Biomedical subjects

S Tura

Publications and source records attributed to S Tura.

At least 19 recordsLinked to original sources

PubMed1999

Antibodies reactive with neutrophils following allogeneic haematopoietic stem cell transplantation.

Allogeneic haematopoietic stem cell transplants might induce immunological alterations leading to autoimmune-like syndromes. In particular neutrophil-associated antigens could represent the target for autoantibodies against neutrophils in patients receiving an allogeneic peripheral stem cell or bone marrow transplantation, giving rise to granulocytopenia. With this aim we studied prospectively 43 allotransplanted patients for the presence of antibodies reacting with neutrophils (ARN), looking for a correlation with a post-engraftment neutropenia. Our data showed that the direct test for ARN was positive in 30 patients. Interestingly, 7/7 patients who received a T-cell-depleted marrow transplant developed ARN. Antibodies with a specific neutrophil-antigen reactivity were detected in 4 patients, 1 with an anti-CD16/FcbetaRIIIb receptor reactivity and 3 with anti-NA 1 reacting patterns, respectively. From a clinical point of view, it was not possible to demonstrate a close and significant relationship between neutropenia and ARN, although patients showing ARN had slightly lower absolute levels of peripheral neutrophils until 6 months after BMT. In conclusion, ARN may be detected in the majority of patients following allogeneic stem cell transplantation; in addition, since ex vivo or in vivo T-cell-depletion leads to a higher percentage of patients positive for ARN, it could be hypothesized that "autoimmune-like" disorders in transplanted patients might be related to a T-cell derangement due to different numbers and subsets of T lymphocytes.

Adult↗

PubMed1998

Prevalence of monoclonal gammopathies in patients with hepatitis C virus infection.

BACKGROUND: An association between monoclonal gammopathies and chronic liver diseases has been reported. OBJECTIVE: To determine the prevalence of monoclonal gammopathies in patients with chronic hepatitis C virus (HCV) infection and the possible association of monoclonal gammopathies with HCV genotypes. DESIGN: Prospective study. SETTING: Departments of internal medicine and hematology at two university hospitals in Italy. PATIENTS: 239 HCV-positive and 98 HCV-negative patients with chronic liver diseases were recruited consecutively. MEASUREMENTS: Clinical data were gathered, liver histologic examination was done, serum immunoglobulin and cryoglobulin levels were measured, and immunoelectrophoresis was done for monoclonal component detection. Patients with monoclonal gammopathy had serum HCV RNA measured and HCV genotype determined by polymerase chain reaction and had histologic examination of bone marrow. RESULTS: Monoclonal band was detected in 11% of HCV-positive patients and in 1% of HCV-negative patients (P = 0.004). The prevalence of HCV genotype 2a/c was higher in patients with monoclonal gammopathies than in those without (50% compared with 18%; P = 0.009). CONCLUSION: The prevalence of monoclonal gammopathies in patients with HCV-related chronic liver disease is striking and is often associated with genotype 2a/c infection.

Adolescent↗

PubMed1998

Anaplastic large cell lymphoma Hodgkin's-like: a randomized trial of ABVD versus MACOP-B with and without radiation therapy.

During the last few years, morphological, immunohistochemical, and genetic findings have placed anaplastic large cell lymphoma (ALCL) as a distinct clinicopathologic entity, and several reports have focused on the existence of different subtypes of the tumor. Particular attention has been paid to the ALCL-Hodgkin's-like (HL) subtype, which seems to be on the border between Hodgkin's disease (HD) and high-grade non-Hodgkin's lymphoma (HG-NHL). From September 1994 to July 1997, during the course of an Italian multicentric trial, 40 ALCL-HLs were randomized to receive as front-line chemotherapy MACOP-B (methotrexate with leucovorin, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin-a third-generation HG-NHL regimen) or ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine-a scheme specific for HD). All patients with bulky disease in the mediastinum at diagnosis underwent local radiotherapy after the chemotherapeutic program. Complete response (CR) was achieved in 17 of the 19 (90%) patients who were treated with MACOP-B, and in 19 of the 21 (91%) patients who were administered ABVD. The probability of relapse-free survival, projected at 32 months, was 94% for the MACOP-B subset and 91% for the ABVD subset. The majority of patients with mediastinal bulky disease obtained CR (evaluated with 67Ga single photon emission computed tomography [SPECT]) after their radiotherapy. The present study suggests that ALCL-HL, in line with its borderline status, responds in an equivalent way to third-generation chemotherapy for HG-NHL and to conventional HD treatment in terms of both CR and relapse-free survival rates. However, as to the latter, a longer follow-up period may be needed before stating the absolute equivalence of the two regimens used.

Adolescent↗

PubMed1998

Therapy with gemcitabine in pretreated peripheral T-cell lymphoma patients.

BACKGROUND: Gemcitabine is a novel nucleoside analogue which has shown promising results in most solid tumors; like the arabinosylcytosine analogue, gemcitabine may be an active drug in lymphoproliferative malignancies. We tested it in pretreated peripheral T-cell lymphoma patients with isolated skin involvement. PATIENTS AND METHODS: We performed a phase II study with the drug in 13 pretreated patients with peripheral T-cell lymphoma, five of whom had advanced-stage mycosis fungoides (MF), and eight peripheral T-cell lymphoma unspecified (PTCLU). Patients were treated on days 1, 8, and 15 of a 28-day schedule at the dosage of 1200 mg/m2 for a total of three courses. RESULTS: Of the 13 patients, one achieved complete response (CR) and eight achieved partial responses (PR); the remaining four showed no benefit from the treatment. Among the responders, one CR and four PR were documented in the PTCLU patients and four PR in MF patients. Treatment was well tolerated; hematologic toxicity was mild and no nausea/vomiting or organ toxicity was recorded. CONCLUSIONS: In view of its significant activity and its modest toxicity profile, the role of gemcitabine deserves further evaluation in the management of pretreated patients with peripheral T-cell lymphoma.

Adult↗

PubMed1998

Big BU/CY is associated with a favorable long-term outcome in patients allotransplanted for chronic myelogenous leukemia in chronic phase.

Twenty-six adult patients, median age 36 years (range 21-53) with chronic myeloid leukemia in first chronic phase were allotransplanted between October 1989 and May 1995. The preparative regimen consisted of busulphan 16 mg/kg and cyclophosphamide 200 mg/kg (big BU/CY). Cyclosporin A and methotrexate were used for GVHD prophylaxis. Twenty-two donors were HLA-identical siblings and four donors were mismatched for one antigen of class I. The global incidence of acute GVHD was 50%, that of severe aGVHD (grades 3-4) was 11%; the global incidence of chronic GVHD was 30%. No patients developed veno-occlusive disease of the liver or interstitial pneumonia. Five patients died, one of relapse, four of transplant-related causes, mostly related to aGVHD; thus, the transplant-related mortality was 16%. Twenty-one patients are alive, in remission, with a median follow-up of 55 months (range 24-90); actuarial probability of survival is 78% (CI 64-96). Our study shows that this conditioning regimen is relatively easy to administer and seems to be as effective as, if not superior to, regimens containing TBI, in patients with chronic myeloid leukemia in chronic phase and the transplant-related mortality is not excessive even in older patients.

Adult↗

PubMed1998

T cell alloreactivity induced by normal G-CSF-mobilized CD34+ blood cells.

In this study, the hypothesis that a subset of granulocyte colony-stimulating factor (G-CSF)-mobilized CD34+ blood cells may actively induce an allogeneic T cell response in vitro was tested. Circulating CD34+ cells were purified to > or =98% by high gradient magnetic separation and then analyzed for the coexpression of HLA-DR, the common beta-chain of the leukointegrin family CD18 and costimulatory molecules CD80 (B7-1) and CD86 (B7-2). These antigens were expressed on average on: 94.9 +/- 2.5%, 64.4 +/- 15.4%, 0% and 1.9 +/- 1.2% CD34+ blood cells, respectively. Irradiated CD34+ cells induced a high proliferative response of allogeneic, but not autologous, purified CD4+ and CD8+ T cells in primary mixed leukocyte culture (MLC). An average three-fold lower CD4+ and CD8+ T cell response was induced by mononuclear cells from G-CSF-treated donors. A lower frequency of allostimulating cells among mononuclear cells rather than among CD34+ cells in the apheresis was documented by limiting dilution assay (LDA). As previously observed with marrow, sorted CD34+/CD18+ cells induced the proliferation of allogeneic T cells in MLC, while CD34+/CD18- cells, which were >94% HLA-DR+ and contained both committed (CFU-C) and early (LTC-IC) hematopoietic progenitors, stimulated allogeneic T cells poorly. Three-color staining cytofluorimetry indicated that expression of CD80 and CD86 were upregulated in 6.9 +/- 4.9 and 10.7 +/- 2.6% CD34+ blood cells respectively, after 24-30 h of culture with autologous or allogeneic mononuclear cells, or with CD4+, or CD8+ T cells, but not with medium alone. Moreover, the upregulation of CD86 was observed on CD34+/CD18+ rather than on CD34+/CD18- cells after 30 h in MLC. Blocking experiments demonstrated that preincubation of stimulator and responder cells with anti-CD80 plus anti-CD86 monoclonal antibodies induced a 84 +/- 8% inhibition of CD34+ cell allostimulating activity after 6 days in primary MLC. These results suggest that G-CSF-mobilized CD34+ hematopoietic progenitors with alloantigen presenting function express CD18 and may upregulate CD80 and CD86 upon interaction with T cells. Since activation of B7 costimulatory molecules represents an active costimulatory pathway on G-CSF-mobilized CD34+ cells, the blockade of these molecules or, alternatively, the use of selected non-immunogenic CD34+/CD18- blood stem cells may represent a new strategy for reducing graft rejection and overcoming HLA barriers in allogeneic stem cell transplantation.

Antibodies, Monoclonal↗

PubMed1998

High-dose busulfan and cyclophosphamide are an effective conditioning regimen for allogeneic bone marrow transplantation in chemosensitive multiple myeloma.

The present clinical trial was undertaken to investigate the toxicity and antimyeloma activity of busulfan (BU) and cyclophosphamide (CY) at the maximum tolerated doses of, respectively, 16 mg/kg and 200 mg/kg (BU-CY 4) as conditioning therapy for allogeneic bone marrow transplantation (BMT) in 19 consecutive patients with multiple myeloma (MM). Twelve (63%) had failed to respond to prior chemotherapy, while the remaining 37% had chemosensitive disease. No life-threatening or fatal regimen-related complications were observed. The incidence of veno-occlusive disease of the liver was zero according to Jones' criteria and 21% according to McDonald's system. Transplant-related mortality was 37%. Using stringent criteria, the frequency of complete remission (CR) was 42% among all patients and 53% among those who could be evaluated. With a median follow-up of 21 months for all patients and 66 months for survivors, the actuarial probability of survival and event-free survival at 4 years from BMT was 26% (95% CI: 7-46) and 21% (95% CI: 3-39), respectively. A more favorable outcome of transplantation was observed in the subgroup of patients with chemosensitive disease who had a transplant-related mortality of 14%, an overall CR rate of 86% (95% CI: 49-97) and a 4-year projected probability of event-free survival of 57% (95% CI: 20-93). Four of these patients are currently alive in continuous CR after 54, 66, 80 and 94 months, respectively. It is concluded that BU-CY 4 as conditioning for allogeneic transplantation for MM is associated with acceptable morbidity and relatively low mortality. This regimen exerts substantial antimyeloma activity, resulting in a high CR rate and durable responses, especially in patients with chemosensitive disease. Long-lasting remission and probable cure is possible following allogeneic stem cell transplantation for MM.

Adult↗

PubMed1998

Alloantigen presenting capacity, T cell alloreactivity and NK function of G-CSF-mobilized peripheral blood cells.

In this study we addressed whether the proportion and the function of antigen presenting cells (APC), T and NK lymphocytes are modified in the apheresis product of six healthy donors who received a stem cell mobilizing treatment with glycosylated G-CSF at 10 microg/kg/day x 5 days s.c. Flow cytometry analysis showed comparable percentages of HLA-DR+, CD19+, CD86+, CD80+ and CD1a+ cells in preG-CSF-peripheral blood mononuclear cells (preG-PBMC) and after mobilization in G-PBMC, whereas the proportion of CD14+ monocytes significantly increased in G-PBMC (3+/-1% vs 17+/-8%, P = 0.003). Analysis of lymphocyte subsets in preG-PBMC and G-PBMC showed similar proportions of CD3+, CD4+, CD8+ and CD28+ T cells, but a significantly lower percentage of CD16+ (11+/-7% vs 4+/-1%, P=0.01), CD56+ (15+/-6% vs 5+/-2%, P= 0.008), CD57+ (16+/-9% vs 5+/-2%, P=0.04), CD25+ (19+/-2% vs 9+/-6%, p=0.009) and CD122+ (5+/-2% vs 2+/-1%, P = 0.05) cells in G-PBMC. Unfractionated preG-PBMC and G-PBMC were irradiated and tested in primary mixed leukocyte culture (MLC) with two HLA-incompatible responders and induced efficient alloresponses in four of six cases, whereas G-PBMC stimulated poorly in the remaining two cases. Also, in allo-MLC with irradiated G-PBMC we detected lower amounts of IFN-gamma (P = 0.04) and of IL-2 (P = 0.06) than in allo-MLC with preG-PBMC. Furthermore, freshly isolated preG-PBMC and G-PBMC from each donor exerted comparable allogeneic responses to HLA-incompatible irradiated mononuclear cells in all cases. However, G-PBMC showed no NK activity against K562 target cells at any effector:target ratio tested. These data suggest that normal G-PBMC may prevent Thl alloresponses, maintain efficient alloreactivity to HLA mismatched antigens and have impaired NK activity.

Antigen Presentation↗

PubMed1998

Autologous peripheral blood stem cell transplantation in acute myeloblastic leukaemia and myelodysplastic syndrome patients: evaluation of tumour cell contamination of leukaphereses by cytogenetic and molecular methods.

We evaluated 18 acute myeloblastic leukaemia (AML) and myelodysplastic syndrome (MDS) patients with abnormal karyotype at diagnosis who underwent peripheral blood stem cell (PBSC) transplantation. To evaluate the presence of residual tumour cells, bone marrow (BM) samples and PBSC collections were analysed by cytogenetics and in selected cases also by fluorescence in situ hybridisation (FISH) and molecular studies. All patients were considered to be in morphologic and cytogenetic complete remission (CR) at the time of mobilisation. Seven patients showed neoplastic cells in PBSC harvest and/or BM specimen before reinfusion. Cytogenetic studies revealed contamination in apheretic collections in one patient only, while three patients had BM but not PBSC contamination. Three more patients had leukaemic cells both in the BM and PBSC. All but one (with only BM contamination) of these patients relapsed within 9 months. However, five more patients relapsed after transplantation: in four cases there was no cytogenetic sign of contamination either in PBSC or BM cells and in one case no molecular evidence was revealed either. This study suggests that, whereas the presence of leukaemic cells in autologous grafts correlates with a poor prognosis, the lack of detection of tumour cells is not always predictive of long-term disease-free survival. More importantly, PBSC collections from AML patients are not contaminated by leukaemic cells if the BM is disease-free.

Adult↗

PubMed1998

Megakaryocyte progenitors derived from bone marrow or G-CSF-mobilized peripheral blood CD34 cells show a distinct phenotype and responsiveness to interleukin-3 (IL-3) and PEG-recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF).

In the present study we investigated the proliferative response of megakaryocyte progenitor cells (CFU-MK) derived from peripheral blood stem cell (PBSC) collections of patients with haematological malignancies and normal donors. Highly purified CD34+ cells and mononuclear cell fractions were assayed in the presence of recombinant interleukin-3 (IL-3) and pegylated-recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF), alone or in combination, and megakaryocyte colony formation was evaluated in the plasma clot. In comparison, steady-state bone marrow samples from normal donors were highly enriched in CD34+ cells and tested with the cytokines studied. Our results showed that IL-3 was able to stimulate CFU-MK colony formation from bone marrow and peripheral blood CD34+ cells. Similarly, PEG-rHuMGDF stimulated, in a dose-response manner, CD34+ cells from the bone marrow. However, normal mobilized peripheral blood CD34+ cells were not induced to generate CFU-MK colonies by PEG-rHuMGDE The same lack of response was observed when patients peripheral blood CD34+ cells primed with chemotherapy plus G-CSF or with G-CSF alone were assessed. In contrast, PEG-rHuMGDF stimulated CFU-MK growth when mononuclear cells, either from the bone marrow or from mobilized peripheral blood, were grown in plasma clot. Moreover, we analysed by flow cytometry the expression of Mpl receptor on the cell membrane of normal mobilized peripheral blood and normal steady-state bone marrow CD34+ cells. Our results showed a reduced expression of Mpl receptor on mobilized peripheral blood progenitor cells in comparison with bone marrow cells.

Antigens, CD34↗

PubMed1998

Selective expansion of normal haemopoietic progenitors from chronic myelogenous leukaemia marrow.

CD34+ and CD34+ DR- cells from the bone marrow (BM) of chronic-phase chronic myelogenous leukaemia (CML) patients at diagnosis were tested for their colony-forming ability in response to early and intermediate-late colony stimulating factors (CSFs). Molecular analysis revealed that 55.6+/-9% SD of CD 34+ DR- colonies, in which actin and ABL mRNA were detectable, expressed the product of the BCR-ABL gene. The percentage and the clonogenic efficiency of CML DR- cells were significantly lower than those of comparable DR- cells from normal donors. However, clonogenic assays using recombinant human CSFs demonstrated a remarkable proliferation of CML cells when stimulated by SCF, IL-11 and IL-3, used as single factors in the presence of erythropoietin (EPO) and was almost entirely due to erythroid progenitors. Conversely, optimal stimulation of CD34 +DR- cells from normal donors required co-incubation with three or more CSFs. Stroma-noncontact long-term cultures were then established in the presence of exogenous CSFs and human irradiated allogeneic stromal layers or the murine stromal cell line M2-10B4, engineered to produce G-CSF and IL-3. In these cultures the combination of SCF and IL-3 induced a 25.4 +/- 5 SD, 40 +/- 6 SD and 20.5 +/- 6 SD fold increase of colony-forming unit cells (CFU-C), at weeks 2, 4 and 5, respectively. At the same time-points the number of primitive long-term culture initiating cells (LTC-IC) showed a 4 +/- 2 SD, 3.3 +/- 1.5 SD and 2.3 +/-1 SD fold increase compared to baseline values. BCR-ABL mRNA analysis of single colonies demonstrated that 27 +/- 9% SD and 7 +/- 3% SD CFU-C at weeks 4 and 5, respectively, expressed the fusion gene, whereas leukaemic LTC-IC disappeared from the culture by week 2. These results suggest that leukaemic CD34+ DR- cells have a different pattern of response to CSFs than normal cells. In addition, we established culture conditions which allow selective expansion of benign haemopoietic cells coexisting with leukaemic progenitors.

Antigens, CD34↗

PubMed1998

Generation and functional characterization of human dendritic cells derived from CD34 cells mobilized into peripheral blood: comparison with bone marrow CD34+ cells.

Dendritic cells (DCs) are the most powerful professional antigen-presenting cells (APC), specializing in capturing antigens and stimulating T-cell-dependent immunity. In this study we report the generation and characterization of functional DCs derived from both steady-state bone marrow (BM) and circulating haemopoietic CD34+ cells from 14 individuals undergoing granulocyte colony-stimulating factor (G-CSF) treatment for peripheral blood stem cells (PBSC) mobilization and transplantation. Clonogenic assays in methylcellulose showed an increased frequency and proliferation of colony-forming unit-dendritic cells (CFU-DC) in circulating CD34+ cells, compared to that of BM CD34+ precursors in response to GM-CSF and TNF-alpha with or without SCF and FLT-3L. Moreover, peripheral blood (PB) CD34+ cells generated a significantly higher number of fully functional DCs, as determined by conventional mixed lymphocyte reactions (MLR), than their BM counterparts upon different culture conditions. DCs derived from mobilized stem cells were also capable of processing and presenting soluble antigens to autologous T cells for both primary and secondary immune response. Replacement of the early-acting growth factors SCF and FLT-3L with IL-4 at day 7 of culture of PB CD34+ cells enhanced both the percentage of total CD1a+ cells and CD1a+ CD14- cells and the yield of DCs after 14 d of incubation. In addition, the alloreactivity of IL-4-stimulated DCs was significantly higher than those generated in the absence of IL-4. Furthermore, autologous serum collected during G-CSF treatment was more efficient than fetal calf serum (FCS) or two different serum-free media for large-scale production of DCs. Thus, our comparative studies indicate that G-CSF mobilizes CD34+ DC precursors into PB and circulating CD34+ cells represent the optimal source for the massive generation of DCs. The sequential use of early-acting and intermediatelate-acting colony-stimulating factors (CSFs) as well as the use of autologous serum greatly enhanced the growth of DCs. These data may provide new insights for manipulating immunocompetent cells for cancer therapy.

Adjuvants, Immunologic↗

PubMed1998

Inv(16) acute myeloid leukemia cells show an increased sensitivity to cytosine arabinoside in vitro.

Karyotype represents the major independent prognostic factor for response and remission duration in acute leukemia. In particular, it has been reported that acute myeloid leukemia (AML) patients with inv(16) abnormality show a better prognosis, especially in case of treatment with high-dose Ara-C (HD Ara-C) containing regimens. In this study we aimed at testing whether leukemic cells from patients showing the inv(16) were more sensitive to Ara-C in vitro, compared to AML blasts from patients with normal karyotype or chromosomal abnormalities other than t(15;17) or t(8;21). We analyzed blast cells from 30 patients who were diagnosed and treated in our institution. The IC50 of Ara-C, as tested by the XTT colorimetric assay, was significantly lower in cases with inv(16) (18.5+/-15.88 micromol/l vs. 38+/-14.6 micromol/l,in cases with other abnormalities, p=0.01). This result was confirmed by a higher incorporation of [3H]-Ara-C into DNA (p=0.02 and p=0.001 compared to samples with normal and abnormal karyotype, respectively). All the same, Ara-C induced apoptosis was significantly increased in cells from patients with inv(16). Our data suggest a possible interaction between the molecular background of inv(16) and a modification of intracellular metabolism of Ara-C, and could thus provide a rationale for HD-Ara-C-based schedules for patients with inv(16) AML.

Acute Disease↗

PubMed1998

Clinical implications of serum levels of soluble CD30 in 70 adult anaplastic large-cell lymphoma patients.

PURPOSE: In the last few years, the search for new biologic markers in high-grade non-Hodgkin's lymphomas has provided important results. In particular, soluble CD30 (sCD30) levels were elevated in most patients with Hodgkin's disease (HD) and anaplastic large-cell lymphoma (ALCL). PATIENTS AND METHODS: From September 1988 to October 1993, treatment was completed in 70 previously untreated patients with ALCL, of whom 38 had the common type (ALCL-CT) and 32 had the Hodgkin's-like subtype (ALCL-HL). Serum sCD30 levels were measured at the time of diagnosis and after induction polychemotherapy in all patients; in addition, the initial sCD30 levels were compared with those obtained from 50 stage-matched patients with HD. RESULTS: Pretreatment levels of sCD30 were highly elevated in the stage-matched group of HD patients compared with healthy controls; median sCD30 levels in patients with ALCL-CT and ALCL-HL were 18 and seven times higher, respectively, than in patients with HD. The sCD30 level normalized on achievement of complete response (CR). The risk of lower relapse-free survival was associated with bulky disease, advanced stage, and high pretreatment sCD30 levels; the risk of lower overall survival was associated with advanced stage and pretreatment levels of sCD30 in both univariate and multivariate analysis. CONCLUSION: The results of this study suggest that sCD30 is a specific prognostic indicator of the risk for lower complete response rate and relapse-free expectancy for patients with ALCL.

Adolescent↗

PubMed1998

Allogeneic peripheral blood stem cell transplantation in patients with early-phase hematologic malignancy: a retrospective comparison of short-term outcome with bone marrow transplantation.

BACKGROUND AND OBJECTIVE: Transplantation of mobilized allogeneic peripheral blood stem cells (PBSC) has recently been reported by several groups. However, few patients receiving an allograft in the early stage of their disease have been described so far. DESIGN AND METHODS: Fifteen patients with early stage hematologic malignancies were transplanted with cryopreserved allogeneic PBSC from HLA-identical siblings. PBSC were collected after priming with 10 micrograms/kg/day of glycosylated granulocyte colony-stimulating factor (G-CSF, lenograstim). Outcomes were compared to a historical control group of 15 patients who received conventional bone marrow transplantation (BMT) from HLA-identical sibling donors. The two groups were matched for diagnosis, stage of disease, age, preparative regimen, graft-versus host (GVHD) prophylaxis, patients' and donors' gender and cytomegalovirus (CMV) serology. Diagnoses in both groups were: chronic myelogenous leukemia (CML) in first chronic phase (= 5), acute leukemia in first complete remission (CR) (= 5), non-Hodgkin's lymphoma in CR (= 1) and multiple myeloma (MM) with sensitive disease (= 4). All patients were given cyclosporin-A (CsA) and methotrexate (MTX) for GVHD prophylaxis. Preparative regimens varied according to diagnosis and included either busulfan/cyclophosphamide combination (BU/Cy) or total body irradiation/cyclophosphamide +/- melphalan (TBI/Cy +/- Mel). RESULTS: The patients in the PBSC group showed a more rapid hematopoietic reconstitution with a significant difference in the median times to 1 x 10(9) neutrophils/L (19 days vs. 26 days; p = 0.03) and to platelet transfusion independence (18 days versus 22 days; p = 0.02). This finding was associated with a significantly shorter hospitalization (28 days versus 33 days after transplantation; p = 0.01). In the PBSC series, grade II-IV acute GVHD occurred in 3 patients (20%) and grade III-IV in 1 patient (7%). In the BMT control group, grade II-IV aGVHD was reported in 2 cases (13%; p = NS) and 1 case had grade III-IV GVHD. Chronic GVHD developed in 7 patients (47%) (limited = 6; extensive = 1) undergoing PBSC transplantation and 5 patients (33%) (limited = 4; extensive = 1) in the BMT series (p = NS). No difference was found in the incidence of grade II-IV (according to the World Health Organization) mucositis, whereas PBSC recipients did have a significantly lower incidence of additional severe (grade III-IV) organ toxicity. After a median follow-up of 300 days (range 180-630), all PBSC patients are still alive with a median Karnofsky score of 100% (range 80%-100%). Thirteen patients are in CR and 2 myeloma patient are in good partial remission (PR). Also, in the BMT group the peritransplant mortality was absent; two MM patients died due to progressive disease at day +796 and +1,023, respectively; one leukemic patient died of chronic GVHD 407 days after transplantation and one additional leukemic individual relapsed 1,140 days after BMT. INTERPRETATION AND CONCLUSIONS: This retrospective comparison suggests that allogeneic PBSC transplantation performed in the early stage of the disease is safe and may be associated with a more rapid hematopoietic reconstitution than BMT, as well as lower transplant-related toxicity and earlier hospital discharge with apparently no increased risk of acute and chronic GVHD.

Adolescent↗

PubMed1998

Clinical use of allogeneic hematopoietic stem cells from sources other than bone marrow.

BACKGROUND AND OBJECTIVE: Peripheral blood stem cells (PBSC) are being increasingly used as an alternative to conventional allogeneic bone marrow (BM) transplantation. This has prompted the Working Group on CD34-Positive Hematopoietic Cells to evaluate the current utilization of allogeneic PBSC in clinical hematology. EVIDENCE AND INFORMATION SOURCES: The method employed for preparing this review was that of informal consensus development. Members of the Working Group met three times, and the participants at these meetings examined a list of problems previously prepared by the chairman. They discussed the single points in order to reach an agreement on different opinions and eventually approved the final manuscript. Some of the authors of the present review have been working in the field of stem cell transplantation and have contributed original papers in peer-reviewed journals. In addition, the material examined in the present review includes articles and abstracts published in journals covered by the Science Citation Index and Medline. STATE OF THE ART: Review of the current literature shows that unmanipulated allogeneic PBSC give prompt and stable engraftment in HLA-identical sibling recipients. Despite the much higher number of T-cells infused, the incidence and severity of acute GVHD after PBSC transplant seems comparable to that observed with bone marrow (BM) cells. In comparison to the latter, PBSC probably ensure faster immunologic reconstitution in the early post-transplant period. Controversial results on the incidence and severity of acute-GVHD have been reported when CD34+ selection methods are used. Prospective randomized trials are underway to compare the results of PBSC and BM allogeneic transplantation. In mismatched family donor transplants, T-cell depleted PBSC successfully engraft immune-myeloablated recipients through a megacell-dose effect able to overcome the HLA barrier. Experience with PBSC in the context of unrelated donor transplants is currently anecdotal and prospective trials should be completed before that practice becomes routine. Finally, there is also limited evidence that, following induction chemotherapy, the addition of PBSC to donor lymphocyte infusion (DLI) for treatment of leukemia relapse after BMT may improve the safety and effectiveness of DLI itself. Concerning cord blood (CB) transplants, the most interesting aspects are the ease of CB collection and storage, the low risk of viral contamination and the low immune reactivity of CB cells. This last property has its clinical counterpart in an apparently reduced incidence and severity of acute GVHD both in sibling and unrelated CB transplants, probably making the level of donor/recipient HLA disparity acceptable a greater degree with respect to what is required for transplants from other sources.

Blood Cells↗

PubMed1998

Prior treatment with alpha-interferon does not adversely affect the outcome of allogeneic BMT in chronic phase chronic myeloid leukemia.

BACKGROUND AND OBJECTIVE: Controlled clinical trials have shown that Interferon-alpha (IFN-alpha) is able to control myeloid proliferation and to suppress the Ph+ clonal hemopoiesis in early chronic phase chronic myeloid leukemia (CML): a growing number of patients are treated with this agent from diagnosis. However, if a CML patient has an HLA-identical sibling, bone marrow transplant (BMT) represents the best choice of treatment. Since IFN-alpha is known to modify the immunologic response and to increase marrow fibrosis, information is needed on the outcome of patients transplanted after IFN-alpha treatment. DESIGN AND METHODS: We analyzed retrospectively 32 Ph+ CML patients submitted to BMT in the last 6 years in Institute "Serágnoli". All the patients were in 1st chronic phase, their median age was 37 years, the donors were HLA-identical (27/32) or 1 Ag-mismatched (5/32) siblings. Big BuCy was the conditioning regimen employed for all and GVHD prophylaxis was based on CsA in 4 patients and Csa+MTX in 28 patients; all patients received homogeneous pre and post-transplant supportive care, antimicrobial and antiviral prophylaxis. These patients were divided into 2 groups according to the treatment before BMT: 16 received IFN from diagnosis to BMT (mean dose 6.9 MU/daily) for at least 6 mos (mean 23 mos, range 8-75) and 16 received chemotherapy alone (hydroxyurea [HU]). RESULTS: Hematological recovery was comparable in the two groups: time to 0.5 x 10(9)/L PMN was 20.5 days (range 11-32) in the IFN group and 20 days (range 10-32) in the HU group; time to 50 x 10(9)/L platelets was 28 days (range 20-117) in the IFN group and 27 days (range 20-112) in the HU group. The incidence of acute GVHD was not different in the two groups for any grade of the disease; in patients who survived more than 100 days, chronic GVHD occurred in the two groups with the same frequency. Seven patients died of transplant related mortality (TRM), 4 in the IFN group and 3 in the HU group. Hematological relapse was observed in only one case in the HU group; no cytogenetic relapse occurred. Disease free survivals at 7 years are 61% and 72%, respectively; the difference is not significant. INTERPRETATIONS AND CONCLUSIONS: Notwithstanding the low number of patients included in this study, the data reported here confirm that prior treatment with alpha-IFN does not adversely affect transplant outcome.

Adult↗

PubMed1998

Therapy-related acute leukemia associated with involvement of 11q23 after high grade non-Hodgkin lymphoma.

Therapy-related acute myeloid leukemias with balanced translocations affecting the 11q23 chromosome region are one of the most serious complications of treatments with topoisomerase II inhibitor drugs as epipodophillotoxins and anthracyclines. 1,2-5 These cases are usually associated with short interval time from previous chemotherapies, absence of myeloid dysplastic phase, hyperleukocytosis and young age. We and others have recently identified and cloned the ALL1 gene at 11q23 band (also named MLL, HRX. Hrxt) which is consistently altered in t-AML following therapies with topo II targeting drugs. However, there are few reports of cases of t-AML, clinically and biologically similar to the subtype of leukemias secondary to exposure to topo II inhibitors drugs but without the involvement of the ALL1 gene. These observations suggest that genes other than ALL1 which are etiopathogenetically relevant for hematological neoplasias are located in this cytogenetic region.

Acute Disease↗