Recombinant alpha 2b interferon in the treatment of refractory autoimmune thrombocytopenic purpura.
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Biomedical subjects
Publications and source records attributed to F Mandelli.
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The incidence of thrombotic complications chronologically related to L-asparaginase administration is retrospectively analyzed in 238 adult ALL patients treated according to the GIMEMA protocol ALL 0288. The patients (126 males and 112 females, aged 12-68 years, median 29) received E. coli L-asparaginase (L-ase) in the induction phase at a dosage of 6000 U/m2/day x 7 d starting on d 15, as well as vincristine, prednisone, daunorubicin and cyclophosphamide, the last-named by random 1:1. Ten patients (4.2%) developed thrombotic complications 5-15 d (median 11 d) after the start of L-ase treatment. The thrombotic events, which were lethal in 5 patients, involved the cerebral sinus (5 cases), the cerebral arteria (2 cases), the portal vein (1 case), the pulmonary district (1 case), and a deep vein in the lower extremity (1 case). The occurrence of these complications was not related to the general thrombotic risk factors, nor to the main clinical and laboratory data registered at diagnosis and immediately before the start of L-asparaginase treatment. The present study documents for the first time in a sufficiently large series of adult ALL patients that the incidence and the severity of thrombotic events related to L-ase administration are relevant and need further consideration.
Five patients whose Hodgkin's disease recurred 10 years or more after the achievement of complete remission are reported. Four out of 5 patients had shown an advanced stage at the onset of disease and therefore had received combination chemotherapy (ABVD or MOPP-like) as primary treatment. Involved-field irradiation was delivered as consolidation therapy in 1 patient only. All pathologically proven relapses occurred in a previously affected area and the histologic subtype differed from the primary subtype. The time interval between the achievement of the first complete remission and the relapse was 120, 170 and 190 months in 3, 1, and 1 patient, respectively. All 5 patients are alive in second complete remission. This paper emphasizes the risk of late relapse even after a prolonged disease-free interval for patients with Hodgkin's disease. Close follow-up is therefore recommended also in this clinical setting.
The histologic and clinical features of 71 cases of peripheral T-cell lymphoma (PTCL) have been studied. All patients were HTLV-1 negative. The T-cell phenotype was demonstrated by immunohistochemistry on cryostat sections (41 cases) and paraffin-embedded sections (30 cases). All cases were histologically classified according to the updated Kiel classification of non-Hodgkin's lymphoma (low and high-grade) and according to a Working Formulation (WF)-based classification (predominantly small cells, mixed small and large cells, and predominantly large cells). Most cases were in the high-grade group according to both classifications. The prognostic value of these two classifications was comparatively assessed. The analysis of the actuarial survival curves showed that, by using the updated Kiel classification, low-grade PTCL had a survival probability higher than high-grade PTCL although the difference was not statistically significant. Similar results were obtained when the WF-based classification was applied: furthermore, actuarial survival curves of mixed small and large cell PTCL, and of large cell PTCL were rather similar, thus indicating that differentiating these two categories has a limited prognostic value.
We review the role of adhesion molecule expression on malignant lymphoid cells as delineated by experimental studies and clinical observation. Adhesion molecules of the Ig superfamily, integrins, selectins, and the lymphocyte homing receptor CD44 mediate cell-to-cell and cell-to-extracellular matrix interactions. These molecules have been investigated with the aim (i) of defining certain biological features of the malignant cells, (ii) of providing a rationale to understand tumor organization, metastasis and organ specificity, and (iii) of detecting disease subsets and prognostic groups.
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.
The results of our ten years experience indicate that F-MACHOP, conceptually designed to exploit cell kinetic and synergistic principles, is an effective regimen with acceptable toxicity in a large proportion of adults with advanced stages of diffuse large cell or small non-cleaved cell lymphoma. More than 60% of all treated patients all expected to achieve long-term EFS. Patients achieving CR within 3 courses have a very high chance of being cured of their disease and do not require, in our opinion, intensification with other regimens. On the other hand the identification of a group of patients with poorer outcome (i.e. those failing to achieve an early CR) enabled testing of the potential efficacy of superintensive salvage regimens. Together with other 6 Italian hematologic institutions, we have recently participated in a prospective comparative randomized trial in which F-MACHOP was compared to MACOP-B in adults with advanced stages of diffuse large cell or small non-cleaved cell lymphoma. The preliminary results of this trial appear to confirm that F-MACHOP is an effective and tolerable regimen in such patients and there is a suggestion that its efficacy is superior to that of MACOP-B. This trial was closed to accrual in September 1991 and we look forward to the first complete analysis in March 1992.
Probable progressive multifocal leukoencephalopathy (PML) was diagnosed on the basis of clinical picture and magnetic resonance imaging in a 63-year-old man with a complete remission of a non-Hodgkin's lymphoma. After the introduction of intramuscular alpha-interferon therapy, his neurological state and MRI findings showed a clear improvement. Eighteen months after the onset of first symptoms the patient has significantly recovered from both aphasia and motor impairment, and shows only a mild attentional deficit.
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From 1987 to 1990, intensive postremission chemotherapy was compared to autologous bone marrow transplant in previously untreated children with AML who received identical induction therapy with two courses of Daunorubicin (DNR) and conventional dose ARA-C (protocol AIEOP LAM 87). Overall, 121 of the 155 eligible patients achieved complete remission (CR) (78%). Patients in CR who lacked HLA-MLC compatible donor were randomized to receive either autologous BMT (Auto-BMT) or further sequential postremission therapy. Patients with HLA-MLC compatible donor were assigned to allogeneic BMT (Allo-BMT). Projected 3-years disease free survival (DFS) are 58% for Allo-BMT group, 24% for Auto-BMT group, 26% for chemotherapy group and 30% for a group of not randomized patients (intention to treat analysis). On March 1990 a pilot study LAM 87M was initiated. Patients in CR after induction therapy (identical to the previous protocol) receive a single intensification course consisting of high dose ARA-C plus DNR. The study continues to accrue patients.
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The data provided in the medical literature suggest that alpha-IFN is a useful agent in the management of myelomatosis. In particular, its combination with conventional induction therapies of previously untreated MM patients may improve the overall response rate and probably increase the number of complete responders. On the other hand, even though alpha-IFN alone, in some patients with previously untreated MM, may induce good objective responses, it certainly remains less effective than conventional chemotherapy. Moreover, in a small proportion of advanced MM patients, alpha-IFN alone has induced objective responses. It is therefore possible that alpha-IFN should be combined with other therapeutic modalities to improve the observed response rate in these patients. Finally, alpha-IFN maintenance treatment seems to be one of the most promising therapies for patients with myelomatosis. However, the achievement of a "true" plateau phase after the induction treatment is certainly necessary to permit alpha-IFN maintenance treatment to prolong the response duration. As for the prolongation of survival duration observed in the Italian study, it requires confirmation by the other ongoing randomized studies. In the future, a better understanding of the mechanisms of action of alpha-IFN, as well as the increasing use of other biologic response modifiers, will improve the therapeutic modalities utilized to treat myelomatosis and therefore lead to better control of this so-far-incurable disease.
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.
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.
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