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Chromosomal Abnormalities in Acute Lymphoblastic Leukemia1

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Chromosomal Abnormalities in Acute Lymphoblastic Leukemia1 [CANCER RESEARCH 41, 4838-4843, November 1981] 0008-5472/81 /0041-OOOOS02.00 Chromosomal Abnormalities in Acute Lymphoblastic Leukemia1 Clara D. Bloomfield,2 Leanna L. Lindquist, Diane Arthur, Robert W. McKenna, Tucker W. LeBien, Bruce A. Peterson, and Mark E. Nesbit Section oíMedical Oncology, Department of Medicine [C. D. B., B. A. P.], and Departments of Laboratory Medicine and Pathology [L. L. L., R. W. M., T. W. LJand Pediatrics [D. A.. M. E. N.], University of Minnesota Health Sciences Center, Minneapolis, Minnesota 55455 Abstract tients were adults (16 to 74 years old; median age, 25 years); 23 were children (1 to 15 years old; median age, 4 years). Chromosome abnormalities in acute lymphoblastic leukemia Twenty-five adults were studied at diagnosis prior to receiving (ALL) and their possible clinical significance are briefly re any treatment; 12 were first studied at relapse. Twenty-one of viewed based upon the literature and 60 cases studied at the the children were studied at diagnosis; 2 were studied at University of Minnesota. Almost all cases of ALL appear to relapse. Bone marrow chromosome studies have been routine demonstrate clonal abnormalities; the major abnormal clone is in all adults with ALL since October 1973 and in all children usually hyperdiploid or pseudodiploid. Among cases of non-T, since April 1978. Mitoses (at least 5) were obtained in 93% of non-B ALL, at least four translocations appear to be present the adults studied and 70% of the children. More than one-half with an increased frequency: t(9;22); t(4;11); t(11;14); and of the children in whom 5 or more mitoses could not be t(1 ;3). Patients with these translocations appear to have unique obtained were 1 year old or less (5 of 9 cases). clinical and laboratory findings. Although the presence of ab The diagnosis of ALL in all cases was made based on the normal clones does not seem to influence remission duration, cytology and cytochemistry of the initial bone marrow aspirate the nature of the abnormality does. Patients whose leukemias and biopsy and blood smear. Leukemic cells in all cases were demonstrate predominantly a pseudodiploid abnormal clone or peroxidase negative. All cases were classified according to the a translocation have significantly shorter first remissions. Most French-American-British classification (1 ); 60% were L1, 34% importantly, among patients with non-T, non-B ALL, the pres were L2, and 2 cases were classified as L3. ence or absence of translocations may separate poor respond- Lymphocyte surface marker analysis of the leukemic cells ers from good responders. were performed in all cases. As a minimum, all were studied for receptors for unsensitized sheep erythrocytes, and surface Introduction immunoglobulin using previously described methods (14, 19). According to lymphocyte surface marker analysis, 47 cases Cytogenetic analysis using banding techniques has been were classified as non-T, non-B ALL; their leukemic blasts did increasingly applied to the study of cancer in recent years (32). not demonstrate receptors for sheep erythrocytes or surface Among the hematological cancers, acute nonlymphoblastic immunoglobulin. Nine cases were classified as T-cell ALL due leukemia has been most extensively evaluated. Chromosomal to the presence of receptors for unsensitized sheep erythro findings have been found to be of clinical use in terms of both cytes (5). Four cases were classified as B-cell ALL on the basis assisting with the diagnosis and predicting the clinical course of the presence of monotypic (single-light-chain type) surface (15). Although multiple studies of ALL3 have been published immunoglobulin (5). Since 1978, cases have also been studied since the first report in 1958 (13), few chromosomal banding for terminal deoxynucleotidyl transferase (41), common ALL studies have appeared, presumably because of the fuzzy and antigen (21), cytoplasmic immunoglobulin (20), and glucocor- ill-defined appearance of the leukemic chromosomes and the ticoid receptors (9). indistinct features of the chromatids (11, 25, 30, 32). In this Induction chemotherapy for the patients <15 years old con paper, we will review chromosome abnormalities in ALL and sisted of vincristine, prednisone, and L-asparaginase adminis their possible clinical significance based on a review of the tered according to Children's Cancer Study Group Protocols literature and 60 cases of ALL studied at the University of 161 to 163. Induction chemotherapy for 29 of the adult patients Minnesota. consisted of vincristine and prednisone; in addition, L-aspara ginase or an anthracycline or both were administered in 21 Description of the University of Minnesota Series cases. The remaining 8 adult patients received varying com binations of prednisone, an anthracycline, 1-ß-o-arabinofu- Patients. The University of Minnesota series consists of 60 ranosylcytosine, cyclophosphamide, and methotrexate. Fol consecutive patients with ALL on whom bone marrow chro lowing the achievement of CR, all patients received prophylac mosome karyotypes could be analyzed. All patients had a tic central nervous system therapy and intensive 4- to 5-drug clinical presentation of acute leukemia; none had a history of maintenance therapy for a minimum of 3 years. a preceding hematological disorder. Thirty-seven of the pa- Cytogenetic Studies. Metaphases for chromosome analysis were obtained from iliac crest bone marrow aspirates. Speci 1 Presented at the Conference on Cell Markers in Acute Leukemia, March 4 mens were received immediately after aspiration and proc and 5, 1980, Bethesda, Md. Supported in part by USPHS Grants CA 26273 and CB-84261, the Masonic Hospital Fund, Inc., the Minnesota Medical Foundation, essed directly or after a 24-hr culture period. Prior to 1978, and American Cancer Society Grant CH-167. the method of cell preparation was a modification of the tech 2 To whom requests for reprints should be addressed, at Box 277 Mayo nique of Tijo and Whang (37); since 1978, the technique of Building, University of Minnesota Hospitals, Minneapolis, Minn. 55455. 3 The abbreviations used are: ALL, acute lymphoblastic leukemia; CR, com Hozier and Lindquist (17) has been used. Slides were stained plete remission; Ph', Philadelphia chromosome. first with a Giemsa:phosphate buffer dilution of 1:50 and ex- 4838 CANCER RESEARCH VOL. 41 Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 1981 American Association for Cancer Research. Chromosomal Abnormalities in ALL amined for suitable metaphases. Modal numbers were re metaphases, and it is possible that they have gone unnoticed corded, and nonbanded karyotype analysis was performed. or been avoided by some investigators. When the quality of the material was suitable, slides were Ninety-one % of the cases of non-T, non-B ALL had abnor destained with a series of alcohols and restained with the malities. Results were similar in non-T, non-B ALL of children Wright's banding technique of Sanchez ef al. (31 ). If proper and adults and cases studied at diagnosis and relapse. All of staining was not obtained, slides could be destained and our B-cell cases had chromosome abnormalities (Table 1) as stained again. In many cases, the material was quite poor and, have all cases of B-cell ALL reported to date (30). We have although banding was done in 44 cases, complete karyotyping also found chromosomal abnormalities in all of our B-cell could be achieved in only 15 cases. In the remaining cases, a malignant lymphomas (7). In contrast, of the 9 cases of T-cell composite karyotype analysis was attempted using several ALL, abnormalities were found in only 4. Similarly, Oshimura et metaphase spreads. Only in the cases with complete G-band al. (25) found abnormalities in only one of 4 cases. Whether karyotyping was it possible to rule out chromosome abnormal metaphases from the malignant cells are not usually obtained ities in addition to those noted. Quinacrine or trypsin banding or abnormalities are not present or detectable with current was not used because of the poor quality and "tightness" of banding techniques is unclear. the chromosomes, which resulted in unclear resolution with Q- Chromosome Number of Major Abnormal Mode. Among banding and in some chromatid swelling with trypsin G-band- the 51 cases with chromosomal abnormalities in the Minnesota ing. In our experience, the Wright's staining technique is ad series, the major abnormal mode was hyperdiploid in 27, vantageous because it results in high-contrast banding with hypodiploid in 9, and pseudodiploid (46 chromosomes with virtually no alteration of the chromatids. Moreover, in cases rearrangements) in 15 (Table 1). These data are similar to where few metaphases are obtained, these can be stained and those of Seeker-Walker ef al. (34). Most studies have found restained several times to achieve optimal banding. that hyperdiploidy and pseudodiploidy are much more common Photographs were taken on Kodak high-contrast SO115 film than hypodiploidy in ALL (32). In our series, similar results using a green filter. However, karyotyping in most cases was were seen in children and adults and in cases studied at performed primarily at the microscope because it was thought diagnosis and relapse. Too few cases of B- and T-cell ALL that more detail could be observed by varying the scope have been studied to compare results among immunological conditions (light intensity, filter, etc.). classes. Definitions and Statistical Methods. Response to treatment Abnormalities According to Specific Chromosomes. From was evaluated using the criteria of Cancer and Leukemia Group our data and those in the literature, it is clear that all chromo B. Duration of CR was calculated from the day of bone marrow somes are occasionally found to be abnormal in ALL. Certain documentation of remission to the first evidence of recurrent chromosomes appear to be involved more frequently than leukemia. Survival was calculated from the date of diagnosis.
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