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Biomedical subjects

F Locatelli

Publications and source records attributed to F Locatelli.

At least 307 records · Page 17Linked to original sources
PubMed1996

Autologous bone marrow transplantation in children with acute myeloblastic leukemia: report from the Italian National Pediatric Registry (AIEOP-BMT).

This report summarizes indications and results of autologous bone marrow transplantation (ABMT) performed in childhood acute myeloid leukemia (AML) in Italy since 1984. A total of 158 patients have been reported from 12 teams to the AIEOP-BMT Registry: 110 have been autografted in first complete remission (CR) and 48 in second remission. Several conditioning regimens have been utilized, mainly consisting of BAVC (an original polichemotherapy schedule, BCNU, mAMSA, VP-16 and Ara-C) (63 cases) and of total body irradiation (TBI) plus Melphalan (33 cases): other 28 patients received different TBI-including regimens, and 34 received various chemotherapy regimens (Busulfan plus cyclophosphamide +/- VP-16, Busulfan plus Melphalan, Melphalan alone). Projected event-free survival (EFS) for patients autografted in first CR is 41.4% (S.E. 5.5%) at 7 years, with a total of 53 patients in continuous CR. EFS is better in patients receiving a TBI-including regimen: 78.8% versus 27.2% (p = 0.0001). In particular, results obtained in a subgroup of 21 cases receiving TBI + melphalan and purged marrow are particularly encouraging, with a EFS > 85% projected a 7 years. The overall EFS in second CR is 41.5% at 7 years, and no difference have been observed after a TBI-including regimen or after a chemotherapy regimen, being EFS 43.1% and 39.3% for these 2 groups respectively. A total of 11 transplant-related deaths occurred, with 5 patients (4.5%) dead in first CR and 6 (12%) dead in second CR within 100 days from transplant. From these data, ABMT is confirmed to represent an effective treatment for AML after first relapse, while the encouraging results obtained in first CR with TBI-including regimens should be confirmed with a longer follow up and a larger number of patients.

Adolescent↗
PubMed1996

Unrelated-donor bone marrow transplantation for Philadelphia chromosome-positive chronic myelogenous leukemia in children: experience of eight European Countries. The EBMT Paediatric Diseases Working Party.

From September 1988 to December 1995 forty-four children (age < 17 years) with Ph1 Chronic Myelogenous Leukemia (CML) received unrelated donor marrow transplantation in 8 European Countries. Thirty-three evaluable children were typed by serological testing on HLA-A, B, and DR loci. Thirty of them were further DR subtyped by DNA techniques. Twenty-four pairs were 6 antigen matched. Seven were mismatched at 1 locus (2 pairs at A and B loci respectively and 3 at DR locus). Two out of 30 pairs evaluated by molecular biology had one antigen mismatched at DRB1 locus. Thirty-two (96%) out of 33 evaluable children reached a sustained granulocyte count higher than 0.5 x 10(9)/l at a median of 21 (range 14-88) days after transplantation. The remaining child failed to engraft. Two children developed secondary graft failure. A platelet count greater than 50 x 10(9)/l sustained for at least seven consecutive days without transfusion support was reached at a median of 25 (range: 20-144) days by 24 out of 33 evaluable children and 9 children never recovered to above 50 x 10(9)/l. Twenty-one out of 33 evaluable children developed grade I (n = 7), grade II (n = 8), grade III (n = 2) or grade IV (n = 4) acute GvHD (63%). Seven of the 30 evaluable children surviving more than 100 days developed chronic GvHD (20%) which was limited in 4 cases and extensive in 3. Relapse occurred in 3 of the 44 (7%) children at 2 to 24 months (median 14). Twenty-four month relapse rate was 14%. Seventeen out of 44 children (38%) died of transplant related mortality (TRM), 4 (9%) of secondary tumor, 4 (9%) of infections, 3 (7%) of organ failure, 1 (2%) of interstitial pneumonia, 5 (11%) of unknown causes. Actuarial TRM was 61% for children grafted before December 1991 and 33% for children grafted after January 1992 (p = .01). EFS was 49.7%; it was 65% for children receiving more than 3.5 x 10(9)/Kg MNC.

Adolescent↗
PubMed1996

Extracorporeal photochemotherapy for the treatment of graft-versus-host disease.

Photopheresis is an extracorporeal photochemotherapy (ECP) used for the treatment of oncological and autoimmune diseases. Lymphocytes are drawn from the patients by leukapheresis, treated with 8-methoxypsoralen (8-MOP) and ultraviolet light A (UVA) in an extracorporeal system; then, reinfused to the host. Because skin exposure to 8-MOP and UVA (PUVA) has been shown to improve cutaneous GVHD, we evaluated in a pilot study, if ECP might be beneficial for patients with GVHD unresponsive to conventional protocols. In this study, we enrolled 9 children or young adults, with acute (no = 1) or chronic extensive GVHD (no. = 8). A significant improvement was observed in three of the 5 patients with scleroderma-like lesions and in one patient with severe liver involvement. Karnofsky performance score improved from 30-50% to 90% in the 4 responders. The better control of GVHD in these patients allowed a reduction of the immunosuppressive therapy that was, finally, discontinued in two. No significant side effects were observed during ECP. Our results suggest that ECP is a nonaggressive treatment that may benefit patients with c-GVHD unresponsive to standard immunosuppressive therapies.

Adolescent↗
PubMed1996

Hematopoietic and immune recovery after transplantation of cord blood progenitor cells in children.

Matched related cord blood transplantation (CBT) has been successfully used to rescue patients undergoing myeloablative therapy. However, few data are available on the kinetics of hematological and immunological reconstitution of CBT recipients. We have investigated the hematological engraftment and immune recovery following related CBT in three patients, with acute lymphoblastic leukemia, aged 10, 9 and 7 years and with a body weight of 31, 40 and 25 kg, respectively. All patients engrafted and none experienced acute or chronic graft-versus-host disease. The time needed to achieve granulocyte recovery was 13, 26 and 29 days, respectively and platelet recovery occurred in 28, 49 and 51 days. All patients presented a marked increase of HbF, the values observed being much greater than those documented in patients given marrow transplantation and comparable with those observed in normal children in the first year of age. The recovery of T cell immunity, as well as that of natural killer subpopulations, mimicked that described in BMT recipients, a quicker return of CD8+ T cells determining the characteristic inversion of CD4/CD8 ratio. An impressive increase in the percentage and absolute number of B lymphocytes, apparently not related to viral infections, was demonstrable in all three cases. These data suggest that CBT recipients can experience a slight delay in hematological recovery when compared with patients given BMT. The reconstitution of erythropoiesis seems to recapitulate the ontogenetic pattern and the kinetics of recovery of the immune system reproduce that observed after BMT with the peculiarity of B cell expansion in peripheral blood.

Antibody Formation↗
PubMed1995

Alloantigen-induced human lymphocytes rendered nonresponsive by a combination of anti-CD80 monoclonal antibodies and cyclosporin-A suppress mixed lymphocyte reaction in vitro.

Induction of a state of long-term, alloantigen-specific T cell nonresponsiveness has significant implications for human transplantation. It has been previously described that alloantigen-specific anergy may be induced by addition of cyclosporin-A together with anti-CD80(B7-1) mAb to a MLR. In this study we endeavored to verify whether alloantigen-induced PBL rendered anergic by the addition of a combination of anti-B7 mAb and cyclosporin-A during a MLR had a suppressive effect when added to autologous lymphocytes activated in MLR. We found that: 1) the addition of cells rendered anergic by this procedure to a MLR suppress both proliferative and cytotoxic response of autologous responsive PBL to either the same or third-party stimulator cells; 2) the suppressive effect is limited to alloantigen-induced T cell activation, as addition of anergic cells does not influence mitogen- or antigen-induced proliferation of autologous responsive T cells; 3) nonresponsiveness of suppressed cells cannot be reversed by either subsequent restimulation with allogeneic cells or addition of exogenous IL-2 to the cultures; 4) the suppressive effect is apparently not due to secretion of anergic cell-derived soluble factors, but it seems to be dependent on cell-cell contact between anergic, responsive, and stimulator cells. These data suggest that: 1) the delivery of a direct signal mediated by anergic lymphocytes through a cell-cell contact is likely to be the mechanism responsible for the suppressive effect here described; 2) anergic cells may propagate alloantigen-specific tolerance to potentially responsive autologous lymphocytes. Preliminary experiments indicate that anti-CD86(B7-2) mAb may play a similar role in the generation of alloantigen-induced nonresponsiveness.

Antibodies, Monoclonal↗
PubMed1995

Cell kinetics of CD34-positive hematopoietic cells following chemotherapy plus colony-stimulating factors in advanced breast cancer.

Bone-marrow (BM) hematopoietic precursors are recruited into proliferative activity when colony-stimulating factors (CSF) are sequenced with chemotherapy (CT). Previous studies suggested that further CT can be safely administered only when the increased proliferative activity of these cells has subsided, because most cytostatic drugs selectively damage cycling cells. The safest interval between CSF discontinuation and the start of the next CT course needs to be ascertained in vivo. Thirty patients with advanced breast cancer were treated with an intensified FEC regimen, planned at 21-day intervals, sequenced with granulocyte-macrophage (GM)-CSF (15 patients) or granulocyte (G)-CSF (15 patients). Using flow cytometry (FCM) we evaluated the proliferation kinetics of CD34+ BM hematopoietic progenitors before CT+CSF and at different times after CSF administration was stopped. FEC+GM- and FEC+G-CSF sequences both induced a rapid and sustained increase in the percentage of BM myeloid precursors (BMMP%) and in the cycling status of CD34+BM cells. However, while the BMMP% remained elevated in both cases after CSF were stopped, the enhanced proliferative activity of CD34+ cells decreased more rapidly after GM- than after G-CSF. Using FCM, CD34+ BM-derived hematopoietic presursor cell kinetics is readily evaluated in the clinical setting. The administration of CSF following CT increases both the proliferative activity of CD34+ BM cells and the BMMP%. After CSF were discontinued a kinetic refractoriness of hematopoietic progenitors was more evident after GM-CSF than after G-CSF. These data may be of value in designing clinical trials to avoid cytostatic damage to the BM hematopoietic stem-cell compartment.

Aged↗
PubMed1995

Oligodeoxynucleotides antisense to c-abl specifically inhibit entry into S-phase of CD34+ hematopoietic cells and their differentiation to granulocyte-macrophage progenitors.

A number of experimental observations suggest that the proto-oncogene c-abl participates in the regulation of hematopoietic cell growth. We used an antisense strategy to study the relationship between c-abl expression and hematopoietic cell proliferation and differentiation. Purified normal human bone marrow-derived CD34+ cells were obtained by immunomagnetic selection and incubated with 18-base-unmodified antisense oligodeoxynucleotides complementary to the first six codons of the two alternative first exons of c-abl, la and lb. At the end of incubation, an aliquot of cells was assayed for clonogenic growth and the remainder was used for flow cytometric analyses. Cell kinetics were evaluated by means of both single parameter DNA and bivariate DNA/bromodeoxyuridine (BrdU) flow cytometry. Apoptosis was routinely studied by DNA flow cytometric analysis and, in some cases, also through DNA agarose gel electrophoresis for detection of oligonucleosomal DNA fragments. Expression of differentiation markers was studied by flow cytometry. Exposure to antisense oligonucleotides specifically inhibited the accumulation of c-abl mRNA in CD34+ cells. Preincubation with the c-abl antisense oligomers reduced the proportion of cells in S-phase from 19% +/- 5% (mean +/- SD) to 7% +/- 4% (P < .05), and BrdU labeling from 13% +/- 6% to 6% +/- 3% (P < .05). Flow cytometry and DNA agarose gel electrophoresis showed that treated CD34+ cells accumulated in the G0/G1 region of the DNA histogram with no evidence of either differentiation or apoptosis. By contrast, both growth factor deprivation and exposure of CD34+ cells to the tyrosine kinase inhibitor tyrphostin AG82 clearly induced apoptosis. When cells were preincubated with antisense oligonucleotides and then plated for evaluation of colony formation, this resulted in a significant inhibition of colony forming unit granulocyte-macrophage growth (from 44 +/- 15 to 22 +/- 9; P < .01) but had no effect on burst-forming unit erythroid growth (24 +/- 11 v 21 +/- 11; P < .05). These results suggest that c-abl expression is critical for entry of human CD34+ hematopoietic cells into S-phase and for their differentiation to granulocyte-macrophage progenitors. They also indicate that other tyrosine kinases besides p145c-alb are active in the prevention of apoptosis, so that inhibition of c-abl RNA accumulation arrests CD34+ cells in G0/G1 without activating programmed death.

Antigens, CD34↗
PubMed1995

Role of busulfan and total body irradiation on growth of prepubertal children receiving bone marrow transplantation and results of treatment with recombinant human growth hormone.

Seventy-six prepubertal children receiving autologous or allogeneic bone marrow transplantation (BMT) were enrolled in a prospective study on the impact of different pretransplant preparative regimens on growth. Patients were divided into three groups: group I, consisting of 37 children who had received total body irradiation (TBI) and cytotoxic drugs as preparative regimen; group II, including 17 children receiving prophylactic cranial irradiation before being conditioned with TBI and cytotoxic drugs; and group III, composed of 22 patients transplanted after a busulfan (BU)-containing myeloablative therapy. All patients have a minimum follow-up of 2 years, whereas 48 and 34 patients have been studied until 3 and 4 years after transplant, respectively. Height and growth rate were expressed as standard deviation score (SDS). Growth hormone (GH) secretion in response to pharmacologic stimuli was evaluated after documented growth failure. Patients with GH deficiency were treated with recombinant human GH, and response to therapy was evaluated. The main impairment of growth rate in patients belonging to group II was observed in the first year after TBI (growth rate SDS changing from -0.12 +/- 0.23 to -1.23 +/- 0.25, P < .005), with only a slight loss in the following years, whereas in group I children growth failure occurred in the third year after TBI (-1.36 +/- 0.28 SDS in comparison to a pre-BMT SDS of 0.10 +/- 0.15, P < .005). Therefore, growth velocity between these two groups differed significantly in the first 2 years (P < .01) but subsequently equalized. On the contrary, all BU-treated children but 2 grew normally. GH deficiency was shown in the vast majority of children with growth impairment. Twenty-three children treated with recombinant human GH are evaluable; a successful response was observed in all but 1, with the mean growth rate increasing from -2.29 +/- 0.27 before treatment to 0.86 +/- 0.38 and to 1.66 +/- 0.56 SDS at 1 and 2 years after treatment, respectively (P < .001). In conclusion, growth rate impairment was common in patients receiving TBI, with the speed of onset of both decreased growth velocity and GH deficiency depending mainly on the total dose of radiation. On the contrary, patients receiving BU did not experience significant problems in terms of growth velocity. The timely start of appropriate hormonal replacement therapy may ameliorate the final growth of children undergoing BMT.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1995

Antilymphocyte globulin, cyclosporin, and granulocyte colony-stimulating factor in patients with acquired severe aplastic anemia (SAA): a pilot study of the EBMT SAA Working Party.

Patients with severe aplastic anemia (SAA) and a neutrophil (PMN) count of less than 0.5 x 10(9)/L are exposed to a high risk of early mortality when treated with antilymphocyte globulin (ALG) and steroids, with the major problem being infectious complications. The addition of human recombinant granulocyte colony-stimulating factor (rhG-CSF) to ALG may reduce early mortality by improving neutrophil counts in the short term. To test the feasibility of this approach, the SAA Working Party of the European Group for Blood and Marrow Transplantation (EBMT) designed a pilot study that included rhG-CSF (5 micrograms/kg/d, days 1 through 90), horse ALG (HALG; 15 mg/kg/d, days 1 through 5), methylprednisolone (2 mg/kg/d, days 1 through 5, then tapering the dose), and cyclosporin A (CyA; 5 mg/kg/d orally, days 1 through 180). Patients with newly diagnosed acquired SAA (untreated) and with neutrophil counts of < or = 0.5 x 10(9)/L were eligible. Forty consecutive patients entered this study and are evaluable with a minimum follow up of 120 days: the median age was 16 years (range, 2 to 72 years), the interval from diagnosis to treatment was 24 days, and the median PMN count was 0.19 x 10(9)/L. Twenty-one patients had hemorrhages, and 19 were infected at the time of treatment. Overall, treatment was well tolerated: the median maximum PMN count during rhG-CSF administration was 12 x 10(9)/L (range, 0.4 x 10(9)/L to 44 x 10(9)/L). There were three early deaths (8%) due to infection. Four patients (10%) showed no recovery, whereas 33 patients (82%) had trilineage hematologic reconstitution and became transfusion-independent at a median interval of 115 days from treatment. Median follow up for surviving patients is 428 days (range, 122 to 1,005). Actuarial survival is 92%: 86% and 100% for patients with PMN counts less than 0.2 x 10(9)/L or between 0.2 x 10(9)/L and 0.5 x 10(9)/L, respectively. This study suggests that the addition of rhG-CSF to ALG and CyA is well tolerated, is associated with a low risk of mortality, and offers a good chance of hematologic response. This protocol would appear to be an interesting alternative treatment for SAA patients with a low PMN count who lack an HLA-identical sibling.

Actuarial Analysis↗
PubMed1995

Juvenile chronic myelogenous leukemia: in vitro characterization before and after allogeneic bone marrow transplantation.

In previously published studies on patients with juvenile chronic myelogenous leukemia (JCML), excessive proliferation of malignant monocyte-macrophage elements and impaired growth of normal hematopoietic progenitors were demonstrated. A selective hypersentivity of granulocyte-macrophage progenitors (CFU-GM) to granulocyte-macrophage colony stimulating factor (GM-CSF) seems to represent the main pathogenetic mechanism. Allogeneic bone marrow transplantation (BMT) has been demonstrated to be the only curative strategy for patients with JCML. In this study, we evaluated the growth of peripheral blood hematopoietic progenitors in semisolid cultures in two children with JCML before and after allogeneic BMT. Serum levels of GM-CSF, interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) were also assessed. IL-1-beta, GM-CSF and TNF-alpha serum levels of the patients before and after BMT did not differ significantly from those obtained in 45 healthy controls. After marrow transplant, the engraftment of donor hematopoietic stem cell was associated with the disappearance of both pretransplant GM-CSF hypersensitivity and CFU-GM spontaneous growth. The inhibitory effect on the growth of normal hematopoietic progenitors also resolved. This confirms that the substitution of the pathological hematopoietic progenitors represents the basis for the curvative effect of allogeneic BMT in the treatment of JCML, abolishing both the excessive responsiveness of JCML progenitor cells even to very low concentrations of GM-CSF and the growth-inhibitory effect on normal hematopoiesis.

Bone Marrow Transplantation↗
PubMed1995

Antibody response to pneumococcal vaccine in children receiving bone marrow transplantation.

Fifty-three pediatric patients given an allogeneic or an autologous bone marrow transplantation (BMT) were immunized with a polyvalent pneumococcal capsular polysaccharide vaccine (Pneumovax II). Vaccine was administered six months or more after BMT and the pneumococcal IgM, total IgG, and IgG subclasses levels were evaluated before and three weeks after immunization. Immunization promoted a significant rise in antibody serum levels (P < 0.000001), and all children vaccinated more than two years after transplantation responded to pneumococcal polysaccharides, whereas only 20-30% and 50% of patients given BMT between six months and one year and one and two years, respectively, mounted an effective antibody production (P < 0.0001). In univariate analysis, lapse of time from BMT to vaccination, chronic graft-versus-host disease occurrence, and female sex influenced the response rate. However, in multivariate analysis, only time between marrow transplant and immunization was a powerful predictor of response. Interestingly, four of 11 patients with IgG2 deficiency before immunization normalized serum levels of this IgG subclass after the pneumococcal antigenic challenge. Our study suggests that time after transplant is the major factor influencing the recovery of immune reactivity to polysaccharide antigens. This seems to confirm the hypothesis that ontogeny of the B-cell repertoire follows a predetermined sequential program in which polysaccharide antigens are some of the last to evoke an antibody response.

Adolescent↗