Karyotypic evolution in Ph-positive chronic myeloid leukemia in relation to management and disease progression

In a prospective study of 32 patients with chronic myeloid leukemia the frequency of chromosome abnormalities in addition to the Philadelphia chromosome (Ph) increased when the disease progressed. Before metamorphosis, 10 patients (31%) had developed additional abnormalities. Such abnormalities were present in three of them at the time of diagnosis; in the other seven, they were detected late in the chronic phase. New clonal abnormalities heralded or accompanied a more malignant phase of the disorder, usually a blastic leukemia. During metamorphosis, 78% of the patients had additional abnormalities, which in 68% of these cases comprised at least one of +8, +22q- or i(17q). Clones with additional abnormalities disappeared in eight cases, either spontaneously or in association with cytostatic therapy during the chronic or blastic phase. Involvement of chromosome #8, usually in the form of a trisomy, was found in 7 of 12 patients treated with busulfan, but was not found in any of the 10 hydroxyurea-treated patients, of whom 8 were splenectomized early during the chronic phase. Cells from the spleen, obtained by fine needle aspiration or splenectomy were cytogenetically examined in 18 cases during the chronic phase, but abnormalities in addition to the Ph were noted in only one patient, who was examined in the late chronic phase. The same abnormalities were present in bone marrow cells of this patient.     

Transformation of chronic myelogenous leukemia: clinical, morphologic, and cytogenetic features

The morphologic, cytogenetic, and clinical features of 58 patients with transformation of Philadelphia chromosome (Ph1) positive chronic myelogenous leukemia (CML) were evaluated. The patients were divided into two groups on the basis of blood and marrow findings: blast crisis and subacute transformation. The evolution of the leukemic process in 41 patients was classified as blast crisis based on one of three criteria: 30% or more blasts in blood and/or marrow smears, intramedullary focus of blast transformation in a marrow trephine biopsy, or blast transformation in an extramedullary site. The 17 patients with subacute transformation of CML had a deteriorating clinical and hematologic picture but did not manifest any of the criteria for blast crisis. The blood and marrow findings in this group of patients were characterized by several qualitative and quantitative changes, including anemia, thrombocytopenia, decreasing leukocyte count, increasing basophilia, myelofibrosis, dysplastic alterations in hematopoietic cells, and increased blasts which, however, never exceeded 25%. Chromosome abnormalities in addition to the Ph1 were found in 65% of the patients with blast crisis and 86% of the patients with subacute transformation. The 41 patients with blast crisis had a median survival of nine weeks; the 17 with subacute transformation had a median survival of 26 weeks. The shortest median survival for patients with blast crisis, four weeks, occurred in the patients with myeloid blast crisis with chromosome abnormalities in addition to the Ph. The longest median survival, 52 plus weeks, occurred in patients with lymphoid blast crisis with only the Ph1 at transformation.     

The cytogenetics of chronic granulocytic leukaemia.

The chromosome abnormalities associated with the classical type of chronic granulocytic leukaemia (CGL) involve a deletion of chromosome number 22 (Ph1) and translocation of the deleted material to another autosome, usually a number 9, t(9;22) (q34;q11). There is no clinically detectable difference between patients showing usual or unusual sites of translocation of 22q. In the chronic phase the typical translocation without additional abnormalities accounts for about two-thirds of the cases. Additional abnormalities include -Y and +8; difference of prognosis in association with aneuploidy has not yet been demonstrated. The presence of Ph1-negative cells in the chronic phase may be related to the time of ascertainment. The isochromosome for the long arm of number 17 is pathognomonic of impending metamorphosis. Additional chromosomal abnormalities are found in the majority of cases in the acute phase. Recent advances in immunological techniques for distinguishing different cytological types of blast cells, in patients who present with acute leukaemia with the Ph1 chromosome, have provided insight into the relationship of the Ph1 chromosome to the pathogenesis of the disease.     

Cytogenetic characterization of ten cases of Ph1-positive acute myelogenous leukemia

Chromosome banding analyses were made on 10 cases of Ph1-positive AML (7 M1 and 3 M2). The standard type Ph1 translocation, t(9q +;22q -), was identified in all of them. Karyotypically normal cells were observed in 6-65% of bone marrow metaphases at the initial cytogenetic examination of 7 patients, whereas the remaining 3 patients had only Ph1-positive cells at diagnosis. Follow-up studies performed in 5 cases indicated that the frequency of karyotypically normal cells increased up to 81-100% when the patients were in remission, whereas it was much reduced in relapse. In 5 cases, there was observed a clone of cells in which the Ph1 translocation was the sole karyotypic abnormality. Various types of other chromosome abnormalities, in addition to the Ph1, were observed in all cases, among which-7 was the most frequent, being found in three cases as a stem line. Other additional changes encountered were + Ph1, del(5), i(17q), - 10, + 18, + X, and various numerical and structural changes including certain secondary translocations that occurred in the Ph1 (22q -) or its partner (9q +). The types and frequencies of these additional changes appeared to be different from those found in the acute phase of CML or in Ph1-positive ALL.     

Philadelphia chromosome (Ph) positive chronic myelocytic leukemia (CML): frequency of additional findings

This article documents the cytogenetic findings in 79 patients with typical Ph-positive chronic myelocytic leukemia (CML). Direct preparations of bone marrow and/or peripheral blood of 46 males and 33 females were studied with different banding techniques. Seventy patients were studied during chronic phase. Three (4.3%) had unusual or complex translocations: t(6;22)(p21;q11), t(8;12;9;22)(p21;q21;q34;q11), and t(9;11;22)(q34;q13;q11). One (1.4%) had a +Ph, 1 (1.4%) had a +8, 1 (1.4%) had a del(3)(p13,p23), and 4 of 30 males (13.3%) showed loss of Y chromosome. Five of 8 cases studied during blast crisis had additional abnormalities. The +8 occurred in 4 cases, +10 and +19 each in 3 cases, +6, + 9q+, and +13 each in 2 cases, and +5, +11, +14, +21, +Ph, i(17q), dic(1;9), and structural abnormalities of chromosomes #1, #5, #12, and #13 each in 1 case. Two cases studied in blast crisis alone had complex translocations leading to the Ph. Because it cannot be ruled out that these translocations are secondary, they were not included in the calculation of the frequency of atypical translocations.     

600例慢性粒细胞白血病的细胞遗传学分析

目的为了探讨我国慢性粒细胞白血病（慢粒）中Ｐｈ染色体的有关特点及其意义。方法染色体制备采用骨髓细胞直接法和／或短期培养法，应用Ｒ显带技术对６００例慢粒患者的细胞遗传学资料进行了回顾性分析。结果３０例（５％）为Ｐｈ（－），５７０例（９５％）为Ｐｈ（＋）；５３５例（９３．８％）有典型Ｐｈ易位，３４例（５．９％）有变异易位，包括简单变异易位和复杂变异易位各１３例（２．２％），隐匿Ｐｈ易位８例（１．４％）；５２６例（９２．２％）的Ｐｈ（＋）细胞为１００％，４４例（７．７％）经异基因骨髓移植、干扰素和脉冲羟基脲等治疗后有部分或全部细胞转为正常核型；５０．６％的慢粒急变患者有额外的染色体异常，其中以＋８、２Ｐｈ和ｉ（１７ｑ）最多见。结论染色体检查不但有助于慢粒的诊断和鉴别诊断，而且有助于预测急变、判断疗效和进行细胞遗传学分型     

Chromosomal characteristics of chronic and blastic phase of chronic myeloid leukemia. A study of 100 patients in India

We report the cytogenetic findings of 100 patients with chronic myeloid leukemia (CML) [72 patients in chronic phase (CP) and 28 patients in blastic phase (BP)]. Of the 95 Ph + patients, six had Ph variant translocations involving chromosomes 1, 6, 7, 10, and 12. The percentage frequency of patients with chromosomal changes other than Ph was 7.3%. The additional aberrations (e.g., + Ph, + 8, i(17q), and + 19 were observed in 66.6% of BP patients. Of these anomalies, the frequency of + Ph and + 19 was higher in our patients than the incidence reported in literature. The association of + Ph and + 19 in patients with extramedullary T-cell blast crisis is an unusual finding as compared with reports in the literature and could be explained by geographic heterogeneity. The extra chromosomal abnormalities were almost absent in lymphoid blast crisis patients with blast phenotype of common acute lymphoblastic leukemia (ALL) type. Discrepancies were noted in different tissues (bone marrow and lymph node) in patients with extramedullary blast crisis of both myeloid and lymphoid type. These findings indicate the cytogenetic correlation with clinical and morphological picture, which consequently implicates the diagnostic and prognostic significance of chromosomal aspects.     

The incidence, type, and subsequent evolution of 14 variant Ph1 translocations in 180 South African patients with Ph1-positive chronic myeloid leukemia

A Philadelphia (Ph1) chromosome translocation was found in 180 of 198 cases of chronic myeloid leukemia (CML). A standard t(9;22) was present in 166 patients, 83 of whom were black, 79 white, and 4 of "mixed" ancestry; whereas a variant Ph1 translocation was detected in 14 patients (7.8%), 11 of whom were black and only 3 white. There was a higher frequency of a variant Ph1 among black patients compared with whites. The significantly higher frequency of a variant among our patients compared with surveys from elsewhere could be due to differing environmental agents. Simple variants were detected in four patients. Complex variants were found in eight cases; in one of these patients, only chromosomes #9 and #22 were involved, but a complex rearrangement of chromosome #9 had occurred. A "masked" Ph1 translocation was detected in two cases, both of which showed monosomy #22 because the Ph1 chromosome was incorporated or interchanged with chromosome #9. Karyotypic evolution of the Ph1-positive cell line was observed more frequently in the variant group (71.4%) than the standard group (29.5%). This difference was significant (p less than 0.005). There was no difference in the type of clonal changes seen in standard and variant groups. The majority of clonal changes were observed during the acute stage in both groups. In the variant group, there was no obvious correlation between the type of variant, type of clonal change, blast morphology, or survival. Their initial survival pattern resembled that of Ph1-negative cases, but those patients who survived longer than 1 year showed a survival trend similar to standard Ph1-positive cases. Possible explanations for the specificity of chromosome #22 involvement and the constancy of the 22q11 breakpoint in all these variant translocations are discussed.     

Mixed phenotype (T/B/myeloid) extramedullary blast crisis as an initial presentation of chronic myelogenous leukemia

Background

Chronic myelogenous leukemia (CML) is a myeloproliferative disorder characterized by the Philadelphia (Ph) chromosome generated by the reciprocal translocation t(9,22)(q34;q11). The natural progression of the disease follows a biphasic or triphasic course. Most cases of CML are diagnosed in the chronic phase. Extramedullary blast crisis rarely occurs during the course of CML, and is extremely rare as the initial presentation of CML.

Diagnostic significance of detecting dysgranulopoiesis in chronic myeloid leukemia

We examined whether the detection of dysgranulopoiesis in blood or bone marrow would predict chronic myeloid leukemia (CML) in transformation in 31 cases that fulfilled World Health Organization criteria for disease transformation, including 14 in accelerated phase (AP), 10 in myeloid blast crisis (MBC), and 7 in lymphoid blast crisis (LBC). Dysgranulopoiesis was detected in 7 cases, 6 in AP and 1 in MBC, but not in LBC or chronic phase cases. In 3 AP cases, dysgranulopoiesis was identified 2 to 5 months before the morphologic diagnosis of transformation. Two AP cases showed no dysgranulopoiesis in previous blood or marrow smears. For 2 cases (1 AP and 1 MBC), no previous blood or marrow specimens were available. Cytogenetic information was available for 6 of 7 cases with and 22 of 24 cases without dysgranulopoiesis. All cases with dysgranulopoiesis had secondary chromosome abnormalities in addition to t(9;22). In 5 (83%) of 6 cases with dysgranulopoiesis, the secondary chromosome abnormalities included abnormalities of 17p. In contrast, none of the 22 cases of CML in AP or BC but without dysgranulopoiesis showed 17p abnormalities (P = .001). Our findings demonstrated that dysgranulopoiesis was associated strongly with chromosome 17p abnormalities and may indicate the onset of or impending disease transformation.     

Nonrandom chromosomal abnormalities in acute lymphoblastic leukemia of childhood

The leukemic cell karyotype was studied in 103 children with acute lymphoblastic leukemia. An abnormal chromosome pattern was revealed in 81 of 98 patients studied before treatment (82.6%) and in the five children studied in relapse. Aside from specific chromosomal abnormalities defined by the Third International Workshop on Chromosomes in Leukemia, other nonrandom rearrangements were observed, particularly del(14)(q11-13), del(12)(p11-12), and t(1;19)(q22-23;p13), often associated with partial trisomy for 1q. Patients with del(14) had tumorous lymph-nodes or other extramedullary tumors. The course of the disease in these children was rapid. Patients with markers such as Ph, 6q-,14q+, and with a t(4;11) had a low incidence of complete remission and short survival. The most favorable course of the disease was observed in the group of children with over 50 chromosomes in the leukemic cells.     

14q+ in Ph-positive chronic myelogenous leukemia

Two cases of chronic myelogenous leukemia with a Ph translocation and an additional chromosome change of the long arm of a chromosome #14 (14q+) are reported. The breakpoints on chromosome #14 were identified as 14q24 and 14q32, respectively. One of the patients did not show any evidence of blastic transformation; the other patient developed a myeloid blastic crisis when the abnormal 14q+ was seen in the bone marrow cells.     

Cytogenetic findings in chronic myeloid leukemia (CML); evaluation of karyotype,blast morphology,and survival in the acute phase

Cytogenetic data on a series of 68 patients with chronic myeloid leukemia (CML) are presented, with emphasis on chromosomal findings in 19 patients who either transformed from a chronic to an acute phase (12 cases) or presented in an acute phase (7 cases). Correlation of chromosome patterns, blast morphology, and survival was attempted, following the aims and recommendations of the First International Workshop in Leukemia (Cytogenet Cell Genet (1977): 19, 321). A Philadelphia (Ph¹) chromosome was detected in 61 of 68 patients (90%) and identified by banding in 40 cases; 39 patients had the usual (9;22) translocation and one patient showed an unusual (17;22) Ph¹ translocation. Clonal abnormalities in addition to the Ph¹ were found in 9% of chronic patients whereas 79% of acute patients showed karyotypic clonal evolution. The three most frequently observed patterns of clonal evolution were trisomy 8, two Ph¹ chromosomes and an isochromosome 17 (i(17q)). Two Ph¹ chromosomes were observed in both chronic and acute cases, but in this series, trisomy 8 and i(17q) were detected only in acute patients. Detection of clonal evolution is generally indicative of an accelerated phase in the majority of cases and the development of an i(17q) clone is particularly ominous. After transformation, no obvious correlation between the pattern of clonal evolution, blast morphology, or survival was found.     

多发性骨髓瘤1q染色体异常与13q缺失的相关性研究

目的 探讨多发性骨髓瘤(multiple myeloma,MM)中13q14的缺失[del(13q14)]和1q染色体异常的相关性.方法 应用CD138单克隆抗体磁珠分选系统纯化48例初治MM患者的骨髓浆细胞,结合SpectrumorangeTM直接标记的位于13q14和1q12的序列特异性DNA探针和间期荧光原位杂交技术检测48例MM患者del(13q14)及1q染色体异常情况.结果 48例MM患者中,用D13S319探针检测,del(13q14)异常22例(45.8%);用CEP1探针检测.23例(47.9%)发现1q染色体异常.其中2例为1q缺失,21例为1q重复.22例伴有del(13q14)MM患者中16例出现1q染色体异常;26例未检测到del(13q14)MM患者中仅7例发现1q染色体异常.经X2检验两者间差异有统计学意义(X2=10.02,P＜0.01).结论 del(13q14)及1q染色体异常在MM中的发生率较高,两者间存在高度相关性.     

Karyotype evolution of Ph positive chronic myelogenous leukemia patients relapsed in advanced phases of the disease after allogeneic bone marrow transplantation.

Sixty-eight patients affected by Philadelphia chromosome (Ph) positive chronic myelogenous leukemia (CML) underwent allogeneic bone marrow transplantation (BMT) and were successfully studied from a cytogenetic point of view, before and after the BMT. Nineteen had evidence of cytogenetic and clinical relapse. Cytogenetic analyses of 14 patients who, after the relapse, showed progression to the accelerated or blastic phase of the disease, are presented. Five of these cases had only the Ph chromosome without karyotype evolution; in one case Ph duplication without other anomalies was detected, while in the remaining eight cases cytogenetic analysis showed apparently random clonal structural abnormalities (translocations, inversions, deletions, and marker formations). Therefore, the classical "non-random" abnormalities (+8, i(17q), +Ph, +19, +21) were not as common as in conventionally treated Ph+ CML. From our data, karyotype evolution during advanced phases in Ph+ CML patients after BMT differs from the evolution seen in conventionally treated patients, by the presence of numerous structural unusual abnormalities, possibly related to radiochemotherapy conditioning to BMT. Therefore, BMT treatment is not always able to eradicate the Ph+ clone but can reduce the incidence of the formation and/or expansion of Ph+ clones with additional non-random abnormalities.     

Chromosomal characteristics of Ph-positive chronic myelogenous leukemia in transformation. A study of 23 Chinese patients in Taiwan

Cytogenetic study was performed in the past 3 years on 23 Chinese patients with Philadelphia chromosome (Ph) positive chronic myelogenous leukemia (CML) in transformation; seven were in accelerated phase and 16 in acute blast crisis. Chromosomal abnormalities in addition to Ph were found in three (43%) of the patients at accelerated phase and 14 (88%) of the patients at blast crisis. The common nonrandom chromosomal aberrations were double Ph, trisomy 8, trisomy 19, and trisomy 21, which occurred in 47%, 41%, 35%, and 29%, respectively, of the total patients with extra chromosomal abnormalities. Isochromosome for the long arm of chromosome 17 was found in only one patient. In patients with blast crisis, the type of blast cell was characterized through morphologic, cytochemical, and immunocytochemical studies. Eleven cases were classified as myeloid and five as lymphoid transformation. Trisomy 8, 19, and 21 were detected only in patients with myeloid blast crisis. This study also revealed a high incidence of trisomy 21 and a low incidence of i(17q) in Chinese patients with transformation of CML.     

Analysis of loss of heterozygosity and X chromosome inactivation in spleens with myeloproliferative disorders and acute myeloid leukemia.

Neoplastic myeloid proliferations are seen in the spleens of some patients with acute and chronic myeloproliferative disorders. Both acute myeloid leukemia (AML) and chronic myeloproliferative disorders have a variety of underlying cytogenetic defects that can be evaluated by loss of heterozygosity (LOH) studies. LOH studies have advantages over conventional cytogenetics by allowing the use of archival tissues. We evaluated the spleens in AML and chronic myeloproliferative disorders with neoplastic myeloid proliferations for the presence of LOH at several chromosome loci, and X-chromosome inactivation. A total of 17 spleens were evaluated (chronic myelogenous leukemia = 6; chronic idiopathic myelofibrosis = 6; essential thrombocythemia = 1; AML arising from previous chronic myeloproliferative disorders = 4). We examined LOH loci 7q (D7S2554), 8q (D8S263), 9p (D9S157, D9S161), 13q (D13S319), common sites of genetic abnormality in chronic myeloproliferative disorders, and TP53. In six cases, spleen LOH findings were compared to those of concurrent or preceding bone marrow biopsies. Five spleens of female patients were evaluated for the presence of clonality using X-chromosome inactivation. Of the 16 cases analyzed, 14 (88%) had at least one abnormal LOH locus, with 6/16 with two abnormal loci. The abnormalities were distributed as follows: D9S161-7/15 (47%), TP53-6/16 (38%), D7S2554-5/16 (31%), D9S157-5/15 (33%), D8S263-3/14 (21%), and D13S319-2/14 (14%). Of the six bone marrows, 4/6 showed concordance in bone marrow and spleen specimens, with additional LOH abnormalities being identified in the spleen specimens of all four cases. X-chromosome inactivation studies were showed nonrandom (clonal) patterns in two cases. Our results show that allelic losses were common in the neoplastic extramedullary hematopoiesis found in spleens of chronic myeloproliferative disorders and AML. Comparison of spleen and bone marrow specimens by LOH demonstrated additional abnormalities in the spleen compared to the marrow.     

Karyotype at relapse following allogeneic bone marrow transplantation for chronic myelogenous leukemia.

Eighty-four patients underwent allogeneic or syngeneic bone marrow transplantation as therapy for chronic myelogenous leukemia (CML) during a 5-year period at The Johns Hopkins Oncology Center. We describe the karyotype at relapse in 19 patients who were Ph chromosome positive (Ph+) at diagnosis. Eighty-four percent of patients demonstrated clonal and/or nonclonal chromosome abnormalities in addition to the t(9;22)(q34;q11) at first detection of relapse or later during relapse. These abnormalities included: Ph plus additional clonal abnormalities (three patients), Ph plus nonclonal abnormalities (five patients), Ph plus additional clonal and nonclonal abnormalities (eight patients). Three patients had only the original Ph+ clone. The additional chromosome abnormalities were primarily structural, and entirely different from those most frequently observed during karyotypic evolution in conventionally treated CML. Chromosome 1 was most frequently involved, with 1q32 being the location of three clonal and two nonclonal abnormalities. Other sites included 6p21-22 (the site of two clonal abnormalities), 7p21-22, and 10q21 (the site of two clonal and one nonclonal abnormality each). Chromosomes 5 and 7q, regions of frequent involvement in acute nonlymphocytic leukemia that follows chemotherapy for other malignancies, were infrequently involved. The clinical significance of these additional abnormalities remains undetermined at this time.     

Ph1-negative chronic granulocytic leukemia: a nonentity

Clinical, hematologic, and prognostic differences between Philadelphia chromosome (Ph1)-positive and Ph1-negative chronic granulocytic leukemia (CGL) have been described. However, Ph1-negative disease may be a mixture of other entities. The authors identified 24 patients given the diagnosis of Ph1-negative CGL after evaluation by the Hematology Department of the Mayo Clinic between January 1976 and August 1984. Each patient was Ph1-negative, and a bone marrow examination was interpreted as CGL. Initial peripheral blood and bone marrow samples were available for review in 22 patients. Their disorders were reclassified as chronic myelomonocytic leukemia (13 patients), chronic myelomonocytic leukemia in transformation (1 patient), preleukemic syndrome (3 patients), and undifferentiated chronic myeloproliferative disease (5 patients). Median survival for the 22 patients was 17 months.     

Chronic myeloid leukemia with variation of translocation at (Ph) [ins (22;9) (q11;q21q34)]: a case report

Chronic myeloid leukemia (CML) is most frequently observed in middle-aged individuals. In most patients, normal marrow cells are replaced by cells with an abnormal G-group chromosome, the Philadelphia (Ph) chromosome. The Ph chromosome that is characterized by the translocation (9;22) (q34;q11) is noted in 90-95% of patients diagnosed with CML. Studies have also shown that CML can be associated with various other cytogenetic abnormalities, with 5-10% of these cases showing complex translocation involving another chromosome in addition to the Ph chromosome. Here, we report the case of a Ph(+) CML patient with an inserted karyotype who presented clinically in the chronic phase but with atypical features. This case highlights the significance of cytogenetic abnormalities on the prognosis in CML.