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Biomedical subjects

F Mandelli

Publications and source records attributed to F Mandelli.

At least 235 records · Page 13Linked to original sources
PubMed1993

What is the best treatment for acute promyelocytic leukemia?

The modern treatment of acute myelogenous leukemia (AML), consists of a polychemotherapeutic induction treatment followed by a post-remission therapy of variable intensity and duration and acute promyelocytic leukemia (APL) does not differ from this behavior. However, differently from the other AML subtypes, APL shows a high response rate to induction monochemotherapies with anthracycline drugs. This high response rate to anthracycline monochemotherapies is very peculiar of APL. Moreover, it has been suggested that maintenance treatment regimens incorporating the drugs Methotrexate and 6-Mercaptopurine, two drugs generally not utilized in the post-remission treatment of other AML subtypes, may be effective in prolonging the leukemia-free survival of APL. Furthermore, the results firstly obtained by a Chinese group in 1988 by using the vitamin A derivative all-trans retinoic acid (ATRA) have been successively confirmed by several other groups in the world. Therefore, at present the all-trans retinoic acid appears to be the best CR inducer in APL. However, these CRs are short lasting when maintained with ATRA alone and eventually all patients relapse. As a consequence, patients achieving CR with ATRA still require intensive post-remission chemotherapy to maintain the CR. As for bone marrow transplantation procedures, it is our opinion that they do not represent the treatment of choice of APL in first CR considering the very good results obtained with standard pharmacological approaches. In conclusion, only future randomized prospective trials will clarify which, among the several proposed therapeutic approaches, should be preferred in this very peculiar subtype of AML.

Bone Marrow Transplantation↗
PubMed1993

Bisantrene in relapsed and refractory acute myelogenous leukemia.

Because of the lack of standard treatment in refractory and relapsed acute myelogenous leukemia (AML) several new drugs have been employed alone to evaluate their efficacy in this peculiar category of patient. Bisantrene, a new anthracene bishydrazone derivative, has shown antileukemic effect in phase I and II clinical trials with acceptable extrahaematological toxicity. Seven patients (six males and one female, median age 41.8 years) received Bisantrene (250 mg/sqm/daily 1-7) as a single agent in relapsed or refractory leukemia. 5 out of 7 patients achieved complete remission, one attained partial remission and one was resistant. However, haematological toxicity was severe with prolonged myelosuppression. Hepatic toxicity was the main extrahaematological side effect and occurred in 3 of 7 patients, however all of them recovered within 40 days. No cardiovascular dysfunction occurred although all the patients had been heavily previously treated with anthracyclines. Our data confirm that Bisantrere is active in relapsed and refractory AML and suggest the need for larger clinical trials to better evaluate its efficacy.

Adult↗
PubMed1993

Anthracycline containing regimens in intermediate grade lymphoma. Italian Cooperative Study Group on Intermediate Grade Malignant Lymphoma.

From March 1991 to April 1992, 44 previously untreated patients with stage II to IV intermediate-grade non-Hodgkin's lymphoma (according to the Kiel classification) were entered in a phase III comparative trial. The objectives of the study were to compare the efficacy and safety of using idarubicin instead of doxorubicin in the combination chemotherapeutic regimen CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone). Forty-four patients were randomly assigned to receive either CI(idarubicin)OP or CH(doxorubicin)OP. The study is ongoing and so far no significant differences in complete response rate and (non-)hematologic toxicity have been observed.

Adult↗
PubMed1993

Pilot study of 5-aza-2'-deoxycytidine (Decitabine) in the treatment of poor prognosis acute myelogenous leukemia patients: preliminary results.

5-Aza-2'-deoxycytidine (Decitabine) is a new cytosine analog with potent antileukemic activity and able to induce in vitro gene activation and cellular differentiation by a mechanism probably involving DNA hypomethylation. The aim of this pilot study was to evaluate the efficacy and the toxicity of Decitabine, used as single induction agent, in the treatment of poor prognosis acute myeloid leukemia (AML) patients, and to explore its mechanism of action. A total of 12 patients were treated with Decitabine at 90-120 mg/m2 as a four hour intravenous infusion, three times daily for three consecutive days every four to six weeks. A minimum of two courses were required for response evaluation and to consider a patient as therapeutic failure. A total of 10/12 patients were fully evaluable for response; three patients achieved a complete remission (CR) and one a partial remission (PR). Extra-hematological toxicity was generally mild. As for the mechanism of action, both a differentiation induction effect and a cytotoxic mechanism have been observed. In particular, CRs and PRs were probably obtained through the induction of leukemia cell differentiation as shown by the kinetic of remission and immunotyping studies. The preliminary results of this ongoing study suggest that Decitabine may have a prominent role in the treatment of those AML patients with poor general conditions and/or advanced age.

Aged↗
PubMed1993

CD5 negative lymphocytosis mimicking typical B-chronic lymphocytic leukaemia. Description of 26 cases.

We report 26 elderly patients (median age 68.3 years) who met diagnostic criteria for B-cell chronic lymphocytic leukaemia (B-CLL) but whose lymphocytes lacked CD5 expression. Haematological and clinical features of this CD5- series were compared with those of 333 CD5+ B-CLL patients from the same institute. No significant differences were observed regarding peripheral blood (PB) and bone marrow (BM) lymphocytosis, Hb level, platelet count, incidence of adenomegaly, hepatomegaly or splenomegaly or diffuse BM pattern. Due to an absence of nodal enlargements or to general clinical condition, lymph node biopsy was performed in only three patients, while spleen histology was examined in two cases following splenectomy. All histological results confirmed the clinical diagnosis of CLL. The distribution of the CD5- subjects according to the different staging categories proposed by Rai, Binet and Mandelli was similar to that of CD5+ subjects. Ten patients received standard chemotherapy with Chlorambucil (CHL) and Prednisone (PDN). All achieved partial remission, although one of these patients later died of disease progression; 80 months after diagnosis. We conclude that rare cases of CD5- lymphocytosis fulfilling all criteria for B-CLL may occur. Haematological and clinical features at presentation and the response to conventional treatment with Chlorambucil support our hypothesis of considering this disease as a less frequent subgroup of B-CLL.

Aged↗
PubMed1993

Elimination of clonogenic Philadelphia-positive cells using BCR-ABL antisense oligodeoxynucleotides.

Synthetic BCR-ABL antisense oligodeoxynucleotides are known to suppress in vitro clonogenic growth of primary cells from patients with CML. To evaluate the use of BCR-ABL antisense oligodeoxynucleotides as in vitro purging agents before autografting, we studied their effect on the clonogenic BV-173 cell line. At a concentration of 80 micrograms/ml, antisense oligodeoxynucleotides suppressed 85%, 95.5% and 95% of leukaemic cell growth after 24, 48 and 72 h of incubation, respectively. A correlation was observed between the concentration of oligomers and cell inhibition; however, concentrations higher than 80 micrograms/ml did not produce significant increase of BV-173 cell elimination. When the antisense treatment was performed on a wide range of target cell concentrations (from 1 x 10(5) to 5 x 10(6)/ml), the efficacy of purging was similar in all the groups. Addition of antisense oligodeoxynucleotides every 24 h produced, after 3 days, a cell growth inhibition superior to any single treatment; in particular, three treatments for 24 h at a concentration of 80 micrograms/ml were more effective than a single treatment at the same concentration or a single treatment at a concentration of 160 micrograms/ml. Incubation of normal human BM cells with the same doses which were very effective at inhibiting BV-173 cell proliferation, did not affect the growth of normal CFU-GM and of more immature progenitors.

Base Sequence↗
PubMed1992

Use of recombinant human granulocyte-macrophage colony-stimulating factor in patients with lymphoid malignancies transplanted with unpurged or adjusted-dose mafosfamide-purged autologous marrow.

The neutropenia-related morbidity and mortality occurring after autologous bone marrow transplantation (ABMT) is increased by marrow purging procedures. While phase I through III clinical trials showed the enhancing activity of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) on neutrophil recovery after ABMT with unpurged marrow, controversial results have been reported when purged marrow was used. Therefore, it was the aim of the present study to evaluate the efficacy of rhGM-CSF administration in a group of patients (n = 15) with lymphoid malignancies transplanted in complete remission with mafosfamide-purged (n = 10) or unpurged (n = 5) marrow. Mafosfamide concentrations used for marrow purging were evaluated on an individual basis by means of a recently described technique that destroys the granulocyte-macrophage (granulocyte-macrophage colony-forming units [CFU-GM]) compartment, but spares 50% of the more primitive stroma adherent colony-forming cells (CFU-Blast). rhGM-CSF (10 micrograms/kg/d) was started within 24 hours of ABMT and administered in a 4-hour infusion daily until the absolute neutrophil count (ANC) reached 500 x 10(6)/L and then for 7 more days. Patients receiving mafosfamide-purged or unpurged marrow failed to show any difference in terms of median number of days required to achieve an ANC > or = 500 x 10(6) (13 v 14.0, P > .4) cells/L. As compared with retrospective controls, granulocytic recovery was reduced by a median time of 11 (P < or = .0005) and 5 (P < or = .0005) days for patients grafted with purged and unpurged marrow, respectively. The number of CFU-GM (mean +/- SD) infused per kilogram of body weight was significantly lower in patients who received purged autografts as compared with those receiving unpurged autografts (0.85 +/- 0.79 x 10(4) v 15.7 +/- 9.2 x 10(4), P < or = .0005). The dose of CFU-GM progenitors infused per kilogram of body weight did not correlate (r = .031, P > .05) with the time required to reach an ANC > or = 500 x 10(6) cells/L. The number of CFU-Blast (mean +/- SD) infused per kilogram of body weight was not significantly different between patients who received purged or unpurged autografts (5.05 +/- 2.51 x 10(3)/kg v 6.18 +/- 2.66 x 10(3)/kg, P < or = .375). A statistically significant correlation (r = -.658, P < or = .05) was observed between the number of CFU-Blast infused and the number of days required to reach an ANC > or = 500 x 10(6) cells/L.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1992

A randomized study of the efficacy of postconsolidation therapy in adult acute nonlymphocytic leukemia: a report of the Italian Cooperative Group GIMEMA.

The Italian Co-operative Group GIMEMA conducted a randomized trial in adult acute nonlymphocytic leukemia (ANLL) to assess the role of postconsolidation treatment. Of 448 evaluable patients entered into the study, 305 (68%) achieved a complete remission after a standard induction with daunorubicin and cytosine arabinoside (3 + 7; 2 + 5). Those in remission after a consolidation therapy including 4 courses of daunorubicin, cytosine arabinoside, and 6-thioguanine (DAT) were allocated to one of three arms: no treatment, conventional maintenance, or intensive postconsolidation therapy. The median disease-free survival (DFS) was 13 months, and the median survival was 14 months, with 26% surviving at 6.5 years. There was no difference in survival and in disease-free survival among the three postconsolidation arms. In conclusion our study, as others, suggests that the critical period of ANLL treatment is within the first 5-6 months.

Adolescent↗
PubMed1992

Ph-negative and bcr-negative atypical chronic myelogenous leukemia: biological features and clinical outcome.

We report the clinical, hematologic, cytogenetic, and molecular characteristics of 13 patients with Philadelphia-negative (Ph-), bcr-negative atypical chronic myelogenous leukemia (CML). In the majority of cases, the phenotypic features at presentation resembled those of typical CML. However, these patients presented with a higher median age, lower median hemoglobin levels, and lower leukocyte and platelet counts than patients with Ph-positive CML. Cytogenetic analysis showed an abnormal karyotype in only one case. Southern blot investigation, using probes exploring the entire M-bcr region, demonstrated the absence of genomic bcr-abl rearrangements. The assessment of clonality in five patients (study of X-methylation patterns in females heterozygous at the DXS255 locus) indicated the proliferation of a monoclonal cell population. Disease evolution was mostly characterized by bone marrow failure, extramedullary infiltrates, and poor response to chemotherapy, without evidence of overt acute transformation. Our observations suggest that some hematologic and clinical features and the modalities of disease progression are presently the most helpful factors in distinguishing these bcr/abl-negative patients from those with typical bcr+CML. The differences existing also with chronic myelomonocytic leukemia (CMMoL), allow the consideration of ph-/bcr- CML as a separate entity, the nature of which remains to be elucidated.

Cytogenetics↗
PubMed1992

Ability of recombinant interferon gamma in vitro to restore the defective polymorphonuclear-cell- but not lymphocyte-mediated cytotoxic activities in patients with myelodysplastic syndromes.

In this study we analysed the in vitro effect of recombinant interferon gamma on cytotoxic activities mediated by both lymphoid and polymorphonuclear cells from 16 patients with myelodysplastic syndromes. Our results indicate the inability of interferon to restore the defective natural killer activity, natural killer cells and lectin-induced cytotoxicity. On the contrary we detected a boosting effect on the depressed polymorphonuclear cell cytotoxic activities. In our view, the ability of interferon to potentiate polymorphonuclear cell lytic efficiency could support an alternative defensive pathway against either neoplastic or infectious agents.

Aged↗
PubMed1992

Pharmacological purging of syngeneic bone marrow ex vivo: effect of treatment with doxorubicin and lonidamine on normal and leukaemic cells of DBA/2 mice.

The in vivo effect of in vitro treatment with doxorubicin plus lonidamine on normal and leukaemic cells was investigated in a mouse model of syngeneic bone marrow transplantation. Different numbers of L5178Y tumour cells or normal bone marrow cells alone, or mixtures of bone marrow and leukaemic cells were incubated with doxorubicin (0.25, 0.5, 0.75, 1 microgram/ml) and/or lonidamine (50 micrograms/ml) and reinfused in DBA/2 mice. Lonidamine potentiated the cytotoxic effect of doxorubicin dependent on doxorubicin dosage and tumour cell concentration. Survival after injection of 10(4) in vitro-treated tumour cells was 42% for doxorubicin 0.75 micrograms/ml alone versus 100% for the combination with lonidamine and 50% for doxorubicin 1 microgram/ml alone versus 100% combination. Reinfusion of normal bone marrow incubated with doxorubicin alone or in combination with lonidamine in lethally irradiated mice did not occur in 12-14% of mice injected, indicating that the repopulating ability of stem cells was spared. These data suggest the potential usefulness of lonidamine in ex vivo purging of bone marrow before autologous bone marrow transplants in haemopoietic malignancies.

Animals↗
PubMed1992

Piperacillin plus amikacin vs. piperacillin plus amikacin plus teicoplanin for empirical treatment of febrile episodes in neutropenic patients receiving quinolone prophylaxis.

A prospective, randomized trial was initiated to evaluate the efficacy of two antibiotic regimens, differing in the agent included with activity against gram-positive bacteria, for the empirical treatment of febrile episodes in neutropenic patients with hematologic malignancies (group 1, piperacillin plus amikacin; group 2, piperacillin plus amikacin plus teicoplanin). After 72 hours of therapy, patients in group 1 who were still febrile were administered teicoplanin and those in group 2 were administered amphotericin B. A total of 158 evaluable episodes were observed within 8 months. The success rate was 50.6% in group 1 and 60% in group 2. The response rate among patients who did not respond to the original regimen increased to 86.7% with the addition of teicoplanin (group 1) and to 90% with the addition of amphotericin B (group 2). There were 86 unexplained febrile episodes and 56 documented episodes of bacteremia (34 caused by gram-positive organisms). Our results indicate that teicoplanin is safe, well tolerated, and effective for the treatment of documented episodes of gram-positive bacteremia and as an empirical agent. The inclusion of teicoplanin in the initial empirical regimen appears unnecessary if a combination of antibiotics active against gram-positive organisms is used, unless infections are due to oxacillin-resistant staphylococci.

4-Quinolones↗
PubMed1992

Treatment of primary refractory or relapsed acute lymphoblastic leukemia (ALL) in children.

Thirty-one intensively pretreated children with ALL in first bone marrow relapse or refractory to initial therapy were treated with a combination of intermediate-dose Ara-C and idarubicin (IDA). Twenty-four patients (77%) achieved complete remission (CR), 8 patients relapsed early and 2 were removed from the study. Fourteen (45% of the original 31 patients) underwent bone marrow transplant (BMT) and 7 of them (22%) are still in continuous CR (CCR) with a median follow-up of 18 months. These results confirm that it is possible to achieve CR even in ALL children who failed on an initial intensive regimen. Newer modalities of post-remission therapy, especially for children lacking an HLA donor, should be considered.

Adolescent↗
PubMed1992

Biology and treatment of multiple myeloma.

Multiple myeloma remains a fatal disease. However, in the last few months new biologic and clinical information has been provided about this disease. In particular, the immunophenotype of myeloma cells seems to indicate, at least in some patients, the possibility of a stem cell involvement in the pathogenesis of myeloma. Moreover, the recent progress in understanding the complex cytokine network has revealed the possibility that myelomatous proliferation is highly influenced by some cytokines such as interleukin-6, interleukin-3, interleukin-2, and granulocyte-macrophage colony-stimulating factor. Furthermore, it has been shown that the mechanism responsible for the resistance of myeloma cells to chemotherapy may be partially overcome by the use of calcium antagonists associated with quinine. Finally, new insights into the pathogenesis and biology of the disease have been provided by studies of molecular biology and flow cytometry undertaken in multiple myeloma patients. The best conventional induction treatment remains to be defined. However, the increased use, as new therapeutic modalities, of interferon-alpha and transplantation procedures in multiple myeloma opens new hopes of a cure. In the future, a better comprehension of the multiple myeloma biology associated with a wider use of new and more effective therapeutic approaches will certainly improve the natural course of the disease.

Bone Marrow Transplantation↗