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PubMed1986

Low dose ara-C administered by continuous subcutaneous infusion: a pharmacologic evaluation.

Low dose ara-C has been widely used in the treatment of preleukemia and leukemia. These studies have generally utilized either a twice daily, subcutaneous bolus schedule or a continuous intravenous infusion schedule. In order to surmount the logistical problems of long term intravenous infusion while providing prolonged ara-C exposure, we have studied the pharmacology of administering ara-C (20 mg/M2/d) by continuous subcutaneous infusion. The results obtained in eight patients demonstrate that steady state plasma ara-C levels achieved during continuous subcutaneous infusion (24.6-65.6 nM) are not significantly different than those obtained during intravenous infusions (26.2-61.5 nM). Subcutaneous infusions result in prolonged myelosuppression similar to that seen with continuous intravenous infusions. The continuous infusion of low dose ara-C by the subcutaneous route provides a treatment option for some outpatients and offers advantages over intravenous infusions which often require placement of venous catheters or hospitalization.

Adult↗

PubMed1981

Platelet function in preleukaemia.

Platelet function was studied in 17 patients with preleukaemia and the results were compared with those of 28 patients with other chronic myeloproliferative disorders. The test pattern included bleeding time (Ivy), platelet retention (Hellem II), PF-3 activity and availability after exposure to ADP and kaolin, and ADP-, epinephrine-, collagen- and ristocetin-induced aggregations. Platelet function was frequently impaired in patients with preleukemia. The defects were similar to those found in other myeloproliferative disorders. The most consistent finding was defective aggregation. Patients with thrombocytosis and/or with increased amounts of megakaryocytes in the bone marrow had fewer defects in platelet function. Retention defect was more common in patients with hypolobulated megakaryocytes, especially in those having a specific marker, the 5q- chromosome, in their bone marrow cells.

Adult↗

PubMed1984

Function of peripheral blood and bone-marrow monocytes in preleukemic patients: normal phagocytosis and intracellular killing of Candida albicans.

Studies were performed to evaluate the function of peripheral blood and bone marrow monocytes from 15 patients with preleukemia and 16 healthy controls. The patients were grouped according to the criteria of the FAB collaborative group. No abnormality in phagocytosis and killing of Candida albicans by peripheral blood and bone marrow monocytes was found in patients compared to normal controls. Normal opsonization by autologous serum was found. No differences were found in this respect between the three groups of patients.

Adult↗

PubMed1985

Treatment of preleukemic syndromes with continuous intravenous infusion of low-dose cytosine arabinoside.

Preleukemic syndromes compose a group of acquired bone marrow disorders characterized by dysplastic maturation of hematopoietic cells and peripheral blood cytopenias. These syndromes have been generally considered untreatable. We administered low doses of cytosine arabinoside by continuous infusion for 14 to 21 days (20 mg/m2/d) to 16 patients with preleukemia in various stages of evolution to acute leukemia. Steady state plasma cytosine arabinoside levels ranged from 41.8 to 64.2 nmol/L. Eleven patients demonstrated marked improvement in hematopoiesis and loss of transfusion requirements for periods ranging from two to 27 + months. All but one responding patient developed recurrent pancytopenia, but additional responses to low-dose cytosine arabinoside were achieved in five of five retreated patients. Median overall survival time is 12 months for the 11 responding cases, and nine months for nonresponders. The major toxicity of low-dose cytosine arabinoside is myelosuppression, and most patients required platelet transfusion support and administration of antibiotics. Chromosome analyses demonstrated evolution to a new clone of hematopoietic cells in three patients, and persistence of the same abnormal clone in another patient. These results suggest that low-dose cytosine arabinoside therapy may result in improved hematopoiesis by promoting maturation or by selecting new stem cell clones. Low-dose cytosine arabinoside therapy thus deserves further evaluation both as a single agent and in combination with other agents in the treatment of myelodysplastic syndromes.

Adult↗

PubMed1979

New aspects of preleukemic disorders.

Preleukemic disorders are a controversial group of panmyelopathic disturbances that often precede the emergence of acute myeloblastic or myelomonocytic leukemia. In most instances, these preleukemic disorders are characterized by slowly developing myeloblastosis of the bone marrow. They include preleukemia, primary acquired panmyelopathy with myeloblastosis or smouldering acute leukemia, erythroleukemia, and subacute myelomonocytic leukemia. Sometimes, transitions between these various preleukemic disorders may be observed in a single individual. Abnormalities in cellular differentiation are expressed in cytochemical aberrations and in elaboration of colony forming units by marrow cells of patients with preleukemic disorders. Cytogenic and cellular kinetic abnormalities link preleukemic disorders closely to acute myeloblastic or myelomonocytic leukemia, although in many patients with preleukemic disorders, conversion to acute leukemia is not observed or perhaps not recognized. Understanding pathogenetic and pathophysiological aspects of preleukemic disorders may shed light on aspects of cellular proliferation and cellular differentiation in the acute leukemias.

Acute Disease↗

PubMed1986

Melphalan may be a more potent leukemogen than cyclophosphamide.

We have evaluated the relation between alkylating agents and leukemic disorders in 3363 1-year survivors of ovarian cancer who were treated in five randomized clinical trials and at two large medical centers. Overall, 28 patients developed acute nonlymphocytic leukemia (expected, 1.2) and 7 developed preleukemia. A 93-fold increased risk for acute nonlymphocytic leukemia was seen in 1794 women treated with chemotherapy; the incidence of leukemic disorders was 7.7/1000 women per year. Risk was highest 5 to 6 years after the first treatment and appeared to decrease thereafter. The use of radiation therapy did not affect risk. The 10-year cumulative risk (mean +/- SE) of acquiring a leukemic disorder was 8.5% +/- 1.6% after treatment with any alkylating agent, 11.2% +/- 2.6% after treatment with melphalan, and 5.4% +/- 3.2% after cyclophosphamide treatment. A dose-response relationship was apparent in 605 women receiving melphalan and suggested in 333 women receiving cyclophosphamide. Women receiving melphalan were two to three times as likely to develop leukemic disorders than were women receiving cyclophosphamide. These data indicate that choice of chemotherapeutic agent and drug dosage may influence significantly the risk for long-term adverse effects of cancer therapy.

Acute Disease↗

PubMed1976

Cytogenetic heterogeneity of the acute leukemias.

Cytogenetic abnormalities have been found in approximately 50% of all patients with acute leukemia. Although no chromosomal abnormalities have been found which are characteristic of a specific cell type, patients with AML and DiGuglielmo's syndrome more frequently have hypodiploid chromosome numbers, while patients with ALL seldom have hypodiploid numbers of chromosomes and may actually exhibit an extreme degree of hyperdiploidy in the leukemic cells. Chromosome analysis may be helpful in characterizing patients with preleukemia and DiGuglielmo's syndrome, and aneuploidy may correlate with shortened survival in these conditions. Although data so far available are conflicting concerning the relationship of aneuploidy to response to therapy in patients with acute leukemia, it is possible that as improved therapeutic regimens become available for the treatment of acute leukemia, more sophisticated cytogenetic analysis may be helpful in predicting survival and response to therapy.

Aneuploidy↗

PubMed1992

Fanconi anemia and leukemia: tracking the genes.

A review of all of the cases of Fanconi anemia (FA) reported to the International Fanconi Anemia Registry (IFAR) indicates that at least 15% manifest acute myelogenous leukemia (AML) or preleukemia. These patients usually have karyotypically abnormal bone marrow clones, but do not exhibit chromosomal translocations involving breakpoints associated with specific oncogenes; leukemia in FA is more likely to be a multi-step process than a single step transformation. The cellular defect in FA results in chromosomal instability, hypersensitivity to DNA damage, and hypermutability for allele-loss mutations. An update of current research to identify the molecular defect in FA is presented. Characterization of the FA genes should further our understanding of the etiology of leukemia.

Adolescent↗

PubMed1992

Initiation and promotion in radiation-induced myeloid leukemia.

Acute myelomonocytic leukemia develops in 10-30% of irradiated (300 rad) SJL/J mice, after a lag period of around one year. Additional treatment with dexamethasone shortly after irradiation increased leukemia incidence up to 50%. Experiments were conducted in order to demonstrate the existence of preleukemic cells in irradiated mice and to explore the possible role of dexamethasone, cyclophosphamide, and different hemopoietic growth factors on their promotion to overt leukemia. Transplantation of bone marrow cells from mice exposed to 300 rad plus dexamethasone into appropriate recipients, performed 4-5 months after leukemogenic treatment, resulted in acute myeloid leukemia (AML) development of donor origin in 70% of the recipients. Transfer of fractionated preleukemic bone marrow showed that the highest AML incidence developed in the recipients of fractions enriched in early hemopoietic precursors. The promoting effect of dexamethasone on preleukemic cells was confirmed by demonstrating its similar coleukemogenic effect whether administered within several hours or 130 days after radiation. Treatment with cyclophosphamide shortly after radiation could not replace the dexamethasone effect but was found to be complementary to the coleukemogenic effect of dexamethasone. Early administration of hemopoietic growth factors (starting 14 days after radiation and dexamethasone) showed that colony-stimulating factor (CSF) 1 increased the AML incidence (75%) and reduced its latency. Treatment with recombinant granulocyte-CSF (rG-CSF) had a reduced effect and recombinant granulocyte-macrophage CSF (rGM-CSF) had no promoting effect. However, administration of different factors several months after the leukemogenic treatment revealed that rGM-CSF increased AML incidence (75%) and shortened its latency, whereas rG-CSF and CSF-1 had no effect. In contrast, the late administration of recombinant interleukin 6 reduced AML incidence significantly (23%). The present results indicate that murine radiation induced AML is a multiphase process involving radiation induced preleukemia that can be promoted by different treatments.

Animals↗

PubMed1991

In vivo regulation of human leukocyte 3-hydroxy-3-methylglutaryl coenzyme A reductase: increased enzyme protein concentration and catalytic efficiency in human leukemia and lymphoma.

The activity of microsomal HMG-CoA reductase in freshly isolated leukocytes from patients with a variety of hematologic malignancies was significantly increased (up to 20-fold) when compared to enzyme activity in leukocytes from normal subjects (average 10.3 +/- 0.8 pmol/min per mg). Increased enzyme activity was not due to nonspecific leukocyte stimulation or to the presence of a malignancy, since normal enzyme activity was observed in subjects with either viral illnesses or solid tumors. Increased HMG-CoA reductase activity accompanying hematologic malignancy could also not be attributed to alterations in enzyme-substrate kinetic parameters (Km), or to alterations in the phosphorylation state or thiol-disulfide status of the enzyme, nor was it correlated with differences in serum lipid or lipoprotein concentrations. The increase (3.6-fold) in HMG-CoA reductase activity in leukocytes from patients with preleukemia was due entirely to a rise in enzyme catalytic efficiency (specific activity), whereas the increase (4.3-fold) observed in leukocytes from patients with overt leukemia or non-Hodgkin's lymphoma was due to a concomitant increase in both enzyme catalytic efficiency (2.5-fold) and enzyme protein concentration (1.6-fold). Similar increases in HMG-CoA reductase activity and catalytic efficiency were also noted for both transformed, nonmalignant, and malignant cultured leukocytes, suggesting that increased enzyme catalytic efficiency is not a nonspecific consequence of physiological changes occurring in response to the malignancy but may be an integral aspect of the malignant phenotype. HMG-CoA reductase protein concentrations, however, were not elevated in either transformed, nonmalignant, or malignant cultured leukocytes, suggesting that increases in enzyme protein levels may be secondary to other physiological changes that occur during the development of overt leukemia. Taken together, these observations suggest that an increase in the activity of HMG-CoA reductase, the rate-controlling enzyme in cholesterol synthesis, is a common occurrence in human hematologic malignancies and that a biphasic elevation of enzyme activity may exist in malignant leukocytes, such that changes in catalytic activity may occur early in tumorigenesis and may be followed by secondary changes in enzyme levels.

Adolescent↗

PubMed1990

[Various morphofunctional characteristics of hematopoietic tissue in preleukemic conditions].

Cultural, ultrastructural, cytochemical and histological investigations of bone marrow tissue were conducted in 26 patients with varying types of preleukemia states. A number of early structural, morphological and functional signs of hemopoietic disorders of different character and manifestation degree have been revealed. Particularly, a relationship has been established between the pathologic changes appearing in the bone marrow stroma and disorders in the morphological and functional state of the hemopoietic cells.

Anemia, Refractory↗

PubMed1990

[Transient monocytic skin infiltrate during preleukemic phase of acute myelomonocytic leukemia].

An acute myelomonocytic leukemia presenting transient skin rash during preleukemic phase was described. Following four years of unexplained leukopenia, a generalized exanthema developed and subsequently regressed spontaneously. The skin biopsy and immunohistochemistry revealed monocytic infiltration into the dermis. Twenty-eight months later, the patient became leukemic and died. The skin lesions, however, did not occur after leukemic transformation. Probably transient monocytic skin infiltrate was a symptom of preleukemia, a stem cell neoplasm manifested by functionally abnormal maturation.

Aged↗

PubMed1989

[Preleukemic disorders].

Certain hematopoietic disorders and immunodeficiency states are known to carry a risk of developing acute nonlymphocytic leukemia. In the past some of them have been classified by a variety of terms ranging from refractory anemia to preleukemia, but are currently grouped into a new concept of the myelodysplastic syndromes (MDS). The purpose of this article is to briefly review the updated knowledge of the MDS with emphasis on the clonal origin, natural history and mechanisms of leukemogenesis.

Cell Transformation, Neoplastic↗

PubMed1989

Stimulation of nonclonal hematopoiesis and suppression of the neoplastic clone after treatment with recombinant human granulocyte-macrophage colony-stimulating factor in a patient with therapy-related myelodysplastic syndrome.

A complete hematologic remission was achieved in a patient with therapy-related preleukemia and transfusion-dependent pancytopenia after treatment with recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF). The patient remained in remission for nearly 1 year despite the discontinuation of GM-CSF treatment. Several lines of evidence suggest that normal hematopoiesis was restored after GM-CSF treatment. First, the cytogenetic anomaly, which was present before GM-CSF, completely disappeared after three cycles of treatment. Cytogenetic conversion was documented by conventional karyotypic evaluation of mitotic bone marrow cell preparations as well as by premature chromosome condensation analysis of the nonmitotic cells of bone marrow and peripheral blood. Second, the growth pattern and cycle status of bone marrow granulocyte-macrophage (CFU-GM) and erythroid (BFU-E) progenitor cells were found to be normal during remission. Third, X chromosome-linked restriction fragment length polymorphism-methylation analysis of DNA from mononuclear cells (greater than 80% lymphocytes) and mature myeloid elements showed a polyclonal pattern. These findings suggest that restoration of hematopoiesis in this patient after GM-CSF treatment may have resulted from suppression of the abnormal clone and a selective growth advantage of normal elements.

Adenocarcinoma↗

PubMed1988

[Chemotherapeutic effects in hypoplastic leukemia].

Clinical effects of a low dose of behenoyl ara-C (LD-BHAC) and K-18, an IgG-melphalan conjugate, were studied in hypoplastic leukemia (HL). Among 8 cases of HL treated with LD-BHAC regimen, in which 50 mg BHAC was administered daily by one-hour drip infusion for 14 days, 4 achieved complete remission (CR) and 2, partial remission (PR). The response rate (CR + PR) was 75%. Hematological toxicities were observed in most of the cases. The peak level of serum ara-C concentration, 3.62-18.9 ng/ml (mean: 11.74 ng/ml), was observed at cessation of infusion, and an ara-C level of 2.75-48.9 ng/ml (mean: 3.45 ng/ml) was still present in the blood 6 hours after cessation of infusion. Six cases of HL were treated with K-18. Eight tablets of K-18, containing 30 mg per tablet, were given daily. Two of 6 cases achieved CR with little hematological toxicities. LD-BHAC and K-18 can be expected in the treatment of hypoplastic leukemia and its related diseases such as hypoplastic preleukemia in the aged.

Adult↗

PubMed1986

Factors influencing leukemic transformation in refractory anemias with excess of blasts, with ringed sideroblasts, and without ringed sideroblasts.

The association between leukemic transformation and various features recorded at presentation in patients with refractory anemia with excess of blasts and with or without ringed sideroblasts was analyzed in 255 patients using the proportional hazard model. Features associated with higher transformation rates were: higher values of blasts in peripheral blood or bone marrow; serum haptoglobin; vitamin B12; megakaryocytes in bone marrow; morphological abnormalities in granulo- or megakaryocyte series; male sex; circulating megakaryocytes in peripheral blood; older age; and lower ringed sideroblast proportion. Multivariate analysis was also performed using the following predictor variables: presence or absence of refractory anemia with excess of blasts; sex; abnormal granules in granulocytes; age; and mononuclear large megakaryocytes. Patients were divided arbitrarily into low (hazard ratio, less than 0.45), intermediate (hazard ratio, 0.45-1.85) and high (hazard ratio, greater than 1.85) risk groups. The cumulative leukemia-free rates in the low and intermediate risk groups showed long plateau phases at 95 and 71%, respectively, while in the high risk group, the rate was 10% at 5 years. For clinical purposes, the low risk group should be considered to have nonpreleukemia and the high risk group to have preleukemia.

Adolescent↗

PubMed1986

[Panmyelopathy and myeloproliferative syndrome].

From the viewpoint of a territorial haematological centre with a certainly preselected number of patients the initial symptom of bi- or pancytopenia in 3/4 of the cases proves as first reference to a myeloproliferative or myelodysplastic syndrome. Of these cases 62.5% transferred into a crisis of blasts; that is, they must be regarded as real preleukemia. The morphology of the bone marrow as well as the stem cell cultures obtained from this give important references to the diagnostic classification of the early changes as well as to their prognosis.

Biopsy, Needle↗

PubMed1985

Serial cell culture and cytogenetic studies of marrow cells from a patient with monosomy 7 syndrome.

Serial bone marrow cell culture studies, with cytogenetic characterization, were performed in an 18-month-old boy with monosomy 7 syndrome--a condition that usually converts to nonlymphoblastic leukemia. Over a 12-month course, his marrow demonstrated: decreased colony formation and increased cluster formation in vitro with disease progression (consistent with preleukemia); persistence of only the monosomy 7 karyotype in direct marrow studies; and in contrast, proliferation of both 46,XY and monosomy 7 cells in in vitro marrow cultures. The findings indicate that certain dormant marrow cell populations may be expressed under in vitro culture conditions and suggest the need for determining factors which would allow their expression in vivo.

Bone Marrow↗