Interferon gamma in chronic myeloid leukemia: dose and side effects.
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Drug Administration Schedule↗
Biomedical subjects
R Fanin
Publications and source records attributed to R Fanin.
In vitro exposure of leukemic cells to low concentration Arabinosyl Cytosine: no evidence of differentiation inducing activity.
Low dose Arabinosyl Cytosine (LD ARA-C) is widely used for treatment of acute non-lymphocytic leukemia (ANLL) and myelodysplastic syndrome (MDS) in the elderly, based on a favorable response rate and on the hypothesis that LD ARA-C can induce differentiation or maturation of leukemic cells. We investigated the effect of low concentration of ARA-C on the growth of marrow cells that were obtained from 6 cases of MDS and from 11 cases of ANLL by using the in vitro culture system for normal granulo-monocyte precursors (CFU-GM). At ARA-C concentrations equal to or higher than 1 ng/ml cell growth was inhibited in a dose-dependent manner. At ARA-C concentration of 0.1 ng/ml cell growth was slightly affected, but colony number and colony cell composition were identical to control cultures. This experiment did not support the hypothesis that ARA-C can induce leukemic cells to recover any normal growth patterns but confirmed that even very low ARA-C concentrations can inhibit or slow down leukemic cell proliferation.
Acute Disease↗
Cell kinetic effect of low dose arabinosyl cytosine.
Low dose arabinosyl cytosine (ARA-C) is effective for treatment of acute non-lymphocytic leukaemia (ANLL). The mechanism of action is not clearly understood and it was suggested that low doses of the drug could induce leukaemic cells to differentiate. We investigated the effect of low dose ARA-C (20 mg/m2/d, divided into two doses s.c. at 12 h intervals, x 20 d) on the cell cycle distribution of leukaemic cells in four cases of ANLL. By comparison, four other cases of ANLL were studied during treatment with standard dose ARA-C (200 mg/m2/d as a continuous i.v. infusion x 7 d). Both treatments induced an accumulation of leukaemic cells in post G1 phases, at a variable extent and rate. During treatment by low dose ARA-C, the mitotic index (MI) fell slowly to zero in two patients who achieved a complete remission (CR), while it fell but recovered during treatment in the patients who did not achieve a CR. The MI fell rapidly to zero in the four cases treated by standard dose, who achieved a CR. These data are consistent with the known cytotoxic activity of ARA-C, via inhibition and slowing of DNA synthesis leading to defective cell proliferation and to cell death.
Acute Disease↗
Relationship of serum lactate dehydrogenase level with first remission length in adult acute lymphocytic leukaemia.
Several features have a prognostic value in adults with acute lymphocytic leukaemia (ALL). However, in about two-thirds of all cases prognosis remains quite variable, with a substantial number of early relapses. This study shows in 118 adult patients who attained complete remission (CR) between 1978 and 1984 that pretreatment serum total lactate dehydrogenase (LDH) activity was inversely correlated with first CR length. The prognostic value of LDH was higher than that of any other features both in univariable and in multivariable analysis. The value was significant in the whole series as well as in patients who lacked other high risk features. Among non-high risk and low-WBC count cases, patients with LDH less than or equal to 500 U/l had a median first CR duration of 27 months, and a projected 5-year relapse free survival of 36%, versus 9 months and 12% of patients with LDH greater than 500 U/l. These results fit well with the results of a study of ALL in children, and suggest that pretreatment serum total LDH activity is an important risk determinant in adult ALL.
Adolescent↗
Hodgkin's disease occurring in a Warthin's tumor: first case report.
The case of a Warthin's tumor whose lymphoid component was totally replaced by a malignant lymphoma, Hodgkin's type, is reported. The disease was characterized by a rapid downhill course, with repeated medullary relapses and subsequent episodes of bone marrow failure. Death occurred 13 months after the initial diagnosis and was due to severe visceral involvement by Hodgkin's lymphoma, as confirmed at post mortem examination.
Adenolymphoma↗
Meningitis and septicaemia in adults splenectomized for Hodgkin's disease.
Splenectomized and asplenic persons are at risk of developing sudden episodes of meningitis and/or septicaemia, frequently due to Streptococcus pneumoniae (overwhelming postsplenectomy infection, or OPSI). The application of staging splenectomy to patients with Hodgkin's disease (HD) generated a new population at risk for OPSI. We reviewed the cases of sudden meningitis and/or septicaemia in a series of 491 consecutive adults with HD. No case was recorded among 149 non-splenectomized patients. 6 episodes of OPSI were observed in 5 of 342 splenectomized patients (crude frequency 1.75%, actuarial frequency at 10 yr 3.87%). The infecting organisms were Streptococcus pneumoniae (5 cases) and Salmonella enteritidis (1 case). 2 episodes (1 fatal) occurred during first complete remission (CR), 15 and 120 months, respectively, after splenectomy, 4 episodes (2 fatal) occurred after first relapse. For splenectomized patients in continuous CR, the cumulative risk of OPSI was 2.30% (95% CL 0-6.10%), and it was 15.25% (95% CL 0-35.37%) for splenectomized patients who had relapsed. These data suggest that, in adults with HD, the risk of OPSI should not limit the indication to staging splenectomy and does not warrant systematic prophylaxis. However, in splenectomized relapsed patients, OPSI can be a troublesome complication and appropriate prophylaxis could be useful.
Adolescent↗
[Hairy cell leukemia. Clinical case].
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Anemia↗
Serum LDH concentration in non-Hodgkin's lymphomas. Relationship to histologic type, tumor mass, and presentation features.
Serum lactate dehydrogenase (LDH) activity is increased in many tumor-bearing patients and can be used as a prognostic marker. We studied serum LDH concentration in 94 consecutive patients with non-Hodgkin's lymphoma who were histologically classified according to the Kiel Classification and were grouped according to the Non-Hodgkin's Lymphoma Pathologic Classification Project Working Formulation. 74 patients were studied at diagnosis, and 20 of them (27%) had an LDH level higher than 250 U/l. High LDH levels were more frequent in cases of true histiocytic, high-grade, and intermediate-grade malignancy lymphoma (4 of 7, 7 of 14, and 7 of 20, respectively) than in cases of low-grade lymphoma (2 of 33). A close relationship of LDH to several prognosis-related disease features was found, including general symptoms, bulky disease, big mediastinal tumor, huge hepatosplenomegaly, bone marrow involvement, and a leukemic syndrome. LDH was higher than normal in a high proportion of cases who were studied in relapse (13 of 20, 65%). These data suggest that in non-Hodgkin's lymphomas the LDH serum concentration is not independent of other disease features, so that the prognostic value of LDH is probably lower than expected from previous studies. Serum LDH activity decreased to normal in all cases of complete remission, but also in cases of partial remission, suggesting that measuring enzyme activity is of a limited usefulness for detecting and monitoring minimal residual disease. For that purpose, LDH isoenzyme studies would be more appropriate.
Adolescent↗
Low dose arabinosyl cytosine for treatment of myelodysplastic syndromes and subacute myeloid leukemia.
Several agents, including arabinosyl cytosine (ARA-C) at a low concentration, can induce leukemic myeloblasts to mature to a variable extent. The therapeutic implications of this observation are worth investigating. A few case-reports have shown that low dose ARA-C can be useful for treatment of the myelodysplastic syndromes (MDS) and of acute myeloid leukemia (AML). However, no information is available yet on the proportion of patients who can be expected to respond. We treated by low dose ARA-C (20-30 mg/sqm/day i.v. or i.m. for 7-10 days) 20 consecutive patients. A complete remission of 5 months was obtained in one of nine cases of subacute myeloid leukemia (SAML). A partial remission (complete normalization of blood counts with a slight excess of marrow blast cells) was obtained twice in one of 11 cases of MDS. An increase of Hb level (more than 11.5 g/dl) was obtained and maintained for 12 months in a case of MDS. A short-lasting increase of granulocyte count was obtained in another two cases of MDS and SAML respectively. It is suggested that low dose ARA-C can advantageously modify the proliferation to maturation imbalance of leukemic cells by slowing down cell proliferation rate. However, the proportion of patients who respond is probably low. This treatment is at a very early experimental stage and should be probably limited to selected cases of MDS and subacute or acute myeloid leukemia.
Adult↗
Serum lactate dehydrogenase fails to predict response to treatment and survival in acute non-lymphocytic leukemia.
Total serum lactate dehydrogenase (LDH) activity was measured in 514 adult patients with de novo acute non-lymphocytic leukemia (ANLL) prior to any treatment and was compared with several disease features, with response to induction treatment, and with relapse-free survival. LDH was higher in the M4 and M5 FAB cytological subtypes and was positively correlated with the white blood cell count (WBC). The proportion of remissions, of deaths during induction, and of failure, and the duration of relapse-free survival, were clearly unrelated to LDH activity, in the whole series as well as in different age groups (below 40 years, and 40 to 60 years) and in any FAB cytological subtype. Multivariate analysis showed that only WBC and sex (female better than male) were marginally related with relapse-free survival. These data provide conclusive evidence that LDH does not help in defining the prognosis of adult ANLL, either because enzyme activity fails to reflect the number and proliferation rate of leukemic cells efficiently, or because with current standard treatment these features are of borderline importance, in contrast with acute lymphocytic leukemia and malignant lymphomas.
Adolescent↗
Castleman's disease: an unusual cause of mediastinal mass and anemia.
We reported a case of thoracic localized, mixed variant, Castleman's Disease (angiofollicular lymph node hyperplasia) with a favourable clinical course presenting with mediastinal mass, microcytic anemia, mild thrombocytosis, polyclonal hyper-gammaglobulinaemia and without symptoms. Castleman's Disease must be always considered in the differential diagnosis of solitary mediastinal masses. Transthoracic fine needle aspiration cytology is usually nondiagnostic; in fact, cytologically, Castleman's Disease can be confused with other mediastinal lymphoproliferative disorders (such as thymomas or lymphomas). The optimal therapeutic approach is unknown but a complete surgical resection is treatment of choice for localized disease.
Adult↗
Cancer chemotherapy does not enhance MDR-associated 170 kd glycoprotein expression in normal blood mononuclear cells.
BACKGROUND: The multidrug resistance (MDR) associated 170kd glycoprotein (P170) is expressed at a low level in normal and malignant cells, but in the latter it becomes frequently overexpressed after chemotherapy. This study evaluated P170 expression in normal blood mononuclear cells after and during cancer chemotherapy. METHODS: P170 was detected by immunocytochemistry with two monoclonal antibodies (MRK-16 and JSB-1). RESULTS: P170 expression was low in all samples before, during and after chemotherapy. CONCLUSIONS: Cancer chemotherapy did not enhance P170 expression in normal peripheral blood mononuclear cells. The mechanisms enhancing P170 expression are likely to be more operative in tumor cells than in normal cells.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Proliferation and maturation effects of in-vivo granulocyte-macrophage colony stimulating factor in acute non-lymphocytic leukaemia.
BACKGROUND: Granulocyte-macrophage colony stimulating factor (GM-CSF) can affect the treatment of acute non-lymphocytic leukaemia (ANLL) by supporting normal haemopoiesis and by enhancing the proliferation and the maturation of leukaemic cells. METHODS: A human recombinant E. Coli synthesized GM-CSF was administered to 7 patients with ANLL at a dose of 5 or 10 micrograms/kg/day for 7 days, prior to antileukaemic treatment. Peripheral blood neutrophil and blast cell count was monitored daily. Changes in marrow blast cell morphologic features, mitotic index, and the reactivity to a panel of monoclonal antibodies were assessed after 3 and 7 days of treatment. RESULTS: Peripheral blood neutrophil and blast cell count increased in 6/7 cases. The mitotic index of marrow cells increased in 6/7 cases. A significant maturation occurred along the granulocytic line (2 cases) and the monocytic line (1 case). Mild to moderate eosinophilia developed in 3/7 cases. Early stem cell markers (CD 34 and HLA-DR) were not lost, or actually increased. Myelomonocytic markers (CD 33, CD 13, and CD 14) rose and fell. Expression of the multidrug resistance-associated 170 kd glycoprotein remained stable. CONCLUSIONS: These data showed that in vivo GM-CSF more consistently enhanced the proliferation than the maturation of leukaemic cells.
Adult↗
Advances in prognosis of chronic myeloid leukemia.
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Age Factors↗
Alpha-interferon as maintenance drug after initial fludarabine therapy for patients with chronic lymphocytic leukemia and low-grade non-Hodgkin's lymphoma.
BACKGROUND: Fludarabine monophosphate (FLU) is an adenine nucleoside analogue with promising therapeutic activity in lymphoproliferative disorders. In addition, the effectiveness of alpha-interferon (alpha-IFN) in low-grade non-Hodgkin's lymphoma (LG-NHL) and B-cell chronic lymphocytic leukemia (B-CLL) has been demonstrated in several clinical trials. METHODS: In a phase II study of 45 patients with B-CLL and 28 with LG-NHL, we used FLU as second and third-line chemotherapy. Dosages of 25 mg/m2 were given in 30-minute infusions for 5 consecutive days. Treatment was repeated every 28 days depending on patients' clinical status for a maximum of 6 cycles. Entrance in the human lymphoblastoid alpha-IFN maintenance portion of the study depended on response to initial FLU. Following randomization we administered alpha-IFN, or no therapy at all, to patients who obtained a complete or a partial response after FLU therapy. The alpha-IFN dose was 3 x 10(6) U three times per week until disease progression. RESULTS: Twenty-one B-CLL patients achieved major responses, as did 17 of those with LG-NHL. Twenty-four of the former group and 11 of the latter failed to respond or obtained only a minor response. The 38 patients who responded well and entered the second part of the trial showed significant prolongation of remission duration with maintenance alpha-IFN. CONCLUSIONS: In consideration of its significant activity, the role of FLU in the management of lymphoproliferative disorders needs to be evaluated further; at the same time, this preliminary analysis seems to indicate that maintenance alpha-IFN may extend remission duration in B-CLL and LG-NHL.
Adult↗
HTLV-I positive adult T-cell leukaemia-lymphoma: report of a typical case from Italy.
A case of acute adult T-cell leukemia-lymphoma (ATLL) was observed in northeast Italy, presenting with fever, lymphadenomegaly, splenomegaly, hypercalcemia and renal failure. Leukaemic cells were morphologically typical, expressed a T-cell CD4+ phenotype, did not display any helper functions, and grew in vitro under supply of exogenous interleukin-2. Antibodies to human T-cell lymphotropic virus (HTLV-I) were found in the serum, and the virus was isolated from leukaemic cells. The family members who could be tested were seronegative. The patient had never travelled outside Italy, had never received blood transfusions and did not belong to any known categories at risk of viral disease transmission. Present knowledge of the epidemiology of HTLV-I infection warns that other cases of HTLV-I induced disease are expected to occur outside already recognised endemic areas. This case suggests that untraceable, presumably short-term exposures can also account for HTLV-I transmission.
Adult↗
Sequential treatment of Ph-positive chronic myeloid leukemia with interferon gamma and interferon alpha.
Several clinical observations have shown that alpha-IFN is presently the most interesting investigational agent for the treatment of Ph+ chronic myeloid leukemia (CML). Gamma-IFN is also effective, and experimental data as well as preliminary clinical observations suggest that the combination of the two IFNs is worth investigating. No comparative data are available on the effects of the two IFNs, given alone, in the same patients. In this study 11 patients with PH+ CML were first treated with gamma-IFN, up to a maximum period of 35 weeks, and after a short rest period were retreated with alpha-IFN. Both IFNs were ineffective in 3 patients in accelerated or instable chronic phase. Both IFNs were equally effective in 8 patients in stable chronic phase, but none of these patients achieved a karyotypic conversion with either IFN. This study did not show any measurable differences in the therapeutic response to gamma-IFN and alpha-IFN given consecutively to the same patients.
Adolescent↗
Serum lactate dehydrogenase is an important risk determinant in acute lymphocytic leukemia.
Pretreatment serum total lactate dehydrogenase (LDH) activity was measured in 341 adult patients (greater than 15 years old) with acute lymphocytic leukemia (ALL) in order to assess its prognostic value. Failure, death during induction and remission were not related to LDH. In contrast, a negative and continuous relationship was found between LDH and relapse-free survival. Though LDH activity was significantly higher in cases with already established risk factors such as high WBC count, FAB L3 cytotype, mature B-cell phenotype, and central nervous system involvement, LDH was confirmed to be the strongest predictor of remission duration by multivariate analysis. This study provides a definitive confirmation of the negative prognostic value of LDH in adult ALL.
Adolescent↗