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Biomedical subjects

F Frassoni

Publications and source records attributed to F Frassoni.

At least 127 records · Page 7Linked to original sources
PubMed1992

Cytogenetic analysis of hemopoietic peripheral blood cells collected by leukapheresis after intensive chemotherapy in advanced phase Philadelphia-positive chronic myelogenous leukemia.

Peripheral hemopoietic blood cells previously collected by leukapheresis were reinfused in advanced phase Philadelphia (Ph)-positive chronic myelogenous leukemic patients to promote the recovery of bone marrow function after intensive radiochemotherapy. Cytogenetic analysis was performed on these cells, induced to proliferate and to be mobilized by a first administration of marrow toxic drugs and collected when the white blood cell count was very low. In five patients only Ph-negative apparently normal cells were found. In five cases different proportions of Ph+/Ph- cells were observed and in the remaining five cases only Ph+ cells were present. Chromosomal abnormalities other than Ph, not detected in the cytogenetic analysis performed on bone marrow cells before chemotherapy treatment, were found in five cases. These findings confirm that Ph- cells can persist in the marrow of Ph+ patients in the advanced phase of disease and indicate that a high percentage of leukemic cells retain karyotype evolution not detectable using standard drawing and culture techniques.

Antineoplastic Agents↗
PubMed1991

Increased risk of leukemia relapse with high-dose cyclosporine A after allogeneic marrow transplantation for acute leukemia.

Eighty-one patients with acute myeloid leukemia (ANLL, n = 44) or acute lymphoblastic leukemia (ALL, n = 37), aged 10 to 50 years were randomized to receive 1 mg/kg per day (n = 41, group A) or 5 mg/kg per day (n = 40, group B) of cyclosporine A (CyA) from day -1 to day +20 after bone marrow transplant (BMT). All patients received CyA orally thereafter. All patients were prepared with cyclophosphamide (CY) 120 mg/kg and fractionated total body irradiation (TBI), and received unfractionated BM from an HLA-identical sibling. The two groups were comparable for diagnosis, disease status, French-American-British (FAB) classification, WBC count at diagnosis, cytogenetic abnormalities, extramedullary disease before BMT, donor/recipient age and sex, number of cells infused, and number of days with intravenous (IV) CyA. Median follow-up for surviving patients in group A was 983 v 632 days in group B. Patients in group A had lower serum levels of CyA (295 v 686 ng/mL, P = .004), lower bilirubin levels (1.9 v 2.6 mg/dL, P = .07), lower creatinine levels (0.9 v 1.4 mg/dL, P = .06), and a lower proportion of CD8+ cells in the peripheral blood (PB) within day +21 (19% v 28%, P = .07). First day to 0.5 x 10(9)/L neutrophils was comparable in the two groups (13 v 14 days; P = .1). In a Cox model, the actuarial risk of acute graft-v-host disease (GVHD) grade II+, after stratification for age (less than 20 years greater than) was significantly lower in group B patients (0.54, P = .04). The actuarial risk of developing chronic GVHD was comparable (P = .9). Actuarial transplant-related mortality (TRM) at 240 days was 28% and 26% (P = .8) in group A and B: the major cause of death was GVHD in group A (P = .02) and multiorgan toxicity in group B (P = .07). The actuarial risk of relapse at 2 years overall was 20% in group A and 52% in group B (P = .001); it was 9% v 43%, respectively, for patients in first remission (P = .0001) and 48% v 63% for patients in non-first complete remission (CR) (P = .1). Actuarial 2-year disease-free survival (DFS) in group A and B was 58% v 32% (P = .02) for all patients, 71% v 35% (P = .01), in first remissions, and 30% v 23% (P = .2) in advanced disease.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗
PubMed1991

Eradication of leukaemic marrow and prevention of leukaemia relapse with total body irradiation and bone marrow transplantation.

A series of studies was carried out to determine the effect of allogeneic bone marrow transplantation (BMT) on leukaemia. The study aimed at two different, but strictly linked issues: (1) identification of the eradication capability of BMT, and (2) evaluation of the effect of BMT, both in preventing relapse and in producing long-term disease-free survival. Fifty-four patients allografted for leukaemia were evaluated at various intervals, after bone marrow transplantation, for the presence of host haemopoiesis using red-blood-cell and cytogenetic markers. Among 40 patients in remission, 10 showed functional host and donor haemopoiesis (mixed chimerism), while in 30, host haemopoiesis was never detected (complete chimerism). Seven of the 14 evaluable patients who relapsed showed the reappearance of host haemopoiesis at the time of relapse. The records of received doses of TBI indicate that patients who achieved mixed chimerism, either relapsing or not, received significantly lower doses than complete chimeras. However, some patients with complete chimerism received a TBI dose equivalent to the dose received by those with mixed chimerism, suggesting that the TBI dose is not the only factor determining the reappearance of host haemopoiesis. The data on chimerism and relapse suggest that there is heterogeneity in radiosensitivity between normal marrow cells and leukaemic cells, and further, within the different types of leukaemia. The incidence/severity of acute and chronic graft-vs-host disease (GvHD) was significantly higher in complete chimeras than in mixed chimeras suggesting that mixed chimerism may play a role in the development of tolerance; however, it could be the tolerance (i.e. absence of GvHD) which is responsible for the persistence of host haemopoietic cells. One-hundred-and-sixty-eight patients undergoing allogeneic bone marrow transplantation (BMT) for acute myeloid leukaemia (AML) and chronic myeloid leukaemia were analyzed for risk factor associated with relapse. All patients received marrow from an HLA identical sibling after preparation with cyclophosphamide 120 mg/kg and total body irradiation (TBI) of 330 cGy on days -3, -2, -1. There was a difference of +/- 18% between the nominal total dose of 990 cGy and the actual received dose as indicated by dosimetric recordings. While interstitial pneumonitis had minimal impact on survival there was a considerable difference in the incidence of relapses. The incidence of relapse was higher in patients receiving less, than in patients receiving more than 1000 cGy respectively and this had a major impact on survival. However, transplant-related mortality was slightly higher in the group of patients receiving higher doses of TBI.(ABSTRACT TRUNCATED AT 400 WORDS)

Bone Marrow Purging↗
PubMed1991

Late complications of allogeneic bone marrow transplantation.

This report underlines the occurrence of multiple early and late complications after allogeneic BMT. Most of these are caused by the conditioning regimen, and especially by the use of total body irradiation. This should discourage the use of radiation for patients with non-malignant disorders such as aplastic anemia. We have shown that interstitial pneumonia is greatly reduced after fractionated TBI, and this should also be considered when designing transplant protocols. Prolonged immunodeficiency post-BMT is responsible for a high rate of infections: this suggests that long-term prophylactic antibiotic therapy should be considered. Great attention should be given to the quality of life of long-term survivors: to this respect a specific program for monitoring and treating gonadal complication can be extremely useful.

Bone Marrow Transplantation↗
PubMed1991

Karyotype evolution of Ph positive chronic myelogenous leukemia patients relapsed in advanced phases of the disease after allogeneic bone marrow transplantation.

Sixty-eight patients affected by Philadelphia chromosome (Ph) positive chronic myelogenous leukemia (CML) underwent allogeneic bone marrow transplantation (BMT) and were successfully studied from a cytogenetic point of view, before and after the BMT. Nineteen had evidence of cytogenetic and clinical relapse. Cytogenetic analyses of 14 patients who, after the relapse, showed progression to the accelerated or blastic phase of the disease, are presented. Five of these cases had only the Ph chromosome without karyotype evolution; in one case Ph duplication without other anomalies was detected, while in the remaining eight cases cytogenetic analysis showed apparently random clonal structural abnormalities (translocations, inversions, deletions, and marker formations). Therefore, the classical "non-random" abnormalities (+8, i(17q), +Ph, +19, +21) were not as common as in conventionally treated Ph+ CML. From our data, karyotype evolution during advanced phases in Ph+ CML patients after BMT differs from the evolution seen in conventionally treated patients, by the presence of numerous structural unusual abnormalities, possibly related to radiochemotherapy conditioning to BMT. Therefore, BMT treatment is not always able to eradicate the Ph+ clone but can reduce the incidence of the formation and/or expansion of Ph+ clones with additional non-random abnormalities.

Bone Marrow Transplantation↗
PubMed1991

Therapy of acute phase chronic myelogenous leukemia with intensive chemotherapy, blood cell autotransplant and cyclosporine A.

The expansion of the Philadelphia (Ph) chromosome positive clone in chronic myeloid leukemia (CML) may depend on its capacity to suppress the proliferation of Ph-negative stem cells, but this proliferative advantage might, in certain circumstances, be reversible. Various lines of evidence suggest that Ph-negative cells, albeit in a suppressed state, must still be present. As recently suggested, the expansion of 'putative' normal Ph-negative hemopoietic stem cells might have, in certain circumstances, a proliferative advantage over the Ph clone in CML. This suggests that the treatment of CML with intensive chemotherapy might allow the collection of Ph-negative hemopoietic cells in the early phase of recovery. Eight patients with acute phase chronic myelogenous leukemia (AP-CML) were treated with idarubicin, intermediate dose cytarabine and etoposide. During recovery from bone marrow aplasia, when the white blood cell count reached 0.3-1 x 10(-9), blood cells were collected with 2-5 (median 3) consecutive leukapheresis. In 5/8 patients, these peripheral cells were Ph-negative at the cytogenetic analysis. Moreover, in one case the polymerase chain reaction analysis performed to detect the presence of minimal residual disease in the cells collected by leukapheresis was negative, further confirming that this approach may induce a very high degree of suppression of the Ph-positive clones. After complete recovery, these five patients were subsequently treated with high-dose etoposide, cyclophosphamide and total body radiation (10 Gy, single dose) followed by reinfusion of Ph-negative peripheral blood stem cells. All these patients received cyclosporine A post-autotransplant in an attempt to induce acute graft-versus-host-disease. Three of 5 patients remain in clinical and cytogenetic remission 5-15 months post-transplant. It is concluded that Ph-negative peripheral blood stem cells can be recovered from patients with AP-CML and used successfully to restore Ph-negative hemopoiesis after high dose therapy.

Adult↗
PubMed1991

An assessment of chimeric transcript detection in CML patients after bone marrow transplantation.

The Polymerase Chain Reaction (PCR) was used to evaluate minimal residual disease in 21 Ph+ CML patients at various intervals after allogeneic bone-marrow transplantation (ABMT) by amplification of bcr-abl cDNA. All patients were cytogenetically Ph- at the moment of molecular analysis. Of these 76% were PCR negative, 24% positive for bcr-abl transcripts. 100% of the Cyclosporine A/Methotrexate treated patients (7/7) were negative. Severe chronic GvHD was twice as frequent in PCR positive patients (60%) than in negative ones (31%). The only patient who relapsed during follow up was PCR positive. The two longest survivors were PCR negative. These data are still insufficient for assessing the predictive value of PCR analysis in CML. Patients. 25 patients with Ph+ CML at diagnosis were enrolled in this study. Two died soon after BMT because of infection for failure of engraftment/early relapse, two were Ph chromosome positive and PCR+, and were therefore dismissed from this study. All remaining 21 patients were cytogenetically Ph- at the time of molecular analysis and underwent ABMT from matched donors. All patients were conditioned with cyclophosphamide and TBI: 330 cGy the three days prior to transplantation (990 cGy total, treatment B), or 200 cGy two times daily for three days (1200 cGy total, treatment A). In 3 cases the marrow was treated for GvHD prophilaxis with Campath alone or Campath plus BT 5/9 monoclonal antibodies (1). All patients were treated with Cyclosporin A (CS) 5 mg/kg i.v. from the day prior to transplantation until 25-30 days after; 9 of these were treated with CS plus Methotrexate (MTX).

Biomarkers, Tumor↗
PubMed1991

Clinical value of PCR in diagnosis and follow-up of leukaemia and lymphoma: report of the third Workshop of the Molecular Biology/BMT study group.

The proceedings of the third workshop of the molecular biology/bone marrow transplantation (BMT) study group held in January 1991 in Verona, Italy. This workshop was convened to review progress in the application of molecular techniques to the diagnosis and follow-up of patients with chronic myeloid leukaemia (CML) as well as other haematologic malignancies. The results of polymerase chainreaction studies in 157 CML patients 1-90 months post BMT suggest that leukaemia is frequently detectable for the first 12 months but rarely detected thereafter except in patients known to have a high risk of relapse. In the acute leukaemias and lymphomas there is a rapidly increasing number of leukaemia-specific as well as clone-specific molecular markers now available for the detection of minimal disease. It may be possible to coordinate multi-center prospective studies to investigate the role of these markers in the diagnosis and follow-up of haematologic malignancies.

Bone Marrow Transplantation↗
PubMed1990

Total body irradiation before allogeneic and autologous bone marrow transplantation: a ten year Genoa experience.

Since 1976 in Genoa, 291 TBI treatments were performed. Before allogeneic BMT, 1000 cGy/1 fx were prescribed in the first 22 patients, and then 990 cGy/3 fx/3 d in AML and CML, and the same or 1200 cGy/6 fx/3 d in ALL. Survival (S) and probability of remaining in remission (PRR) were 54% and 69% at 80 months in 80 AML; in 62 CML 45% and 60% at 60 months; in 69 ALL, 32% and 45% at 82 months. Differences in favour of higher doses and dose rates were observed and are presented. Before autologous BMT, 1000 cGy/1 fx were prescribed to AML and NHL, and 1200 cGy/3 fx/3 d to ALL patients. Disease free survival (DFS) was 71% and 13% at 82 months in 21 AML treated in first R and 9 ALL, respectively; 81% at 32 months in 11 NHL treated in R.

Clinical Protocols↗
PubMed1990

Growth of CD34+ acute myeloblastic leukemia colony-forming cells in response to recombinant hematopoietic growth factors.

In order to minimize the interactions of clonogenic cells with accessory cells and characterize the direct effect of recombinant hematopoietic growth factors (HGF) on acute myelogenous leukemia colony-forming cells (AML-CFU), the response of CD34+ AML-CFU to individual or combined recombinant HGF, i.e., interleukin-1 (IL-1), interleukin-3 (IL-3), interleukin-6 (IL-6), granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), and macrophage colony-stimulating factor (M-CSF), was studied in 10 patients and compared with the growth response obtained from unfractionated marrow cells. IL-3 and GM-CSF had a similar stimulating activity on AML-CFU growth. G-CSF resulted the most efficient stimulus for colony formation and was additive or synergistic with IL-3 and GM-CSF, M-CSF, used alone, had a negligible stimulating activity. When CD34+ cells were used, IL-1 by itself had a low stimulating activity and displayed little or no synergy with IL-3, GM-CSF, and G-CSF. On the contrary, when unfractionated cells were used, IL-1 was very effective in inducing AML-CFU formation and was markedly synergistic with IL-3 and GM-CSF. These results show that IL-1-induced leukemic colony formation is prevalently mediated by accessory cells. IL-6 supported AML-CFU growth in seven of 10 cases, thus showing a direct effect on CD34+ leukemic cells, and enhanced the growth of IL-3-(+47 to +167%) and GM-CSF-dependent (+60 to +110%) AML-CFU. Recloning studies of single colonies demonstrated that primary CD34+ AML-CFU, stimulated by IL-3 and GM-CSF, generated secondary and tertiary colonies, whereas primary AML-CFU stimulated by G-CSF and IL-6 failed to give rise to secondary colonies, thus indicating a complete suppression of self-renewal. Sequential recloning of colonies grown in the presence of IL-3 + IL-6 demonstrated that addition of IL-6 and IL-3-containing plates resulted in a nearly complete suppression of self-renewal. In conclusion, these results demonstrate the heterogeneity of the CD34+ leukemic cell fraction and indicate the existence of complex regulatory events at the level of CD34+ leukemic cells. Data obtained from recloning experiments are of therapeutic interest in view of the clinical application of HGFs in the treatment of myeloid leukemias.

Adult↗
PubMed1990

Mixed chimerism after allogeneic marrow transplantation for leukaemia: correlation with dose of total body irradiation and graft-versus-host disease.

Fifty-four patients allografted for leukaemia were evaluated at various intervals after bone marrow transplantation for the presence of host haemopoiesis using red blood cell and cytogenetic markers. Out of 40 patients in remission, 10 showed functional host and donor haemopoiesis (mixed chimerism), whereas in the other 30 (complete chimerism) host haemopoiesis was never detected. Seven of the 14 evaluable patients who relapsed showed the reappearance of host haemopoiesis at the time of relapse. Analysis of the dose of total body irradiation (TBI) indicated that patients who achieved mixed chimerism, whether or not they relapsed, had received significantly lower doses than those with complete chimerism. However, some patients with complete chimerism had received a TBI dose equivalent to the dose received by those with mixed chimerism, suggesting that the TBI dose is not the only factor determining the reappearance of host haemopoiesis. The data on chimerism and relapse suggest that there is heterogeneity in radiosensitivity between normal marrow cells and leukaemic cells, and also within the different types of leukaemia. The incidence/severity of acute and chronic graft-versus-host-disease (GVHD) was significantly higher in patients with complete chimerism than in mixed chimeras, suggesting that mixed chimerism may play a role in the development of tolerance. Alternatively the absence of GVHD (i.e. tolerance) may be responsible for the persistence of host haemopoietic cells.

Bone Marrow Transplantation↗
PubMed1990

Early and long term follow-up with minisatellite probes in bone marrow transplanted patients.

Twenty-five patients who received bone marrow transplantation (BMT) for chronic granulocytic leukemia (CGL), acute leukemia and severe aplastic anemia were studied before and after BMT in order to document and characterize the events following transplantation. DNA analysis was performed using minisatellite probes, which give rise to extremely polymorphic Southern blot band patterns specific to each individual and are regarded as "genetic fingerprint." Sensitivity studies using a mixture of donor and recipient cells could distinguish the presence of 1% of cells from one individual. Blood specimens were obtained from donor recipient before BMT and at days 10, 30, 90, and 270 after BMT. Karyotype analysis was also performed in CGL patients at the same time of DNA analysis. Engraftment was identified by DNA analysis as early as 10 days posttransplant and correlated with cytogenetic findings. This confirmed that a single hybridization filter is informative in 100% of patients and is easily applicable for early and long term studies of chimerism in BM transplanted patients.

Adolescent↗