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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Australian Leukaemia Study Group has performed a randomized trial of interferon alpha-2A (Roferon-A) as a co-induction agent together with intensive combination chemotherapy and as maintenance following completion of 12 cycles of induction treatment. When used as a co-induction agent, interferon-alpha did not improve response rates, time-to-treatment failure, or overall survival. Patients who had interferon together with intensive combination therapy (PCAB: prednisone 60 mg/m2 days 1-5, cyclophosphamide 600 mg/m2 day 1, BCNU 30 mg/m2 day 1, doxorubicin 30 mg/m2 day 1, repeated every 28 d for a total of 12 cycles) had more leucocyte and granulocyte toxicity and received a lower dose intensive of cytotoxic drugs than those patients who received PCAB without interferon. There was a trend towards prolongation of plateau phase which did not reach significance. Interferon, however, did improve the survival of patients who achieved plateau; for those patients interferon was associated with a 33% decrease in the rate of death after adjusting for initial beta-2 microglobulin level.
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PMID:Australian Leukaemia Study Group myeloma II: a randomized trial of intensive combination chemotherapy with or without interferon in patients with myeloma. 913 40

All-trans retinoic acid (ATRA) has recently been shown to synergize with the inhibitory effect of interferon alpha (IFN alpha) on the growth of malignant cells isolated from solid tumors. We investigated whether ATRA could potentiate the inhibitory effects of IFN alpha on the proliferation of leukemic progenitors in chronic myeloid leukemia (CML). CD34+ cells from chronic phase, newly diagnosed patients, were incubated in short-term liquid culture with ATRA, IFN alpha or a combination of both molecules and then plated on semi-solid cultures for colony-forming cell assay. IFN alpha was found to inhibit preferentially the generation of late progenitors. ATRA at a concentration of 10(-8) M was found strongly to inhibit CFU-M colonies. Addition of ATRA to IFN alpha dramatically potentiated the inhibitory effects of INF alpha on CFU-GM growth. In the presence of both molecules the inhibition of day 14 CFU-GM from CD34+ cells was lowered to 27 +/- 4% of control. CFU-M colonies were completely inhibited. RT-PCR analysis of the colonies resulting from the action of the combination IFN alpha plus ATRA showed the presence of an increased number of BCR-ABL-negative colonies relatively to what was observed with IFN alpha alone. FISH analysis showed a higher percentage of Ph-negative cells in the ATRA plus IFN alpha-treated samples, confirming PCR experiments. These results indicate that, in vitro, the combination of IFN alpha and ATRA effectively inhibits CFU-GM colony formation in CML and suggest that it has a potential interest for the treatment of CML.
Leukemia 1997 May
PMID:All-trans retinoic acid potentiates the inhibitory effects of interferon alpha on chronic myeloid leukemia progenitors in vitro. 918 Feb 90

New treatments which may change the course of a disease, or which have potential carcinogenicity, may result in the development of new cytogenetic or clinical disorders. Three patients with Philadelphia chromosome-positive (Ph-positive) chronic myeloid leukemia (CML) who developed new cytogenetic abnormalities after achieving a cytogenetic complete remission (CR) of their Ph-positive disease with interferon alpha (IFN-alpha) based therapy are described. Patient 1 developed chromosomal abnormalities involving chromosomes 5 (5q13-34) and later 7 (monosomy 7) 60 months after the start of therapy and 20 months after IFN-alpha was discontinued. A myelodysplastic syndrome was noted 83 months from the start of therapy. Patient 2 developed a myeloproliferative syndrome with 18p11 chromosomal abnormalities 90 months after the start of the therapy and 60 months after IFN-alpha was discontinued. Patient 3 developed a chromosome 11 abnormality (11q21-23) 23 months after the start of therapy, without hematological manifestations. All three patients remain in cytogenetic CR of Ph-positive disease with the hypermetaphase fluorescent in situ hybridization and polymerase chain reaction studies for BCR/ABL showing minimal residual disease. The emergence of new cytogenetic or clinical disorders in patients with CML on IFN-alpha therapy needs to be monitored. These findings may be related to changing the natural course of CML, to therapy, or to the emergence of suppressed clones in a stem cell disorder.
Leukemia 1997 May
PMID:Emergence of new clonal abnormalities following interferon-alpha induced complete cytogenetic response in patients with chronic myeloid leukemia: report of three cases. 918 Mar 6

The interaction between HTLV-I infected immortalized cells and transformed cells was studied. HTLV-I infected immortalized human lymphocytes (Coculture-5) dependent of IL-2 medium (IL-2+PHA+TPA) and transformed cells (UV-5) derived from Coculture-5 following UV irradiation were cocultured in equal numbers in IL-2 medium. UV-5 cells were suppressed and disappeared about 1 month in cocultivation. UV-5 cells were not suppressed in IL-2 medium. Coculture-5 cells and UV-5 cells were seeded in Transwell dishes that were separated by membrane with pores 0.4 micron in diameter and cultured in IL-2 medium. UV-5 cells were suppressed indicating that cell-cell contact was not required for the observed suppression. UV-5 cells were markedly suppressed in IL-2 medium harvested from Coculture-5 cells when recombinant interferon alpha (1000 U/ml) was added to the medium. These findings demonstrated that growth of HTLV-I infected transformed cells could be suppressed by cytokine(s) released by HTLV-I carrier lymphocytes.
Leukemia 1997 Apr
PMID:Cytokine mediated growth inhibition of HTLV-I infected transformed human lymphocytes. 920 89

In order to clarify the significance of p16 gene (CDKN2) inactivation and its disease specificity among hematopoietic tumors, configurations of the p16 gene as well as those of the adjacent p15 and interferon alpha (IFN alpha) genes were examined in primary hematopoietic tumors. Loss of the p16 gene is frequent in and highly specific to lymphoid tumors among hematopoietic tumors. Gene deletions but not minute mutations should be the predominant mechanism of p16 gene inactivation in these types of tumors. The p16 gene is most frequently deleted among the p16, p15 and IFN alpha genes and thus should be the target of deletions in this locus. Deletions of the p16 gene were frequently observed in tumors carrying chromosome 9p abnormalities while a significant number of cases showed loss of the p16 gene without chromosome 9p abnormalities. So far inactivation of p53 and Rb tumor suppressors have also been found in lymphoid tumors. In our study, we detected homozygous deletions of p16 gene in 20%, loss of Rb protein in 28%, and p53 gene alterations in 8% of lymphoid tumors. Notably, 44% of lymphoid tumors showed inactivation of at least one of the three tumor suppressors, suggesting these tumor suppressors are important for lymphoid tumorigenesis. Inactivations of these tumor suppressors should independently occur in development of lymphoid tumors.
Leukemia 1997 Apr
PMID:Recent progress in molecular mechanisms of leukemogenesis: the cyclin-dependent kinase 4-inhibitor gene in human leukemias. 920 89

Four randomized prospective studies on interferon alpha (IFN) in CML report varying degrees of prolongation of the chronic phase of CML and of survival as compared to conventional therapies. There is agreement that IFN prolongs survival as compared to standard busulfan. There is disagreement, however, as to which degree IFN is superior to hydroxyurea. Whereas the randomized studies of the Italian cooperative group and of the British MRC find a statistically significant survival advantage of IFN over hydroxyurea of about 20 months, this difference is only 10 months in the German randomized study and not significant. One reason for this difference might be the more intensive treatment schedule for the hydroxyurea control group in the German study. Other reasons might be differences in risk profiles between the patient groups studied and in strategies of IFN therapy. About 1% of the human genome consists of retroviral or retroviral-like sequences. By analogy to animal models, endogenous retroviruses might also have pathogenic potential in human disease. The transposon-like structure of retroviruses that enables them to integrate at almost any position in the host genome and the capability of retroviruses to serve as efficient vehicles of cellular genes are in support of a pathogenic potential. Furthermore, particles resembling retroviruses have been observed long ago in human embryonic and malignant tissues and cell lines. Sequence information and the transcriptional activity of the endogenous sequences argue against the possibility that these sequences are only fossil relics of early evolutionary periods. Most of the sequences appear to be inactivated by stop codons or frameshifts, making the genomic localization of open reading frames with biological activity difficult. Up to now, mutagenesis by insertion of retroviral-like sequences in sporadic cases of human disease appears to be the only example of pathogenic relevance of retroviruses in man.
Leukemia 1997 Apr
PMID:Randomized studies with interferon in chronic myelogenous leukemia (CML) and comparative molecular aspects. German CML Study Group. 920 40

The myeloid cell nuclear differentiation antigen (MNDA) is a nuclear protein expressed specifically in developing cells of the human myelomonocytic lineage, including the end-stage monocytes/macrophages and granulocytes. Nuclear localization, lineage- and stage-specific expression, association with chromatin, and regulation by interferon alpha indicate that this protein is involved in regulating gene expression uniquely associated with the differentiation process and/or function of the monocyte/macrophage. MNDA does not bind specific DNA sequences, but rather a set of nuclear proteins that includes nucleolin (C23). Both in vitro binding assays and co-immunoprecipitation were used to demonstrate that MNDA also binds protein B23 (nucleophosmin/NPM). Three reciprocal chromosome translocations found in certain cases of leukemia/lymphoma involve fusions with the NPM/B23 gene, t(5;17) NPM-RARalpha, t(2;5) NPM-ALK, and the t(3;5) NPM-MLF1. In the current study, MNDA was not able to bind the NPM-ALK chimera originating from the t(2;5) and containing residues 1-117 of NPM. However, MNDA did bind the NPM-MLF1 product of the t(3;5) that contains the N-terminal 175 residues of NPM. The additional 58 amino acids (amino acids 117-175) of the NPM sequence that are contained in the product of the NPM-MLF1 fusion gene relative to the product of the NPM-ALK fusion appear responsible for MNDA binding. This additional NPM sequence contains a nuclear localization signal and clusters of acidic residues believed to bind nuclear localization signals of other proteins. Whereas NPM and nucleolin are primarily localized within the nucleolus, MNDA is distributed throughout the nucleus including the nucleolus, suggesting that additional interactions define overall MNDA localization.
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PMID:MNDA binds NPM/B23 and the NPM-MLF1 chimera generated by the t(3;5) associated with myelodysplastic syndrome and acute myeloid leukemia. 932 47

Treatment of recurrent leukemia after bone marrow transplantation with the transfusion of lymphocytes from the marrow donor has been successful in a majority of patients with chronic myelogenous leukemia and a minority of patients with acute myeloid leukemia and myelodysplastic syndrome. It has been disappointing in patients with acute lymphoblastic leukemia and in advanced stages of chronic myelogenous leukemia. In chronic-phase chronic myelogenous leukemia remissions were of good quality and the actuarial relapse rate was less than 20% at 3 years. In acute leukemias remissions were less durable. Graft-versus-host disease and marrow aplasia were the major complications of this form of treatment. In patients with marrow aplasia hematopoiesis could be restored by infusion of donor marrow without further conditioning treatment. Preceding or concomitant treatment with interferon alpha is not essential for a response, but the exact role of interferon alpha remains to be determined in a randomized study. Similarly, the best time for treatment remains to be defined. Treatment of cytogenetic and molecular recurrence of chronic myelogenous leukemia is most effective in preventing marrow aplasia, but a few patients may be treated unnecessarily, for some cytogenetic recurrences may remit spontaneously. The mechanism of the graft-versus-leukemia reaction is still not clear. Effector cells and target antigens remain to be defined. Observations are compatible with a graft-versus-host reaction directed against minor histocompatibility antigens presented at the cell surface of hematopoietic cells, but reactions against leukemia-specific antigens are possible. Future studies will focus on differences of reactions against possible leukemia-specific antigens and histocompatibility antigens on hematopoietic cells and cells of other organs.
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PMID:Donor leukocyte transfusions for leukemic relapse. 937 31

A patient presented with chronic large granular lymphocyte leukemia associated with chronic active Epstein-Barr virus infection (CAEBV). Cell cycle analysis revealed a minimal growth compatible with chronic lymphocytic leukemia After 5 months of treatment, the patient died from acute transformation of the leukemia. Cell harvested during chronic phase were analyzed for sensitivity to interleukin 2 (IL-2) and interferon alpha (IFN alpha) in vitro by means of surface phenotyping and cell cycle assay. IL-2 induced remarkable growth of the cells, whereas IFN alpha did not confer a growth advantage. Since IFN alpha was expected to have no growth induction effect on the leukemia cells, it was administered to the patient to treat the CAEBV.
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PMID:Characterization and sensitivity to interleukin 2 and interferon alpha of leukemic cells from a patient with large granular lymphocytic leukemia associated with chronic active Epstein-Barr virus infection. 940 5

Response rates of 20% were achieved when interferon alpha (IFN) was applied as single agent treatment for multiple myeloma. A synergistic activity was observed when IFN was combined with chemotherapeutic agents in vitro and in vivo. These observations led to a series of randomized trials comparing chemotherapy alone with the combination of IFN and chemotherapy which yielded controversial results. Ludwig et al have analyzed presently available data of randomized trials in a systematic overview. In 16 trials, 2286 patients were randomized either for induction therapy with chemotherapy or IFN combined with chemotherapy. The IFN dose ranged between 4.8 and 18.7 MU/week. The overall response rate was 45.9% for patients treated with chemotherapy alone compared to 54.4% for patients treated with IFN alpha and chemotherapy. The gain of relapse-free survival was 6 months and the gain of overall survival was 5 months for IFN-treated patients. Advances in treatment were due to the expense of more severe side-effects in IFN-treated patients expressed by hematological side-effects, fever, nausea and neurological as well as psychological alterations. IFN maintenance therapy was evaluated from eight trials comprising 929 patients randomized for IFN-treatment or 'wait and see'. IFN maintenance treatment prolonged the average relapse-free survival by 7 months and prolonged the average overall survival by 5 months. Younger patients, patients in good performance status and patients with lower tumor burden seem to benefit most from the addition of IFN to chemotherapy or from IFN maintenance therapy. In conclusion, IFN shows a minor beneficial effect on response rates, progression-free and overall survival in the above mentioned patient group and might be applied when high-dose chemotherapy with transplantation is not feasible. IFN has been shown to be effective for maintenance therapy in patients with lower tumor burden who have responded to induction therapy.
Leukemia 1997 Dec
PMID:Interferon alpha in the therapy of multiple myeloma. 943 40


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