A collaborative study of the relationship of the morphological type of acute nonlymphocytic leukemia with patient age and karyotype.
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Biomedical subjects
Publications and source records attributed to J D Rowley.
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We studied the clinical and karyotypic features of 50 patients with acute lymphoblastic leukemia, including 33 American and 17 Japanese patients, at two institutions. Clonal chromosome abnormalities were found in 39 of the 50 patients (78%) at diagnosis. Eleven patients had diploidy (N patients). Among the 39 aneuploid patients, 17 had pseudodiploidy (A1 patients), eight had hyperdiploidy with 47 to 49 chromosomes (A2 patients), nine had hyperdiploidy with 50 to 59 chromosomes (A3 patients), and five had other chromosome abnormalities. Of 14 patients whose chromosomes were also studied at relapse, eight had karyotypic progression, five had abnormalities identical or similar to those observed at diagnosis, and one had a change of karyotype from diploidy to aneuploidy. The median age and the median WBC of A1 patients were higher than those of any other group of patients, although one-third of the patients had WBC below 20 x 10(3)/microliters, and they often had leukemic cells of T-cell or B-cell lineage. The A2 patients were relatively old and tended to have higher WBC. The N patients were relatively young and tended to have low WBC, although these tendencies were not as marked as those in A3 patients. The A3 patients had longer survival times than the A1 (p = 0.003) or A2 (p = 0.002) patients. Also, N patients had longer survival times than A1 (p = 0.03) or A2 (p = 0.05) patients. The difference in survival times between A3 and N patients was not significant. Our study demonstrated that the karyotype is correlated with survival and with other recognized prognostic factors. However, in some A1 and A2 patients, the karyotype was a more reliable factor in indicating a poor prognosis than was the WBC or age.
We studied the karyotype in 26 children with ANLL, which was diagnosed on the basis of the FAB classification. Clonal chromosome abnormalities were found in 21 of 26 patients. Four patients, including 3 with Down's syndrome, had AML(M1). Nine patients, including 3 with t(8;21), had AML(M2). All 3 patients with APL(M3) had t(15;17). Four patients had AMMOL(M4); 3 of these had a normal karyotype. Six patients had AMOL(M5); 5 and 11q rearrangements, and 3 of these had a break in 11q23. Only one patient had EL(M6), and he had a normal karyotype. One patient with t(11;19), classified as AML(M2) on Wright-Giemsa-stained cells, had a strong alpha-naphthyl acetate esterase reaction, indicating that the leukemic cells had a cytochemical feature characteristic of monocytes. Whereas t(8;21) and t(15;17) are uniquely associated with AML(M2) and APL(M3), respectively, the 11q rearrangements are also seen in AML(M1/M2), although they are more common in AMOL(M5) and AMMOL(M4). The case with t(11;19) suggests that cells with 11q rearrangements and with AML(M1/M2) may have both monocytic and granulocytic features. When we used our data and previous reports on 243 aneuploid patients (169 adults and 74 children) to correlate the chromosome abnormalities with patient age, we found differences in the chromosome pattern seen among various age groups. This suggests that different etiologic factors as well as changes in host susceptibility may influence the development of and the karyotypic pattern in the various types of leukemia. Moreover, the frequency of various chromosome abnormalities in childhood ANLL can provide a baseline for comparison of the frequency of the same abnormality in adults. The karyotypic analysis of childhood ANLL is important not only because of the information that can be obtained about childhood ANLL, but also because the data can provide substantial insight into the etiology of ANLL in adults.
Nonrandom chromosome changes have been observed in human acute nonlymphocytic leukemia (ANLL). Two specific translocations have been detected only in ANLL arrested in a particular stage in myeloid maturation, i.e., t(8;21) associated with acute myeloblastic leukemia (AML) with maturation (M2) and t(15;17) associated with acute promyelocytic leukemia (M3). Patients with these translocations are substantially younger then patients with the same type of leukemia who have either a normal karyotype or other chromosome abnormalities. Patients who have ANLL secondary to treatment for a prior malignant disease tend to have AML (M1 or M2) and an abnormal karyotype with losses of chromosome #5 and/or #7. A similar high incidence of AML and aneuploidy affecting particularly #5, 7, 8, and 21 was seen in patients with ANLL who were exposed to chemicals and pesticides. Complete unselected data are available for 239 patients with ANLL; 128 of these were classified as having AML (M1 or M2). Within the AML group, 65% of the patients were chromosomally abnormal. Except for 16 patients with a t(8;21), the percentage of those with an abnormal karyotype increased with age, particularly above the age of 50 years. In regard to abnormalities other than t(8;21), 29 patients had loss of part of all of #5 and/or #7, 11 had +8, and 27 had other abnormalities. On the other hand, of 70 patients with acute myelomonocytic leukemia (M4), 42 were normal, only 3 had loss of #5 or 7, 1 was -7, +8, and 4 were +8, whereas 20 had other abnormalities. This difference in karyotype may reflect different etiologic factors in these two types of leukemia.
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Chromosome studies in lymph nodes from patients with Hodgkin's disease have been limited by the low yield of dividing cells. Of 25 consecutive involved lymph nodes, 12 had no mitotic cells, three had only normal cells, seven had a mixture of normal and abnormal cells, and three had only abnormal cells. Correlating histology with the karyotype, 66% of unsuccessful samples were of the nodular sclerosing type. The majority (58%) of samples with no dividing cells were from previously treated patients. Distinct clones were obtained in samples from only four of ten patients with abnormal cells. Samples from the other six patients had single abnormal cells with bizarre marker chromosomes; these single cells probably represent the only dividing malignant cell. The high failure rate and the low number of clear-cut aneuploid clones in Hodgkin's disease contrast markedly with other lymphomas in which 80% of the samples yield mitotic cells that represent an aneuploid clone in virtually every instance.
Seventy-four adult patients with acute nonlymphocytic leukemia (ANLL) were classified retrospectively as to whether or not they had had occupational exposure to insecticides, chemicals and solvents, or petroleum products. Fifty-eight patients were considered nonexposed and 16 were considered exposed. The chromosome banding pattern was abnormal in 37 of the 74 patients (50%). Twenty-five of the 58 (43%) nonexposed patients had a clonal chromosome abnormality, compared with 12 of the 16 (75%) exposed patients (p = 0.02). Only 2 of 23 (8.7%) females with an abnormal karyotype were exposed, whereas 10 of 14 (71%) males with an abnormal karyotype were exposed. Either a -5/5q- or a -7/7q- was present in 67% of the exposed patients with a chromosome abnormality, compared to 28% of the aneuploid nonexposed patients. The -7/7q- abnormality was present in 7 of the 12 (58.3%) exposed patients, versus 5 of the 25 (20%) nonexposed patients with abnormal karyotypes (p less than 0.05). The -5/5q- anomaly was observed in 4 of the 12 (33%) exposed patients and in 4 of the 25 (16%) nonexposed abnormal patients. Our study supports the observation that a subset of patients with ANLL de novo have a history of occupational exposure and a unique pattern of chromosome abnormalities.
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Clinical and cytogenetic studied were done on 12 patients with lymphoblastic lymphoma. The ages of the patients ranged from 17 to 58 years (median, 24.5 years). Males predominated by a ration of 5:1. Ten of the 12 patients had a mediastinal mass at diagnosis; two thirds of the patients had involvement of the bone marrow (3 of 12 patients initially were in a leukemic phase), and 5 of 12 patients had involvement of the central nervous system (CNS) with lymphoma. In all patients, the malignant cells were characterized by nuclear convolutions. Cytogenetic studies done on four patients showed clonal chromosome abnormalities in two cases. Six of the 12 patients were treated with the combination chemotherapy regimen COPA and received CNS prophylaxis; their survival was slightly longer than that of the other patients, who were treated with a variety of treatment regimens. Two of the 12 patients achieved a complete remission. The median survival of all patients was 11.5 months but was shorter in patients with initial CNS involvement or leukemia. The poor results achieved thus far in the treatment of this disease demand a new therapeutic approach.
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We studied a series of 34 polycythemia vera (PV) patients to determine the incidence of chromosome abnormalities and their relationship to leukemic transformation. Metaphase chromosomes from bone marrow or unstimulated peripheral blood were examined with conventional stain and, in 20 patients, also with banding techniques. The overall incidence of clonal abnormalities in first samples was 44% (15 of 34 patients), with a higher incidence in patients who had received prior therapy. The most frequent abnormalities were long-arm deletion of No. 5 (5q-; four patients), gain of all or most of a No. 8 (five patients), gain of all or most of a No. 9 (four patients), and long-arm deletion of No. 20 (three patients); these sometimes occurred in combination. Some of the PV patients who had cytogenetic abnormalities early in the disease have had long survivals without developing leukemia. For example, one patient has been 48,XX,+8,+9 in sequential samples obtained over the last 15 years. Five patients developed acute myeloblastic leukemia (AML); each had a complex chromosomal pattern. Two of these five patients were cytogenetically normal during the polycythemic phase; the change in karyotype occurred with the leukemic transformation. Three AML patients were studied only in the leukemic phase. Three AML patients had a 5q-, and a fourth showed loss of a B-group chromosome. Evolutionary changes in the karyotype during the disease course and the occurrence of a 5q- appear to be associated with a terminal phase of PV.
Karyotypes were analyzed from 14 patients with various myeloproliferative disorders who had marrow samples processed directly and cultured in various ways. Eleven patients had acute nonlymphocytic leukemia (ANLL) (seven patients) or a dysmyelopoietic syndrome (four patients). All of these patients were known to have an abnormal karyotype, and in each case, two samples of a bone marrow aspirate were available: one processed directly and another cultured for 24 hr. Five of the 11 patients had essentially the same proportion of abnormal cells in the direct and 24-hr samples; in five other patients, the percentage of aneuploid cells in the sample cultured for 24 hr was higher than that in the direct preparation. A higher percentage of aneuploid cells was observed in the direct preparation in only one case. In three other cases of ANLL, a marrow aspirate was cultured with methotrexate in addition to samples processed directly and after 24-hr culture; only two of these had an abnormal clone in any sample. The results of karyotype analysis differed in these two patients. The proportion of aneuploid cells was substantially higher in the methotrexate culture than in the 24-hr culture in one patient; in the other patient, the 24-hr culture contained aneuploid cells, whereas the methotrexate culture showed none. Three of the 13 aneuploid patients would have been incorrectly classified as being karyotypically normal on the basis of the initial analysis of the direct preparation, since only a single abnormal cell was detected in each case. The karyotypic pattern in untreated patients with ANLL has prognostic significance; therefore, the method of processing marrow aspirates may substantially influence the degree of correlation between the karyotype and survival reported by different laboratories.
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Chromosome abnormalities of a clonal nature have been found in approximately 50 per cent of the patients with acute nonlymphocytic leukemia and acute lymphocytic leukemia. Patients with acute myeloblastic leukemia (M1 and M2) with only abnormal metaphases have the worst prognosis among patients with acute nonlymphocytic leukemia, whereas patients with acute myeloblastic leukemia (M1 and M2) with only normal metaphases have the best prognosis. Specific abnormalities include a t(8;21) in approximately 8 per cent of the patients with acute nonlymphocytic leukemia and a t(15;17) in approximately 50 per cent of the patients with either hypergranular (M3) or microgranular (M3 variant) promyelocytic leukemia. In patients who develop acute leukemia after cytotoxic or radiation therapy for a previous malignant disease, clonal chromosome abnormalities are almost always present.