ALBERT

Description: Chromosome banding patterns were obtained for 50 of 55 consecutive adult patients with acute nonlymphocytic leukemia during a 5-yr period. Twenty-two of the 50 cases were diagnosed as acute myelocytic leukemia (AML), 24 as acute myelomonocytic leukemia (AMMol), 2 as acute promyelocytic leukemia (APL), and 2 as erythroleukemia. Twenty-five patients had initial chromosome abnormalities during the course of the disease. The median survival of patients with normal chromosomes initially (group I) was 10 mo, whereas that of patients with abnormal chromosomes initially (group II) was 2 mo. Similar times were obtained for treated patients with AML and AMMol. However, when the AML patients were separated into those with and those without a chromosome abnormality, the median survival times were markedly different (2 mo versus 18 mo, respectively). Patients with AMMol demonstrated no difference in median survival times when subgrouped according to the presence or absence of chromosome abnormalities. The treated group II patients whose marrow samples had only abnormal metaphases had a poorer response (10% complete remission) and median survival (2 mo) than the group II patients who had at least one normal metaphase (42% complete remission with a median survival of 9 mo). The two cases of APL demonstrated a deletion of the long arm of No. 17 which occurred in the same region of the chromosome in each case. Both patients had similar clinical histories, with disseminated intravascular coagulation, and neither responded to therapy.

Description: Clinical and cytogenetic studies were done on 8 patients with dysmyelopoietic syndrome: 6 of these patients had refractory anemia with an excess of blasts (RAEB), and 2 patients had chronic myelomonocytic leukemia (CMML) according to the French-American-British classification. The ages of these 8 patients (3 female and 5 male) ranged from 45 to 70 yr (median, 61.5 yr). Seven of the 8 patients died 3–86 mo (median, 11 mo) after the onset of symptoms of hemorrhage or infections. Cytogenetic studies of bone marrow cells with the Q-banding technique showed clonal karyotypic abnormalities in 7 of the 8 patients (87.5%). Five of the 7 chromosomally abnormal patients had very complex karyotypes; all 7 patients, however, had at least 1 of 4 specific changes: -5 (or 5Q-), -7, +8, and +21. Three of the 7 patients with abnormal karyotypes had had some exposure to potential mutagenic/carcinogenic agents. Five of the 7 patients had serial cytogenetic analyses, 4 of which showed evolution of the karyotype to further complexity; in 2 cases, this coincided with the evolution of the disease into acute leukemia. The median survival time of patients whose initial cytogenetic samples showed both normal and abnormal metaphases was more than twice that of patients who had only abnormal metaphases initially (12 mo versus 4.5 mo).

Description: The t(12;21) (p 13; q22) results in the fusion of the TEL gene located on chromosome 12 with the AML1 gene located on the derivative chromosome 21. Because this translocation is difficult to detect using standard cytogenetic techniques, 27 previously karyotyped B-lineage acute lymphoblastic leukemia (ALL) cell lines were evaluated for the presence of the TEL-AML1 fusion using the reverse transcriptase- polymerase chain reaction (RT-PCR), fluorescence in situ hybridization (FISH), and cDNA sequencing. Six cell lines expressed the TEL-AML1 chimeric transcript by RT-PCR and the t(12;21) was confirmed by FISH analysis with probes for TEL, AML1, and chromosome 12. While only one of the 6 cell lines with the t(12;21) lost the der(12)t(12;21)-encoded AML1-TEL fusion transcript, 4 cell lines lacked expression of the nontranslocated allele of TEL and 5 cell lines lacked expression of CDKN2. Moreover, in 2 patients (1 with the TEL-AML1 transcript and 1 without), TEL expression was lost with disease progression; le, TEL was expressed in the initial cell lines (established at diagnosis or first relapse) whereas TEL was not expressed in the cell lines established from these patients in late-stage disease. These data show the coexistence of multiple genetic defects in childhood B-lineage ALL Cell lines with t(12;21) will facilitate the study of TEL-AML1 and AML1-TEL fusion proteins as well as TEL and CDKN2 gene inactivation in leukemia transformation and progression.

Description: We have performed a retrospective analysis of the clinical, morphologic, and cytogenetic findings in 26 patients diagnosed between January 1969 and September 1991 with acute erythroblastic leukemia de novo (EL or AML-M6). Clonal chromosomal abnormalities were found in 20 (77%) patients (95% confidence interval [CI], 61% to 93%). Loss of all or part of the long arm (q) of chromosomes 5 and/or 7 was observed in 17 (65%) patients (95% CI, 47% to 83%). In addition, the karyotypes were often complex, with multiple abnormalities and subclones. Among the remaining nine patients, six had a normal karyotype and one each had trisomy 8, t(3;3), or t(3;5). The overall frequency of abnormalities of chromosomes 5 and/or 7 observed in our M6 patients is similar to that observed in our patients with therapy-related acute myeloid leukemia (t-AML; 99 of 129 patients, 77%), but substantially higher than that noted in our other patients with AML de novo (French- American-British [FAB] subtypes M1-M5: 52 of 334 patients, 16%). Our M6 patients with abnormalities of chromosomes 5 and/or 7 were older and had a shorter median survival (16 v 77 weeks [P = .005]) than did the M6 patients without these abnormalities. We found no correlation between morphologic features and either cytogenetic abnormalities or clinical outcome. Of note was the finding that the percentage of myeloblasts, which may account for only a small fraction of the total marrow elements when the revised FAB criteria are applied, had no bearing on prognosis. We conclude that acute erythroblastic leukemia, when defined by morphologic criteria, consists of two distinctive subgroups: one group tends to be older, has complex cytogenetic abnormalities, especially of chromosomes 5 and/or 7, and shares biologic and clinical features with t-AML; the other group, with simple or no detectable cytogenetic abnormalities, has a more favorable prognosis when treated with intensive chemotherapy.

Description: The translocation between chromosomes 8 and 21, t(8;21) (q22;q22), is the most frequent abnormality in acute myeloid leukemia (AML) with French-American-British type M2 (FAB-M2) morphology. The breakpoints in this translocation have been characterized at the molecular level, and the genes involved are AML1 on chromosome 21 and ETO on chromosome 8. The rearrangement of the two chromosomes results in a fusion gene and in the production of a consistent fusion transcript on the der(8) chromosome. We have used oligonucleotide primers derived from both sides of the fusion cDNA junction and reverse transcription-polymerase chain reaction (RT-PCR) to analyze six AML-M2 patients with a t(8;21) during various stages of their disease. Two patients studied at diagnosis and one studied at first relapse are alive off therapy and in continuous complete remission for 83 to 94 months. We have detected the AML/ETO fusion transcript in recent peripheral blood samples from each of them. Three other patients also had a fusion transcript detected after 1 to 4 months in remission. Two of these patients subsequently relapsed and died whereas the third patient is alive and in continuous complete remission 70 months later. Thus, our preliminary data suggest that cells with the translocation are still circulating in t(8;21) patients in long-term remission. This finding raises serious questions regarding the interpretation of positive results obtained only with this technique that may not be suitable to decide appropriate further treatment for patients in clinical remission.

Description: The aggressive clinical course and the distinctive histologic, cytochemical, and cytogenetic features of an adult non-Sezary T-cell lymphoma with suppressor activity have been investigated. Morphological and ultrastructural analysis of neoplastic cells from peripheral blood and involved lymph nodes revealed cells with convoluted nuclei, prominent cytoplasmic azurophilic granules, well developed Golgi apparatus, short strands of endoplasmic reticulum, and moderate numbers of ribosomes and mitochondria. Cytochemical reactions showed acid phosphatase (ACP) positivity in virtually all of the neoplastic cells; and a substantial percentage of the cells, the tartrate-resistant acid phosphatase (T-ACP) isoenzyme was observed. Granular naphthyl acetate esterase (A-EST) reactivity was not present. The histological and cytochemical features of these neoplastic suppressor cells were compared with those recently described for the suppressor T-cell fraction isolated from normal peripheral blood T-cell by Fc gamma- rosette formation. The aneuploid clone had 47 chromosomes with multiple complex abnormalities, including a 14q + chromosome formed by the tandem translocation of two no. 14 chromosomes and translocations involving the long arms of no. 2 and no. 9 at band 9q34. These latter changes are particularly common in T-cell disorders. The extensive analysis of this histologic, cytochemical, and cytogenetic features of this adult T-cell suppressor lymphoma should help to clarify the criteria for distinguishing among the subsets of T-cell neoplasms with definable immunologic function.

Description: Clinical and cytogenetic studies were done on 8 patients with dysmyelopoietic syndrome: 6 of these patients had refractory anemia with an excess of blasts (RAEB), and 2 patients had chronic myelomonocytic leukemia (CMML) according to the French-American-British classification. The ages of these 8 patients (3 female and 5 male) ranged from 45 to 70 yr (median, 61.5 yr). Seven of the 8 patients died 3–86 mo (median, 11 mo) after the onset of symptoms of hemorrhage or infections. Cytogenetic studies of bone marrow cells with the Q-banding technique showed clonal karyotypic abnormalities in 7 of the 8 patients (87.5%). Five of the 7 chromosomally abnormal patients had very complex karyotypes; all 7 patients, however, had at least 1 of 4 specific changes: -5 (or 5Q-), -7, +8, and +21. Three of the 7 patients with abnormal karyotypes had had some exposure to potential mutagenic/carcinogenic agents. Five of the 7 patients had serial cytogenetic analyses, 4 of which showed evolution of the karyotype to further complexity; in 2 cases, this coincided with the evolution of the disease into acute leukemia. The median survival time of patients whose initial cytogenetic samples showed both normal and abnormal metaphases was more than twice that of patients who had only abnormal metaphases initially (12 mo versus 4.5 mo).

Description: Cytogenetic studies were performed on 26 patients who developed acute nonlymphocytic leukemia (ANLL) or a dysmyelopoietic syndrome after treatment of a primary malignancy. Fifteen patients had radiotherapy and chemotherapy, seven had only chemotherapy, and four had only radiotherapy. The median times from diagnosis of the initial disease to the development of bone marrow dysfunction for these treatment groups were 50, 46, and 49 mo, respectively. Twenty-five patients had an abnormal karyotype in myeloid cells. Loss of part or all of no. 5 and/or no. 7 was noted in 23 of 25 patients with aneuploidy. Loss of no. 5 was noted only in patients who previously had malignant lymphoma, whereas loss of no. 7 was seen in these patients as well as in those who had other malignancies. Abnormalities of both nos. 5 and 7 occurred in 53% of the patients treated with combined therapy and in only 27% of patients treated with either modality alone. Although these changes are distinctly different from those noted in lymphomas, they are similar to those seen in 25% of aneuploid patients with ANLL de novo.

Description: A 22-yr-old man with acute myelocytic leukemia received a bone marrow transplant from a genotypically HLA-identical female sibling after cyclophosphamide preparation. He remained in complete remission for 18 mo, when he developed a chloroma in the perineum. The chloroma was treated with local radiotherapy. The chloroma recurred 8 mo later and was treated with radiotherapy followed by combination chemotherapy. At 34 mo after transplant, marrow relapse and chloroma were documented. The first chloroma contained host cells by fluorescent Y-chromatin body analyses of interphase nuclei. All metaphase cells and karyotypes from peripheral blood and marrow samples showed no evidence of host cells from 3 wk after transplant through the time of marrow relapse. Data from autosomal and sex chromosome studies indicate that the marrow relapse occurred in cells of donor origin. A new consistent chromosome abnormality [45, X, -X, t(8;21) (q22; q22)] was observed in a majority of donor cells. The patient received a second bone marrow transplant from the same donor after preparation with busulfan and cyclophosphamide and attained a complete remission with full hematologic engraftment.