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Biomedical subjects

F Gavosto

Publications and source records attributed to F Gavosto.

At least 19 recordsLinked to original sources
PubMed1992

Has IL2 a role in the management of minimal residual disease for acute leukemia?

Based on pre-clinical findings and on more recent preliminary in vivo data it has been suggested that immunotherapy with Interleukin 2 (IL2) may be employed in the treatment of acute leukemia patients. Here we shall discuss the biological and clinical observations which indicate that this innovative therapeutic approach may play a role in the management of minimal residual disease.

Acute Disease↗
PubMed1992

Interleukin 2 (IL2) in the management of acute myeloid leukemia: clinical and biological findings.

In this paper we review some of the preclinical findings which have led us to believe that immunotherapy with interleukin 2 (IL2)/lymphokine activated killer (LAK) cells may be a feasible approach in the management of acute myeloid leukemia. The main clinical and biological results so far obtained with IL2 treatment, and the currently ongoing protocols and strategies are discussed.

Acute Disease↗
PubMed1992

Autologous bone marrow transplantation followed by interleukin-2 in children with advanced leukemia: a pilot study.

In an attempt to prolong disease-free survival in children with acute leukemia, we tested the feasibility of interleukin-2 (IL-2) administration after an autologous bone marrow transplantation (ABMT). We report the clinical and biological data obtained in three children with acute myelocytic leukemia (AML) in second complete remission (CR) and in seven children with acute lymphocytic leukemia (ALL) in second or subsequent CR, who received IL-2 at a median interval of 78 days (range 38-125) from ABMT. Patients were treated with 1-2 cycles of IL-2 given by continuous infusion over a 5-day period using a daily escalating protocol, from 100 micrograms/m2 per day to the maximum tolerated dose, followed after 3 weeks by low-dose IL-2 for 5 days monthly over a 6-h infusion on an out-patient basis. Side effects greater than grade 2 (WHO system), consisting of thrombocytopenia, fever, cutaneous rash, nausea and vomiting, diarrhoea were common during the high-dose IL-2 cycles, but resolved 24-48 h after stopping IL-2. Only one patient developed liver toxicity (grade 3, WHO) on day +3 of the first cycle which prompted us to stop the administration of IL-2. An increase in lymphocytes and eosinophils was also observed. IL-2 treatment was followed by a normalization of NK function and by the generation of a high proportion of endogenous LAK cells. All seven ALL patients relapsed at a median of 5 months (range 1-23). Two AML patients relapsed at 1 and 11 months, while the other is still in continuous CR at 23 months after IL-2 treatment. Our IL-2 schedule for treatment of leukemia in children after ABMT is thus feasible but its efficacy requires further investigation.

Adolescent↗
PubMed1991

Defective lymphokine-activated killer cell generation and activity in acute leukemia patients with active disease.

In 26 myeloid and lymphoid acute leukemia patients at presentation the capacity to generate interleukin-2 (IL-2)-induced lymphokine-activated killer (LAK) cells effective against the natural killer (NK)-resistant Raji cell line, as well as the susceptibility of the blasts to normal peripheral blood (PB) LAK cells and to autologous LAK effectors was analyzed. The overall PB LAK activity against Raji cells was significantly lower in acute leukemia patients compared with normal controls (mean, 1,473 +/- 971 SD LU/10(8) LAK effectors v 3,340 +/- 1,862; P less than .001). The sensitivity of the blasts to autologous LAK cells was also significantly lower than to normal LAK effectors (517 +/- 593 LU/10(8) LAK effectors v 1,304 +/- 1,066; P less than .01). When the data were analyzed independently, four patterns of behavior could be recognized. The relatively largest group (9 of 26) included patients in whom effective LAK cells could be generated against the Raji line, but in whom the blasts were resistant to autologous PB-LAK effectors while being susceptible to normal LAK cells (defective specific LAK activity). In 5 of 26 cases, an incapacity to generate LAK activity against both allogeneic and autologous target cells was observed (defective LAK generation). In six further cases, the blasts were resistant to both allogeneic and autologous LAK populations, though the latter were effective against the Raji line (resistant blasts). The same defects could also be shown with bone marrow-derived LAK cells. Only in six cases did the leukemic blasts appear susceptible to autologous and allogeneic LAK cells. In four patients the analysis could be repeated at remission, and in three a restoration of the LAK function against the primary blasts was recorded. In the 10 cases studied at relapse, the blasts were resistant to autologous LAK effectors in nine and to normal LAK in seven. These data demonstrate that in most acute leukemia patients with active disease, a defect of the LAK machinery, either a deficient generation of LAK cells or the resistance of the blasts to LAK effectors, may be documented, pointing therefore to a possible contributory role of the LAK system in the control of leukemic cell growth. In view of the frequent normalization of the autologous LAK activity at the time of remission, immunotherapy with IL-2/LAK cells should be primarily aimed to patients with minimal residual disease.

Cell Line↗
PubMed1991

Peripheral blood and bone marrow immunophenotypic and functional modifications induced in acute leukemia patients treated with interleukin 2: evidence of in vivo lymphokine activated killer cell generation.

The effect of treatment with interleukin 2 (IL2) on the phenotypic and functional immune system of acute leukemia patients was investigated. Fifteen acute myeloid leukemia and acute lymphoid leukemia patients with evidence of persistent disease were further subdivided into two groups according to the percentage of bone marrow (BM) blasts: group a had 6-15% blasts and group b had 30-65%. Following two cycles of IL2 (Glaxo Imb, Geneva, Switzerland) given i.v. by continuous infusion at escalating doses, no major changes in the proportion of CD3-, CD4-, and CD8-positive cells were encountered in the blood or in the marrow of either group of patients. When these could be retested after four cycles of IL2, a significant increase of CD3+ and CD4+ cells was documented in the peripheral blood (PB), as well as a significant increase of CD3+ cells in the BM. Irrespective of the number of cycles administered, the proportion of CD16+ cells increased significantly in the blood in both groups of patients and in the marrow of group a patients only. The expression of CD25 was significantly enhanced in all samples tested. Following IL2 administration, an enhancement of the natural killer compartment was documented. This was consistently more evident in patients with more limited disease. A significant amplification of the in vitro-induced lymphokine-activated killer function was noted in the BM of the treated patients. Furthermore, we documented the presence both in the PB and in the BM of "spontaneous" lymphokine-activated killer cells generated in vivo following IL2 administration. These results demonstrate that in acute leukemia of both myeloid and lymphoid origin, treatment with IL2 is capable of inducing profound immunophenotypic and functional modifications in PB and in BM lymphocytes, particularly in patients with more limited disease. The evidence of the in vivo activation of cytotoxic cells, particularly in the BM, may help to explain the clinical responses preliminarily observed in individual acute leukemia patients.

Acute Disease↗
PubMed1991

Hodgkin's disease in 63 intravenous drug users infected with human immunodeficiency virus. Gruppo Italiano Cooperativo AIDS & Tumori (GICAT).

Sixty-three cases of Hodgkin's disease in intravenous drug users (IVDUs) have been collected by the Italian Cooperative Group on AIDS-Related Tumors (GICAT). In most patients (74%) the histological pattern was that of mixed cellularity and lymphocyte depletion. In 39% of patients the initial symptom was a persistent lymph node enlargement due to persistent generalized lymphadenopathy (PGL). Unusual presentations included Waldeyer's ring, skin, meninges, colon, and pleura. After MOPP alternated or followed by ABVD, MOPP alone, or ABVD alone, 15 of 32 patients (47%) had a complete remission (CR) and 15 of 32 (47%) had a partial remission (PR). The median duration of CR was 14 months, while the median survival of patients with CR has not been reached; the median survival of patients treated with chemotherapy who had CD4 levels at presentation greater than or equal to 400/mm3 was significantly superior to that of those who had CD4 less than 400/mm3. The overall median survival was only 14 months. Forty-four percent of patients receiving chemotherapy, with or without radiotherapy, developed opportunistic as well as nonopportunistic infections. Lethal hepatic toxicity was observed in one patient. Among IVDUs, unusual presentations of Hodgkin's disease occurred at a lower rate than was previously reported for homosexuals. Complete remissions could be achieved in almost half the patients, but non opportunistic infections, in addition to parenchymal function impairment due to drug abuse, may limit treatment administration in IVDUs.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Treatment of acute myeloid leukaemia patients with recombinant interleukin 2: a pilot study.

Twelve patients with acute myeloid leukaemia (AML) with evidence of resistant disease were treated with recombinant interleukin 2 (rIL2) given intravenously by continuous infusion. No objective response to rIL2 alone was documented in the seven patients with advanced disease (20-90% resistant blasts in the marrow), except for a partial response to rIL2 plus chemotherapy in one. Of the five patients with limited disease (8-15% marrow blasts), three obtained a complete disappearance of the blasts following two to four 5d courses of rIL2 alone. One patient persists in fourth complete remission (CR) 30 months later, another obtained a third CR for 4 months, and the last remained in third CR for 9 months before relapsing. This latter patient achieved a fourth CR with low-dose cytarabine. The remissions have been maintained with low-dose monthly courses of rIL2 given on an out-patient basis. Two AML did not respond to rIL2 alone; one, however, obtained a fourth CR with chemotherapy and rIL2. Administration of rIL2 was accompanied by organomegaly and leucocytosis, with a frequent lymphocytosis and increase in eosinophils and large granular lymphocytes, both in the blood and in the marrow. Side effects, though often severe, were controllable using a daily dose escalating protocol and never required intensive care treatment. The results of this pilot study indicate that treatment of AML patients with rIL2 is feasible and may result in the disappearance of chemotherapy-resistant blasts in patients with limited but detectable disease. Further controlled trials in AML in CR appear warranted.

Acute Disease↗
PubMed1990

New type of Bcr/Abl junction in Philadelphia chromosome-positive chronic myelogenous leukemia.

A new and rare type of Bcr/Abl junction between exon C3 of the 3' portion of the Bcr gene and Abl exon 2 has been identified in the leukemic cells of two Ph1-positive chronic myelogenous leukemia patients in chronic phase. This is the fourth type of Bcr/Abl junction so far identified in Ph1-positive hematologic malignancies and is a consequence of an unusual breakpoint position on chromosome 22 that falls approximately 20 kb downstream of the major breakpoint cluster region (bcr) of the Bcr gene. The new hybrid mRNA is 540 base pairs (bp) longer than that expressed by the K562 cell line and could codify for a Bcr/Abl protein carrying 180 additional aminoacids with respect to the larger P210 protein so far identified. The hematologic phenotype expressed by the two patients carrying this unusual type of Bcr/Abl rearrangement does not significantly differ from that commonly seen in chronic myelogenous leukemia.

Amino Acid Sequence↗
PubMed1990

Human GM-CSF in vivo: identification of the target cells and of their kinetics of response.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) was given for three days (8 micrograms/kg/day) to 14 subjects who had solid tumors and normal hemopoiesis. The treatment induced a rapid 3- to 5-fold increase in the number of circulating neutrophils, eosinophils and monocytes. Lymphocytes, platelets and reticulocytes were unmodified during treatment. Activation of circulating neutrophils during GM-CSF treatment was demonstrated by a significant, increased release of neutrophil-derived platelet-activating factor after stimulation with N-formyl-methionyl-leucyl-phenylalanine, tumor necrosis factor-alpha or phagocytosis. The granulomonocytosis was dependent on increased bone marrow production of mature cells. Using the thymidine suicide technique, we observed that GM-CSF more than doubled the percentage of granulocyte-macrophage and megakaryocyte colony-forming units (CFU-gm and CFU-meg) and erythroid burst-forming units (BFU-e) in the S phase of the cell cycle. However, at the level of morphologically recognizable cells with autoradiography, we observed that GM-CSF increased the labeling index of the granulo-monopoietic cells, whereas that of the erythroblasts was unchanged. These data suggest that in accordance with in vitro observations, GM-CSF exerts its activity through all granulo-monopoietic lineages, whereas other cytokines (erythropoietin, thrombopoiesis-stimulating factors) may be needed to fully exploit the proliferative stimulus of GM-CSF on BFU-e and CFU-meg. After treatment discontinuation, the proliferative activity drops to values lower than before treatment, suggesting a period of relative refractoriness of marrow progenitors to the cytocidal effect of cell cycle-specific antineoplastic agents. This hypothesis is under evaluation in a controlled clinical trial where GM-CSF is given prior to chemotherapy.

Bone Marrow Transplantation↗
PubMed1990

Immunoglobulin and Myc gene structure in lymphnode biopsies from HIV-positive patients with LAS and lymphoma.

The pattern of immunoglobulin (Ig) gene rearrangement and the genomic structure of the Myc locus were investigated in the DNA of 20 lymphnode biopsies of patients suffering from lymphoadenopathy-associated syndrome (LAS) and from 3 patients with Burkitt's lymphoma. Although polyclonality was the prevalent pattern of Ig gene rearrangement observed in LAS, in 30% of the cases discrete bands of Ig heavy chain gene rearrangement were identifiable due to the presence of monoclonal or oligoclonal cell populations. However, structural alterations of the Myc gene were not detected in any cases. As expected, in all three Burkitt's lymphomas studied, the lymphnode DNA displayed a clonal pattern of Ig heavy chain gene rearrangement. The Myc was altered in two cases, which presented a truncation of the gene beginning within a very short region of the first intron. By contrast, the breakpoint positions on chromosome 14 mapped in different regions of the Ig loci, which in both cases involved the switch (SH) area. Data confirm the relatively common occurrence of oligoclonal expansions within B cells in LAS and the frequent involvement of the Myc oncogene in the process of lymphomagenesis in individuals positive for human immunodeficiency virus (HIV).

AIDS-Related Complex↗
PubMed1989

N-ras mutations in myeloid leukemias.

The presence of mutations activating the N-ras gene was investigated by the polymerase chain reaction technique in twenty patients with acute myeloblastic leukemia (AML) at onset and in four patients with Ph1 positive chronic myelogeneous leukemia (CML) either in chronic phase or in blast crisis. Four remission samples and four relapses from the AML cases were also studied. Mutations were found in five out of twenty (25%) untreated AML cases at onset. No mutations were detected in the complete remission samples, two of them with N-ras mutations during the leukemic phase. Two out of the four leukemia relapses were positive for the same N-ras mutation shown at presentation, whereas no new mutations were found in the other two initially negative cases. An N-ras mutation appeared during the blast crisis of one of the four CML, which were all negative during the chronic phase. In conclusion, whereas some data appear to be consistent with a role of the N-ras mutations as initiating events in myeloid leukemias, in other cases N-ras activation seems to represent a factor involved in progression. These data suggest that a partial overlapping between initiation and progression factors could exist in naturally occurring tumors.

Codon↗
PubMed1989

Kinetics of human hemopoietic cells after in vivo administration of granulocyte-macrophage colony-stimulating factor.

The kinetic changes induced by granulocyte-macrophage colony-stimulating factor (GM-CSF) on hemopoietic cells were assessed in physiological conditions by administering GM-CSF (8 micrograms/kg per d) for 3 d to nine patients with solid tumors and normal bone marrow (BM), before chemotherapy. GM-CSF increased the number of circulating granulocytes and monocytes; platelets, erythrocytes, lymphocyte number, and subsets were unmodified. GM-CSF increased the percentage of BM S phase BFU-E (from 32 +/- 7 to 79 +/- 16%), day 14 colony-forming unit granulocyte-macrophage (CFU-GM) (from 43 +/- 20 to 82 +/- 11%) and day 7 CFU-GM (from 41 +/- 14 to 56 +/- 20%). The percentage of BM myeloblasts, promyelocytes, and myelocytes in S phase increased from 26 +/- 14 to 41 +/- 6%, and that of erythroblasts increased from 25 +/- 12 to 30 +/- 12%. This suggests that GM-CSF activates both erythroid and granulomonopoietic progenitors but that, among the morphologically recognizable BM precursors, only the granulomonopoietic lineage is a direct target of the molecule. GM-CSF increased the birth rate of cycling cells from 1.3 to 3.4 cells %/h and decreased the duration of the S phase from 14.3 to 9.1 h and the cell cycle time from 86 to 26 h. After treatment discontinuation, the number of circulating granulocytes and monocytes rapidly fell. The proportion of S phase BM cells dropped to values lower than pretreatment levels, suggesting a period of relative refractoriness to cell cycle-active antineoplastic agents.

Bone Marrow↗