of the tract deleted from 22 to some other chromosome site.
Leukemia Research 02/1985; 9(9):1149-53. · 2.92 Impact Factor
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ABSTRACT: Severe combined immunodeficiency disease (SCID) with adenosine deaminase (ADA) deficiency is a genetic autosomic recessive disorder with profound impairment of T-cell function, invariably complicated by fatal infections. The absence of ADA-enzyme and the accumulation of deoxy-ATP, with toxic effects on the T-lymphocytes is the common feature of this disease. As a consequence, lymphoid precursors failure to develop into mature T-cells, resulting in absolute lymphopenia and atrophy of the thymus. Bone marrow transplantation from an HLA-identical donor is considered the treatment of choice for this disease. We describe the case of a 1-month-old child with ADA deficiency SCID who underwent bone marrow transplantation (BMT) using paternal haploidentical, lectin-separated marrow, as a source of hemopoietic stem cells.
Haematologica 75(6):546-50. · 6.42 Impact Factor
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ABSTRACT: Attention is focused on the active feedback protection of a multistorey r.c. building against strong acceleration impressed at the base.A hydromechanical alternative to the standard electrohydraulic system is proposed, which seems to offer advantages in terms of compactness, high specific power and low costs. The action of the servodrive confers additional damping and stiffness to the vibrating structure. General criteria for pre-sizing hydraulic and structural subsystems are presented, establishing simple relations between certain known building parameters and the main design variables of the active servodrive. An assessment of the practical feasibility - in the ambit of current building and hydraulics technology - of both the power subsystem and of the auxiliary structure subsystem transmitting control action from the actuators to the building, has been undertaken. The results go some way to providing quantitative and qualitative criteria for the design engineer in evaluating the effectiveness and ultility of an active alternative to the problem of structural safety.When construction and installation costs are also considered, criteria for providing a rational choice between different active and passive solutions emerge. The work paves the way to shaking table experiments on reduced scale models.
Soil Dynamics and Earthquake Engineering.
