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PubMed1987

Childhood monosomy 7 syndrome: clinical and in vitro studies.

The clinical and cell growth characteristics of 11 children with monosomy 7 presenting as preleukemia (eight cases) or acute nonlymphoblastic leukemia (three cases) were studied. Anemia was common to all patients, with nine showing leukocytosis, seven thrombocytopenia, and one thrombocytosis. There was a striking predominance of males (M/F ratio, 10:1) and a young median age (3 years). Preleukemia evolved to acute nonlymphoblastic leukemia in five patients and to myelofibrosis in one. In vitro studies of bone marrow progenitor cells cultured in leukocyte feeder-stimulated agar revealed abnormal cell proliferative patterns, most often an increased number of small clusters, for all 11 subjects. The cells of some preleukemic patients showed increased growth even in the absence of an exogenous source of colony-stimulating factor, suggesting autonomous growth or possibly autocrine stimulation. Combination chemotherapy or bone marrow transplantation failed to induce complete remission in the seven patients who were treated. Our findings in these 11 cases confirm the poor prognosis of monosomy 7 presenting as preleukemia in children. The in vitro studies suggest an association between altered cell growth in vitro and clinical evolution to frank leukemia.

Acute Disease↗
PubMed1982

[Cytogenetic study of preleukemic phases and of acute leukemia secondary to chemo-and/or radiotherapy. Review of the literature (102 cases)].

A review of the literature upon 102 cases with cytogenetic study of preleukemic states (Prel.) and/or acute secondary leukemia (ASL) following chemotherapy and/or radiotherapy treatment has been made. The karyotype was almost always abnormal (91%) of cases). There was a predominance of hypodiploidy with abnormalities including chromosome number 5 (-5 ou 5q-) and/or number 7 (7- or 7q-) (chromosomes studied with banding). The abnormalities were present in preleukemia state. The pattern of the acute secondary leukemia was particularly different from that acute leukemia de novo: high frequency of preleukemia state, ANLL type of leukemia, very bad prognosis, importance of cytogenetic abnormalities. There was a great interest in the study of the karyotype for the previous detection in ASL: this allowed their discovery as soon as the preleukemia state.

Acute Disease↗
PubMedDate not supplied

Treatment-related leukemia in Hodgkin's disease: a multi-institution study on 75 cases.

Hematological and cytogenetic characteristics of 75 cases of therapy-related acute non lymphoid leukemia (t-ANLL) occurring in Hodgkin's disease (HD) are analysed in this multi-institution study. Combined radio and chemotherapy had been given in 88 per cent of patients, either as adjuvant (44 per cent) or as salvage modality (44 per cent). Radiotherapy alone and chemotherapy alone had been given in 3 per cent and 9 per cent respectively. Eighty per cent of patients were in remission of HD and 71 per cent off-therapy while developing leukemia. The median latent time from remission of HD to leukemia was 34 months. The myeloblastic variety of leukemia accounted for 43 per cent of total cases; the myelomonocytic and monocytic for 17 per cent and 4 per cent, the promyelocytic and erythroblastic variants for 5 per cent and 7 per cent of t-ANLL. Twenty four per cent of cases were unclassifiable; one of these was TdT-positive. Dysplastic features of erythrocytic line were invariably present with circulating erythroblasts; defects of granulocytes, circulating megathrombocytes and micromegakaryocytes were also present. Bone marrow hypoplasia and marked fibrosis were documented in 47 per cent and 30 per cent of cases. Preleukemia heralded overt leukemia in 73 per cent of cases; 37 per cent had refractory anemia with no excess of blasts; 16 per cent of preleukemias were unclassifiable. Cytogenetics revealed chromosome abnormalities in 83 per cent of cases; 72 per cent presented chromosome 5 and/or 7 monosomy or partial deletion (5q- or 7q-) of the long arm (94 per cent in the combined modality therapy group). In 3 cases, a pure monosomy 7 was observed; in none 5q-alone. Response rate to conventional therapy was 14 per cent; low and high-dose cytarabine were of little benefit. Long-term CR (28 + and 16 + months) was achieved in 2 cases with allogeneic bone marrow transplantation (BMT) as first-line therapy. A better knowledge of t-ANLL in HD and new therapies, including BMT, may improve the prognosis of this late complication of intensive HD treatment.

Adult↗
PubMed1980

The preleukemic syndromes (hematopoietic dysplasia) in childhood.

The preleukemic syndrome or hematopoietic dysplasia is a marrow stem-cell disorder with clinically recognizable hematologic abnormalities which precede the development of acute nonlymphocytic leukemia. Its occurrence in childhood is extremely rare; seven "true" cases who fulfill all the criteria for the disorder have been reported until now. The preleukemic syndrome is generally characterized by peripheral cytopenia with fairly specific morphologic abnormalities in cell differentiation. The hematological and clinical features permit recognition of preleukemia even before the development of overt leukemia. Experimental data indicate that preleukemia is an "early" leukemic syndrome in which hematopoietic cell differentiation becomes progressively impaired with termination in the nearly complete maturation block which is characteristic of acute myelogenous leukemia.

Age Factors↗
PubMed1977

Cytochemical observations in preleukemic states and remission of akute leukemia.

In preleukemia and in remission of acute leukemia abnormal mononuclear cells ("string of bead" cells) have been observed and characterized with cytochemical methods. These cells may be resistant to cytostatic therapy and may be characterized as a source of a newly developing leukemic blast cells. Preleukemia and leukemic remissions seem to be identical states. Based on the morphological and cytochemical parallelity of cells in CFU-c-enriched fractions of the bone marrow and the so called string of bead cells we consider these cells to be closely related to the human commited stem cell.

Acute Disease↗
PubMed1978

Preleukemic syndromes.

Acute nonlymphocytic leukemia (ANLL) is preceded by a hematologic illness representing the "preclinical" stages of the disease in many patients. This "preclinical stage" or preleukemic stage is difficult to recognize by conventional hematologic morphologic techniques. A prospective study was carried out to determine whether cytogenetic studies would be helpful in the recognition of preleukemic states and whether the presence of cytogenetic abnormalities would have prognostic significance. A study of 284 patients with suspected preleukemia has yielded 62 patients with progression to overt ANLL. Cytogenetic abnormalities were found in 30% of suspected preleukemic patients, whereas 53% of the patients progressing to acute leukemia had cytogenetic abnormalities. These studies show that the presence of cytogenetic abnormalities aid in the recognition of preleukemia but are not specific for early leukemia. Patients with cytogenetic abnormalities are more likely to develop overt ANLL. Banded chromosome studies demonstrated cytogenetic abnormalities in the preleukemic phase in 13 of 26 patients. A variety of clonal chromosomal abnormalities were observed.

Acute Disease↗
PubMed1976

The myeloproliferative disorders. Correlation between clinical evolution and alterations of granulopoiesis.

Patients with myeloproliferative disorders were prospectively studied by in vitro agar-gel marrow culture technics to evaluate factors involved in the evolution of abnormal granulopoiesis. Marrow granulocytic colony-forming capacity was determined in 78 patients with chronic myeloid leukemia, subacute myeloid leukemia, preleukemia, Di Guglielmo's syndrome, polycythemia vera or essential thrombocythemia. A wide range of marrow colony-forming capacity values was noted early in disease courses; however, in 26 of 33 patients decreased colony-forming capacity was associated with disease transformation into acute myeloid leukemia or other clinically aggressive stages. An increased proportion of abnormally light buoyant density (less than 1.062 g/cm3) colony-forming cells was present in the marrow and peripheral blood of 15 of 16 patients with chronic myeloid leukemia, subacute myeloid leukemia, preleukemia or essential thrombocythemia; in seven of eight patients with greater than 35 per cent abnormally light colony-forming cells their disease subsequently underwent transformation. Elevated levels of urinary colony-stimulating factor output were noted in 17 of 31 patients, and in 10 of 12 patients whose disease subsequently underwent acute transformation within 10 months of study. In six of seven patients who simultaneously had an increased urinary output of colony-stimulating factor and low colony-forming capacity in marrow, transformation occurred within 10 months. These findings indicate that progressive abnormalities of both marrow clonal growth patterns and levels of possible humoral regulatory substances develop during evolution of these diseases. In contrast, patients with idiopathic sideroblastic ineffective erythropoiesis had normal values for marrow colony-forming capacity, proportion of light density colony-forming cells and urinary colony-stimulating factor output, and in none has their disease transformed into acute myeloid leukemia. These in vitro studies appear useful for clinical staging, evaluating prognosis and categorizing patients with myeloproliferative disorders.

Adolescent↗
PubMed1988

A hypothesis regarding the development of acute myeloid leukemia from preleukemic disorders. The role of protooncogenes.

Acute nonlymphocytic leukemia is often preceded by a preleukemic phase that can be characterized by a reduction in hematopoiesis, by ineffective hematopoiesis, or by a myeloproliferative/myelodysplastic state. The time between onset of the preleukemic state and the appearance of leukemia is quite variable, and at times such evolution does not occur. These clinical observations are compatible with the multistep hypothesis of tumor development. In studies underway in our laboratory, chronic myelogenous leukemia (CML) is being used as a model system to study the steps in and possible mechanisms underlying the development of preleukemia and its evolution to acute leukemia. Chronic myelogenous leukemia is particularly suited for this role because the chronic phase of the disease is an easily identifiable myeloproliferative state that invariably evolves into acute leukemia. In the discussion that follows, this clinical entity is used to develop a general model for the preleukemias and their evolution to acute leukemia.

Blast Crisis↗
PubMed1995

N-ras mutation in 7,12-dimethylbenz[a]anthracene (DMBA)-induced erythroleukemia in Long-Evans rats.

Intravenous injections of 7,12-dimethylbenz[a]anthracene (DMBA) induce erythroblastic leukemia (erythroleukemia) with No.2 trisomy in Long-Evans rats. Activation of some oncogenes such as abl and Ha-ras has been reported to occur in relation to the secondary chromosomal translocations. In the present studies, a consistent type of mutation, A to T transversion in codon 61 of N-ras gene, was found in all of 6 cultured leukemia cell lines and 5 primary leukemias induced by DMBA. The N-ras mutation was also found in bone marrow cells of 2 out of 8 preleukemias. On the contrary, no mutation was observed in Ha- and Ki-ras genes in all leukemias and preleukemias. The consistent occurrence of above N-ras mutation in leukemias indicates that it plays an important role in DMBA-leukemogenesis.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1983

Response of preleukemic syndromes to continuous infusion of low-dose cytarabine.

Preleukemic syndromes are a group of acquired bone-marrow disorders characterized by dysplastic maturation of hematopoietic cells and peripheral-blood cytopenias. Although the clinical course is variable, most patients succumb to hemorrhage, infection, or acute leukemia. These syndromes are generally considered untreatable. We administered low doses of cytarabine by continuous intravenous infusion for 7 to 21 days in eight patients with preleukemia or with preleukemia in evolution to acute leukemia. Eight of 13 courses were associated with marked increases in peripheral-blood granulocyte, platelet, and red-cell counts, with the result that six of the eight patients needed no transfusions for 2 to over 14 months. These preliminary results demonstrate that continuous infusion of low-dose cytarabine can offer patients with preleukemic syndromes hematologic improvement with limited toxicity.

Adult↗
PubMed1986

Increased expression of p53 protein in human leukemia cells.

We examined synthesis of the cellular phosphoprotein p53 in fresh bone marrow or peripheral blood cells from normal donors and from patients with leukemia, preleukemia, or other hematopoietic disorders. Lysates of cells labeled with [35S]methionine were immunoprecipitated with monoclonal antibodies to p53, and the immunoprecipitates were analyzed by NaDodSO4/polyacrylamide gel electrophoresis and autoradiography. Bone marrow or peripheral blood cells from 8 of 33 patients with hematopoietic disorders showed increased p53, seven of the eight occurring in cells of patients with preleukemia or acute myelogenous leukemia. Increased p53 synthesis was not associated with p53 gene amplification, as shown by Southern blot analysis. Synthesis of p53 was not increased in any of nine normal human bone marrow samples or eight normal human peripheral blood granulocyte, macrophage, and lymphocyte samples. The hematopoietic cells of patients in remission or with chronic forms of leukemia did not generally synthesize elevated levels of p53. In addition, we found negligible p53 mRNA and protein expression in a variety of human myeloid leukemia lines blocked at different stages of differentiation. Southern blot analysis showed that, except for the HL-60 cells, the p53 gene of the myeloid cell lines was intact. In view of recent evidence implicating p53 in transformation of cultured cells, our results using fresh leukemia cells suggest that p53 may contribute to the phenotype of certain leukemias in vivo.

Bone Marrow↗
PubMed1987

S1 nuclease analysis of alpha-globin gene expression in preleukemic patients with acquired hemoglobin H disease after transfer to mouse erythroleukemia cells.

The loss of alpha-globin gene transcriptional activity rarely occurs as an acquired abnormality during the evolution of myeloproliferative disease or preleukemia. To test whether the mutation responsible for the loss of alpha-globin gene expression (hemoglobin H disease) in these patients is linked with the alpha-globin genes on chromosome 16, we transferred chromosome 16 from preleukemic patients with acquired hemoglobin H disease to mouse erythroleukemia cells and measured the transcriptional activity of the human alpha-globin genes. After transfer to mouse erythroleukemia cells, the expression of human alpha-globin genes from the peripheral blood or marrow cells of preleukemic patients with acquired hemoglobin H disease was similar to that of human alpha-globin genes transferred to mouse erythroleukemia cells from normal donors. These data showed that factor(s) in the mouse erythroleukemia cell can genetically complement the alpha-globin gene defect in these preleukemia patients with acquired hemoglobin H disease and suggest that altered expression of a gene in trans to the alpha-globin gene may be responsible for the acquisition of hemoglobin H disease in these patients.

Animals↗
PubMed1981

Thrombocytopenia with decreased megakaryocytes. Evaluation and prognosis.

The presenting clinical pictures and courses of seven patients with thrombocytopenia, decreased megakaryocytes in the marrow, and minimal changes in other hematopoietic cell lines are described. Little information exists in the literature on such patients. Initial bone marrow aspiration and biopsy in all patients showed decreased megakaryocytes with an otherwise normal marrow. Erythrocyte mean corpuscular volume was elevated in five of seven patients. Bone marrow karyotypes of six of the seven patients were normal. Chromium-51 platelet survival studies with platelet sizing, done in five of the seven patients, showed normal results. In two patients the course progressed to aplastic anemia. One of these died 9 months after presentation, and one responded dramatically to lithium. One patient developed preleukemia and died. The other four patients have remained thrombocytopenic but clinically stable. No useful therapy was identified. The differential diagnosis of such patients should include idiopathic thrombocytopenic purpura with misinterpretation of morphologic findings, hereditary and acquired aplastic anemia, preleukemia, and systemic lupus erythematosus.

Adult↗
PubMed1990

Leukemia following chemotherapy for breast cancer.

Leukemia following chemotherapy for breast cancer was studied among patients diagnosed during 1973-1985 within the population-based tumor registries in the Surveillance, Epidemiology, and End Results Program. Among 13,734 women given initial chemotherapy, 24 developed acute nonlymphocytic leukemia (ANLL) compared to 2.1 expected based on general population rates (observed/expected = 11.5; 95% confidence interval = 7.4-17.1). Overall, 58 excess ANLL occurred per 100,000 women-years at risk for patients treated with chemotherapy. The cumulative incidence was 0.7% at 10 years. Risk remained high over all periods of observation up to 9 years after treatment. Among 7974 women treated only with surgery during 1973 and 1974, a period before the widespread use of adjuvant chemotherapy for breast cancer, ANLL was not significantly increased (observed = 7, expected = 5.1). A case-control study was then conducted in Connecticut to evaluate in more detail the risk associated with adjuvant chemotherapy in the general population. Among 20 cases (17 incident leukemias and 3 deaths due to preleukemia) and 60 matched controls, alkylating agents were linked to an 11.9-fold risk of ANLL and preleukemia (95% confidence interval = 2.6-55). Chemotherapy regimens including melphalan were related to a higher risk of leukemic conditions than those including cyclophosphamide. These data suggest that women in the general population treated with adjuvant chemotherapy for breast cancer are at an increased risk of leukemia, that the risk remains high among long-term survivors, and that risk differs by type of alkylating agent administered.

Age Factors↗
PubMed1985

Cellular and clinical pharmacology of low-dose ara-C.

Although the mechanism of action responsible for the effects of low-dose ara-C remains unclear, certain insights are available concerning the interaction of this agent with DNA. Ara-C incorporates into DNA, and the extent of (ara-C)DNA formation correlates significantly with loss of clonogenic survival. The inhibition of DNA replication by ara-C also results in DNA fragmentation and terminal differentiation of leukemic cells. Other studies have demonstrated that inhibition of DNA replication by ara-C results in an aberrant form of DNA synthesis with certain segments of DNA being replicated more than once within a single cell cycle. The additional copies of certain segments of DNA could lead to the accumulation of DNA fragments and alterations in gene expression. It is of interest that other inhibitors of S-phase DNA replication such as aphidicolin and hydroxyurea can also induce similar phenotypic changes in HL-60 and K562 leukemia cells. Although the in vitro data support the concept that ara-C is capable of inducing leukemic cell differentiation, there is no evidence to suggest that this agent induces differentiation of human leukemic cells in vivo. Drug levels achieved by administration of low-dose ara-C (42-64 nmol/L) result in the incorporation of ara-C into bone marrow mononuclear preparations from patients with preleukemia syndromes. This concentration of ara-C (5 X 10(-8) mol/L) slows DNA replication of human leukemic cells in vitro. Thus, the clinical use of low doses of ara-C that achieve plasma concentrations of 10(-8) to 10(-7) mol/L could theoretically induce maturational effects by partially inhibiting DNA synthesis. At the present time we have no available data to support this contention. On the basis of chromosomal analyses, low-dose ara-C apparently maintains sufficient drug levels to suppress more "malignant" clones, but even "clonal" selection may represent elimination of leukemic cells by either cytotoxicity or induction of terminal differentiation. Further studies will be necessary to define the mechanism of action of low-dose ara-C in preleukemia.

Adult↗
PubMed1981

On the 5q- deletion: clinical and cytogenetic observations in ten patients and review of the literature.

Clinical and cytogenetic findings in 10 patients with deletions of the long arm of chromosomes 5 (5q-) are reported. Five cases had refractory anemia, the preleukemic syndrome, or refractory anemia with an excess of blasts; in all but one, the 5q- was the single initial abnormality. Three patients had overt leukemia; in all, the 5q- was accompanied by additional anomalies. Two patients had a myeloproliferative disorder. In one of these, a case of polycythemia vera, the 5q- appeared secondarily to other karyotypic abnormalities and concomitantly with transformation into a "spent phase." The deletions were interstitial in most cases, and even if the size of the deletion varied, the region q15-q31 was lost in all cases except 2. Bone marrow from all cases except one showed a marked increase in the number of megakaryocytes. A survey of the literature yielded a total of 69 evaluable patients with 5q- deletions, including the present series. The 5q- has now been observed in a wide spectrum of hematologic disorders. However, most cases had either preleukemia (39%) or leukemia (46%). When detected during preleukemia, the 5q- usually appeared alone (74%), while during overt leukemia it regularly was accompanied by other abnormalities (88%).

Aged↗
PubMed1981

[Preleukemic states].

The preleukemic states are disorders which constitute early phases of acute non-lymphoblastic leukemia. The nomenclature associated with the preleukemias has been confusing, and therefore the problems of their definition and diagnosis are discussed. The laboratory investigations are reviewed and the contribution of cytogenetic and cell cultures to improved knowledge of the pathophysiology is stressed. The preleukemic states are clonal hematopoietic stem cell malignancies manifested by maturation and proliferation defects of the different cellular strains of the marrow. Treatment of preleukemias remains controversial. While the use of cytostatic drugs is not generally accepted, remissions are reported to have been achieved by polychemotherapy. Chemotherapy in patients with severe complications of cytopenias thus appears to be justified. On the other hand, controlled studies of therapy in preleukemic states are needed.

Acute Disease↗
PubMed1975

[Aplastic anemia-a preleukemic stage (author's transl)].

In a group of 44 patients with primary and secondary aplastic anemia, four (9%) developed an acute leukemia. Cytological changes that pointed to a preleukemia were not observed during the preleukemic stage. The possibility is discussed whether a aplastic anemia and a preleukemia can be distinguished by cytological, cytochemical and cytogenetic tests, by agar-culture technique, liquid-culture and determination of reverse transcriptase.

Acute Disease↗