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The clinical and cytogenetic findings of a patient with a preleukemic state and trisomy 11 are reported. Trisomy 11 was present as the sole karyotypic alteration at the time of overt leukemia. Trisomy 11 presents an additional chromosomal abnormality not previously described in preleukemia.
Three children, two boys and one girl, with Down syndrome (DS) who presented with preleukemia and loss of all or part of chromosome 7 were studied. Initial presentation, with cytopenias and less than 25% blasts in the bone marrow, was between 13 and 30 months of age. Progression to acute nonlymphocytic leukemia occurred 1-8 months after initial presentation. The morphologic type was megakaryoblastic in two, and undifferentiated in one. Two children achieved remission with intensive therapy, and one continues in remission off therapy; the other child died in remission of accidental causes. The third child died of respiratory distress and leukemia after no intervention was chosen. These cases represent the first examples of chromosome 7 abnormalities associated with DS and leukemia, and suggest differences from the "monosomy 7" syndrome seen in children without DS.
Cytogenetic analysis of the bone marrow from a woman with preleukemia showed an aberrant clone with trisomy 4, double minutes, and a translocation t(8;9)(q21;q34). Fluorescence in situ hybridization (FISH) demonstrated that the double minutes were c-myc amplifications. A review of six cases in the literature and the present case with trisomy 4 and double minutes showed a preponderance of females and that the patients were mostly elderly. The acute myelogenous leukemia (AML) in these patients was either FAB subtype M2 or M4. In two out of seven cases, the double minutes were c-myc amplicons. The patients responded to treatment and there was karyotypic normalization during remission. There was no strong evidence of exposure to genotoxic agents.
Thirty-five years ago, a handful of astute clinical hematologists began to notice that some of their patients with acute nonlymphocytic leukemia had a history of a preceding ill-defined hemopathy. This "preleukemic" hemopathy was increasingly reported anecdotally and through careful retrospective analyses. In more recent prospective studies, this syndrome has been relatively well defined. Indeed, it is widely accepted that there exists a hematopoietic abnormality not recognizable as classical, overt, acute nonlymphocytic leukemia, which, nonetheless, can represent an early phase of leukemia. In this manuscript, the author reviews the original case reports, the initial retrospective studies, and the prospective studies which have clarified some of the clinical and laboratory features of the preleukemic syndrome. The notion that the preleukemic syndrome represents an established neoplastic process will be reviewed with special attention to assessment of clonal hematopoiesis, cytogenetic studies, and clonal evolution. Studies on induced leukemia and preleukemia in experimental animals and humans will be reviewed as will be the semantic issues which have complicated our ability to compare interinstitutional studies. A simple classification scheme of the myelodysplastic syndromes will be presented as will be a framework agenda for future studies on the pathophysiology of these syndromes.
During the period from 1970 to 1981, 391 nonselected patients with Hodgkin's disease were staged and treated with chemotherapy or radiotherapy or both at the Finsen Institute, Copenhagen. Secondary acute nonlymphocytic leukemia or its earlier stages--preleukemia or an acute myeloproliferative syndrome with cytopenia and specific cytogenetic abnormalities of the bone marrow--were observed in 17 patients. A Kaplan-Meier estimate of the cumulative probability of leukemic complications was 3.9 +/- 1.3 per cent (mean +/- S.E.M.) five years after the start of treatment, and 9.9 +/- 2.9 per cent at nine years. All 17 cases of leukemic complications occurred among the 312 patients treated with chemotherapy or combined-modality therapy, whereas no case was observed among 79 patients treated exclusively with radiotherapy (P = 0.003). A significantly increased risk of leukemic complications was observed in chemotherapy-treated patients 40 years old or older (P = 0.001). Despite the observed relatively high risk of secondary leukemia, the rate of death from progressive Hodgkin's disease, nonleukemic complications, and unrelated causes still far exceeds the rate of leukemia-related deaths in these patients.
We evaluated the risk of acute nonlymphocytic leukemia, acute myelodysplastic syndrome, and preleukemia in 3633 patients with gastrointestinal cancer who were treated in nine randomized clinical trials. Among 2067 patients given semustine (methyl-CCNU) as adjuvant therapy, leukemic disorders developed in 14, whereas only one leukemic disorder (acute nonlymphocytic leukemia) occurred among 1566 patients given other therapies (relative risk = 12.4; 95 per cent confidence interval = 1.7 to 250). The six-year cumulative mean risk (+/- S.E.) of acquiring a leukemic disorder after treatment with semustine was 4.0 +/- 2.2 per cent; the incidence rate was 2.3 cases per 1000 persons per year. Risk increased significantly with time after treatment. The risk of leukemic disorders did not differ according to sex, race, age at treatment, or initial tumor type, nor was it enhanced by concomitant radiotherapy or immunotherapy. In addition, no excess of acute nonlymphocytic leukemia was seen in 44,370 patients treated for gastrointestinal cancer in Connecticut during the period 1935 to 1974, before the advent of nitrosourea chemotherapy. This study provides quantitative evidence that nitrosoureas are leukemogenic in human beings and confirms previous observations that adjuvant chemotherapy with alkylating agents may increase the risk of leukemia.
A somatic mutation(s), acquired during the evolution of preleukemia in a 75-year-old Caucasian male of North European origin, resulted in a marked decrease in alpha-globin mRNA. The small amount of alpha-globin mRNA present in bone marrow cells was normally processed, had a normal (alpha 1/alpha 2)-globin mRNA ratio, and was translated normally. No detectable zeta-globin mRNA was found. The alpha- and zeta-globin genes were both hypomethylated and restriction endonuclease maps of the alpha- and zeta-globin genes were comparable in the patient's marrow and fibroblast DNA. The data are most consistent with the acquisition of a mutation(s) that resulted in decreased expression of all four alpha-globin genes.
Of 602 patients treated for non-Hodgkin's lymphomas, 9 developed overt acute nonlymphocytic leukemia or preleukemia with refractory cytopenia and cytogenetic abnormalities of the bone marrow. A Kaplan-Meier estimate of the cumulative probability of leukemic complications was 6.3 +/- 2.6% (mean +/- SE) 7 years after start of treatment. All 9 patients with leukemic complications belong to a major subgroup of 498 patients treated with alkylating agents, predominantly cyclophosphamide. The risk of leukemic complications in this subgroup was compared with the risk in 312 patients treated with other alkylating agents for Hodgkin's disease, and with the risk in 553 patients treated with dihydroxybusulfan for ovarian carcinoma. Cumulative 9-year risks were 8.0 +/- 3.3%, 12.8 +/- 3.5%, and 7.1 +/- 1.9%, respectively. The general risk of secondary leukemia after long-term treatment with alkylating agents ranges from 1% to 1.5% per year from 2 to at least 9 years after start of treatment.
In refractory anemia with hypercellular bone marrow and in preleukemia the primary cellular defect probably is located at the level of the morphologically not definable stem cell. This defect causes reduced proliferative activity and ineffectivity of the morphologically definable stem cell and consequently is accompanied by peripheral cytopenia. The disarrangement of cellular metabolism first of all manifests itself in morphological anomalies of bone marrow hemopoietic cells. Using 17 own observations and in reference to previous literature the manifold manifestations of this disturbance are described.
OBJECTIVE: To investigate the relationship between MDS-RA (refractory anemia subtype of myelodysplastic syndromes) and preleukemia (PL). METHODS: Hematological parameters of 86 RA and 6 PL patients were retrospectively analyzed. RESULTS: Thirty-four RA cases (39.53%) transformed into acute leukemia (AL), RA with excess blasts (RAEB), or RAEB in transformation (RAEB-t). As compared with 52 non-transformed RA cases, the transformed cases showed the following hematological features: 1. higher frequencies of immature granulocytes (P < 0.005), erythroblasts (P < 0.05) and megaloerythrocytes (P < 0.05), and higher granulocyte nuclear lobulation (P < 0.001) in peripheral blood; 2. higher percentages of early erythroid and granulocytic lineages (P < 0.05), and higher frequencies of erythroblasts with multiple nuclei (P < 0.05), pseudo Pelger-Huet abnormality (P < 0.05), and micromegakaryocytes (P < 0.005) in bone marrow. CONCLUSION: There is a higher overlap between RA and PL; the above hematological features may be useful for predicting the transformation of RA patients. Based on those findings, a score system for predicting the transformation of RA was proposed.
Based on pre-clinical and in vitro studies demonstrating enhanced granulocytic proliferation and differentiation induced by granulocyte-monocyte and granulocyte-colony stimulating factors (GM-CSF and G-CSF), these recombinant human hormones have been used to treat cytopenic patients with preleukemia [i.e., myelodysplastic syndromes (MDS)]. To date, five studies have been reported using GM-CSF short-term (generally 7-14 days, x 1-5 courses). Thirty-eight of 45 treated patients had improvements in neutrophil counts, 14 had increased reticulocyte counts with three of these individuals having decreased RBC transfusion requirements, and eight had transient increases in platelets. In 12 patients an increase in marrow and/or peripheral blood blasts was noted. Seven patients progressed to acute myeloid leukemia (AML), particularly patients with greater than 15% marrow blasts. In a longer term study, five patients received GM-CSF for 2 to 9 weeks, although only one individual maintained increased neutrophil counts, one developed antibodies to GM-CSF and one evolved into AML. Eighteen patients have been treated for 2 months with G-CSF, 16 of whom had normalization of neutrophil counts with improved marrow maturation, five had increased reticulocyte counts with three having decreased transfusion requirements, no substantial changes in platelet counts were noted. Eleven patients have received maintenance therapy with G-CSF for 6-16 months, ten had persistent increases in neutrophil counts with enhanced marrow myeloid maturation and five had increased reticulocytes. Decreased infectious episodes were notedat times of neutrophil improvements. Four of the 18 individuals have subsequently developed AML after 6-16 months.(ABSTRACT TRUNCATED AT 250 WORDS)
Bone marrow cells from three preleukemic patients with prominent marrow karyotypic abnormalities were studied in liquid culture to determine if the neoplastic clones were capable of maturation. Parallel cytogenetic and cytologic studies were performed in sequentially harvested bone marrow cultures. Maturation, albeit delayed, occurred in cultures from all three patients. By 14 days of culture in vitro, morphologic, cytochemical, and functional evidence of maturation was observed in about 70% of the cells. By day 21, 85% of the cells were mature by these criteria. All but 2 of 249 metaphases from the cultured cells contained the cytogenetic abnormality of the neoplastic clone. We conclude that some preleukemic cells identified by a chromosomal abnormality can mature in vitro. Preleukemia may be viewed as a syndrome of "early leukemia" in which the neoplastic clone is established and manifested functionally as ineffective hematopoiesis. Hematopoietic cell differentiation becomes progressively abnormal with termination in the nearly complete maturational block characteristic of acute myelogenous leukemia.
The repopulation of thymus inoculated with radiation-induced preleukemia cells was studied in 400 R irradiated mice grafted with normal bone marrow cells. These marrow cells gave rise to an actively regenerating thymic progeny, as well as in 400 R treated mice receiving only a bone marrow graft. Moreover, the marrow graft did not prevent the progression of inoculated preleukemic cells towards lymphoma growth.
A 27-year-old patient manifested severe hemolytic anemia during a preleukemia phase. Low levels of adenosine triphosphate and decreased activity of pyruvate kinase were found. Acute myeloblastic leukemia developed in this patient 20 months later. The case suggests that acquired enzyme deficiency may play a role in the development of anemia in the preleukemic state.
Previously, cloning efficiencies and mitogenic responsiveness of lymphocytes from patients with preleukemic disorders were shown to be significantly depressed. Whole blood T lymphocyte colony formation and 3H-TdR incorporation were used to assess the effects of interleukin-2 (IL-2) and thymopoietin (TP-5) on the proliferation of lymphocytes from patients with preleukemia. There were no statistically significant differences (p greater than 0.05) between any of the test groups stimulated with mitogen alone when compared to groups stimulated with mitogen plus TP-5 and/or IL-2 in either assay system for either patient or control groups. Nevertheless, TP-5 and IL-2 markedly increased the cloning efficiency and mitogenic responsiveness of lymphocytes from many of the patients studied, but in no case restored the proliferation response to the level of mitogen stimulated control lymphocytes. These findings suggest that other soluble mediators/factors may be needed to fully compensate for deficient mitogenic responsiveness and colony formation of lymphocytes from patients with preleukemic disorders which may be multifactoria in origin. Of importance, enhancement of lymphocyte responsiveness to PHA/Con-A with TP-5 and IL-2 suggests the presence of maturational/functional defects in lymphocytes from some of these patients which may be compensated for in part by addition of TP-5 and IL-2.
A 67-yr-old woman had follicular thyroid carcinoma metastatic to several osseous sites. There was also evidence of functioning pulmonary metastases. She was treated by total thyroidectomy and multiple doses of radioiodide (131I). Approximately 2.5 yr after the initial ablative dose, and a total dose of 820 mCi of sodium iodide 131I, preleukemic changes were noted in the bone marrow. This appears to be the second case of preleukemia that bears a temporal relationship to radioiodide therapy of thyroid carcinoma, and the first in which radioiodide alone has been used in therapy (without additional external radiation).
The six cases of Preleukemia (or Preleukemic States) are described. The peripheral blood was characterised with Pancythopoenia in 5 and bicytopoenia in 1 patient. Morphological alterations of Erythrocytes were present in all cases. The Bone Marrow was hypercellular in 3 and hypocellular in 3 patients. Erythropoiesis was megaloblastic or partly megaloblastic in 5 cases, with "ring" sideroblasts present in all cases. The percentage of Leukemic blast cells was as follow: 0, 5, 6, 10, 30 and 33. The duration of the preleukemic phase varied from 3-53 months. With the manifestations of overt Acute Nonlymphatic Leukemia the agressive therapy was applied. The results were poor in 5 patients (the survival 1, 5-4 m.). Only one survived more than 60 months and is still in full remission.
Human blood plasma from patients with myeloid leukemias, potentially preleukemic disorders and healthy individuals contains antibodies which react with purified glycoproteins of the baboon endogenous virus and the gibbon ape leukemia virus. Experiments are presented which illustrate characteristic distributions of antiviral antibodies in the plasma of different investigated groups. The presence of high-titer antibodies is associated with remission of acute myeloid leukemia and longer survival of patients with preleukemia.