Ph1-positive Chronic Granulocytic Leukemia Research Articles

Chronic granulocytic leukemia: Reassessment of morphologic and cytogenetic characteristics in Ph1-positive and Ph1-negative cases

33 cases of chronic granulocytic leukemia (CGL) were reassessed to determine if, by strict morphologic criteria. Philadelphia chromosome (Ph1)-negative CGL exists as a diagnostic entity and if Ph1-positive CGL could be distinguished from Ph1-negative CGL. Cases were reassessed using published criteria and, of 11 Ph1-negative cases, only 4 could be reclassified as myelodysplastic syndromes or undifferentiated chronic myeloproliferative disorder. Of the morphologic parameters evaluated, peripheral blood basophilia and bicytopenia proved to be good discriminators between Ph1-positive and Ph1-negative cases. As a group, Ph1-negative cases were more heterogeneous and tended to have lower hemoglobin, WBC, platelet count and absolute eosinophilia. Chromosomal abnormalities other than Ph1 were seen only in the Ph1-positive cases. Based on these findings, we conclude that Ph1-negative CGL constitutes a heterogeneous group, a subgroup of which is morphologically identical with the Ph1-positive CGL. The parameters that best discriminate between Ph1-positive and Ph1-negative cases are peripheral blood absolute basophilia and bicytopenia.

Prognostic Evaluation of Initial Bone Marrow Histopathological Features in Chronic Granulocytic Leukemia

In 100 patients with nonblastic Ph1-positive chronic granulocytic leukemia (CGL) the main features from the initial bone marrow biopsy were correlated with other clinical and hematological parameters and analyzed for prognostic significance. The mean number (+/- SD) of megakaryocytes per square millimeter of marrow tissue was 25.9 +/- 18.8. Marked reticulin fibrosis was observed in 19% of the patients but in only 5 cases it was diffuse, whereas collagen deposition was found in 10 patients. Reticulin fibrosis correlated significantly with white blood cell count and peripheral blood blast cell percentage, but not with platelet count. Actuarial survival studies demonstrated that marked diffuse reticulin fibrosis (p = 0.0005) and more than 15 megakaryocytes/mm3 of marrow tissue (p = 0.01) were associated with a poorer prognosis. However, they lost their prognostic influence when included in a multivariate regression model together with the patients' relative risk according to the currently most widely accepted CGL prognostic system. Such results indicate that bone marrow biopsy features add little prognostic weight to known prognostic indicators in CGL.

Myelofibrosis in chronic granulocytic leukaemia: clinicopathologic correlations and prognostic significance.

We performed 221 marrow trephine biopsies in 139 patients with Ph1-positive (Ph1+) chronic granulocytic leukaemia (CGL) in order to assess the incidence, degree and prognostic significance of marrow fibrosis (MF) at various stages of the disease. We also attempted to elucidate the relationship between development of MF and the various clinical and haematological features of CGL. A significant correlation was found between the amount of fibrosis (graded from 0 to 3) and the stage of CGL, indicating that major fibrotic changes are associated with accelerated or blastic disease. Survival studies performed to assess the prognostic significance of the various degrees of MF, showed a progressively worse life-expectancy from grade 0 to grade 3 fibrosis. Multivariate regression analysis indicated Hb level, age, number of marrow megakaryocytes (MKs), time from diagnosis as the features most significantly correlated with the degree of MF. This study demonstrates that the natural history of CGL involves a progressive increase in reticulin deposition towards severe MF, although the rate of this progression varies widely. Monitoring changes of fibrosis with sequential biopsies could give a measure of the rate of progression of the disease and help in prognostic assessment of CGL patients. Our findings also confirm that among marrow features the number of MKs is the cytological variable most significantly correlated with MF.

Competitive survival/proliferation of normal and Ph1-positive haemopoietic cells.

Bone marrow (BM) cells from 10 patients with Ph1-positive chronic granulocytic leukaemia (CGL) were placed in long-term cultures in the presence of fetal calf serum (FCS) and horse serum (HoS), or in the presence of human AB serum. The long-term cultures were started with three different cell combinations: (1) CGL BM cells (four cases), (2) CGL BM cells + normal BM cells (1:1 ratio) from an HLA identical sex-matched sibling (five cases), (3) CGL BM cells + normal BM cells (1:1 ratio) from an HLA identical sex mismatched sibling (five cases). Cytogenetic studies were performed at weeks 0, 3, 4 and 5 of culture. The results of this study can be summarized as follows: (a) Ph1-positive cells could be detected at any time of culture in all three of the described cell combinations; (b) a population of Ph1-negative cells of patient origin could be detected after 3-5 weeks of culture; (c) there was a trend for a better survival of Ph1-negative cells in cultures supplemented with FCS + HoS and, conversely, of Ph1-positive cells in cultures containing human serum. These results warrant further studies on the possibility of manipulating survival and proliferation of normal and leukaemic cells by varying the culture conditions.

Chemotherapy and autografting for chronic granulocytic leukaemia in transformation: probable prolongation of survival for some patients.

Between June 1977 and July 1983 51 patients with Ph1-positive chronic granulocytic leukaemia (CGL) in transformation were treated either by chemotherapy or by chemoradiotherapy followed by autografting with haemopoietic stem cells collected from their peripheral blood at the time of diagnosis. Forty-eight patients were restored to a second chronic phase. The median duration of survival after autografting was 26 weeks (range 2-152 weeks). Twenty-one patients with relatively long durations of second chronic phase were treated again by autografting as consolidation or when transformation recurred; this selected group of patients survived longer than the 30 patients treated by autografting only once (medians 52 v. 13 weeks respectively, P less than 0.01). There was no significant influence of the patients' age, splenectomy status, type of transformation, treatment pre-autograft or number of nucleated cells autografted on the duration of survival. Three patients treated in myeloid blastic transformation were restored to partially Ph1-negative haemopoiesis. We conclude that this approach to the management of CGL in transformation can offer benefit for a minority of patients and that further chemotherapy and autografting for patients still in second chronic phase may be valuable.

GENOMIC ALTERATIONS INVOLVING THE C-MYC PROTO-ONCOGENE LOCUS DURING THE EVOLUTION OF A CASE OF CHRONIC GRANULOCYTIC LEUKAEMIA

In a patient with Ph1-positive chronic granulocytic leukaemia who had 3 separate episodes of promyelocytic transformation associated with new cytogenetic and genetic changes DNA from the peripheral-blood leucocytes obtained during the second episode of transformation showed an 8-fold to 16-fold amplification of cellular myc proto-oncogene (c-myc) sequences, and rearrangement of these sequences. There was no amplification or rearrangement of c-myc sequences in DNA from leucocytes collected during the chronic phase, nor were these sequences amplified in DNA from leucocytes collected during the third episode of transformation. These observations show that new clones of cells that proliferate during the evolution of a myeloid leukaemia can carry genetic changes in addition to any recognisable karyotypic changes. Such genetic changes might underlie the progression of the disease.

Iron stores in chronic granulocytic leukaemia at presentation.

In 87 patients with Ph1 positive chronic granulocytic leukaemia (CGL), the bone marrow iron content was studied on smears obtained at diagnosis. A low sideroblast score and a decreased or absent marrow iron on semiquantitative estimation were found in 91% and 85% of cases, respectively. These findings did not correlate with blood parameters reflecting iron status such as Hb concentration, mean corpuscular volume, mean corpuscular haemoglobin, serum iron, total iron-binding capacity and transferrin saturation, which were normal in most cases. In 30 patients, initial serum ferritin was estimated, normal or slightly increased levels being as a rule found. In 24 of such patients, serum ferritin was again measured in remission following busulphan and, although values remained normal, a significant decrease was observed with respect to the initial levels (P less than 0.001). Thus, in spite of the consistent marrow pattern of iron depletion, initial iron stores appear to be normal in CGL. It seems, however, that the disease activity may partially influence the serum ferritin levels.

Monosomy 7 in a girl with Ph 1 positive chronic granulocytic leukemia

A case is reported of an 11-year-old girl with Ph 1-positive chronic granulocytic leukemia. Very early in her illness the original 46,XX,t(9:22) cell population in the marrow became replaced by a second abnormal cell line, 45,XX,−7. This hypodiploid clone then remained dominant in the marrow until her death from myeloid blast crisis over 3 years later. It is suggested that the 45,XX,−7 cell line may have been induced by chemotherapy, and this possibility is discussed with particular reference to similar changes seen in secondary ANLL following treatment for lymphomas and other hematological malignancies.

A NEW APPROACH TO THE CLASSIFICATION OF HUMAN LEUKAEMIAS: MEASUREMENT OF THE RELATIVE ABUNDANCE OF A SPECIFIC RNA SEQUENCE BY MEANS OF MOLECULAR HYBRIDISATION

A recombinant plasmid library representing polyadenylated RNAs in the leucocytes of a Ph 1-positive chronic granulocytic leukaemia (CGL) has been constructed. One recombinant (designated pCG14) isolated from this library contains a DNA sequence complementary to a small polyadenylated RNA that is abundant in RNA from CGL leucocytes. The relative concentrations of pCG14 RNA in the RNAs from a variety of normal and leukaemic leucocytes and human haemopoietic cell lines have been measured with a molecular hybridisation assay. This has shown that pCG14 RNA is 10 to 50 times more abundant in RNA from CGL leucocytes than in the RNAs from these other cells. The data indicate that the occurrence of pCG14 RNA in high abundance is sufficiently characteristic of a CGL leucocyte population to distinguish it from other populations of leucocytes. They suggest that the measurement of the concentrations of specific RNA species in leucocyte RNA by means of molecular hybridisation with cloned complementary DNAs may provide additional markers for the objective classification of human leukaemias which could be particularly useful since the method exploits a criterion different from any currently in use.

The relation of platelet kinetics to bone marrow megakaryocytes in chronic granulocytic leukaemia.

The relation of thrombokinetics to quantitative determinations of megakaryocytes (mgkc) in bone marrow sections was studied in 11 consecutive cases of untreated Ph1-positive chronic granulocytic leukaemia (CGL). The results were compared with controls and with previously obtained data in polycythaemia vera (PV), primary thrombocythaemia (PT) and in idiopathic thrombocytopenic purpura (ITP). Platelet survival was significantly reduced in CGL. Platelet production was 5.8 x normal and the mgkc number and volume/microliter bone marrow were significantly increased as compared to controls. The increase in mgkc volume was not in proportion to that of number due to a significant decrease of mgkc size. Platelet production was strongly related to mgkc number/mm2 and to the mgkc volume/microliter bone marrow. The platelet production rate in relation to a unit of mgkc volume/microliter bone marrow was, however, greater in CGL than in controls, PV, PT and ITP. The chief reason for this is most probably the greater expansion of the total bone marrow mass in CGL.

Double 9;22 translocation with hyperdiploidy appearing in blastic transformation of chronic granulocytic leukemia

Chromosome studies in a 26-year-old female with Ph 1-positive chronic granulocytic leukemia showed the development of both hyperdiploid and tetraploid cell lines in the blastic transformation phase. An additional 9;22 translocation and additional chromosomes No. 8, 11, 13, and 22 were found in the hyperdiploid cell line. This unusual finding suggests that the hyperdiploidy may have developed from misdivisions in the tetraploid cell line rather than by the more accepted mechanism of nondisjunction or selective endoreduplication from a diploid cell.

Significance of non-standard Philadelphia chromosomes in chronic granulocytic leukaemia.

One hundred and nineteen unselected and similarly treated patients with Ph1-positive chronic granulocytic leukaemia (CGL) had the precise nature of their chromosome rearrangements producing the Ph1 studied to determine whether this had any clinical relevance. Eighteen (15%) did not have the usual 9/22 translocation and these, by life-table analysis, had a significantly shorter benign phase of their disease than the others (P less than 0.01). It further appeared that possession of a non-standard Ph1 was related to age, in that whereas only 24 patients were over 60 at diagnosis, 9 (33%) had a non-9/22 translocation (P less than 0.01). As the duration of the benign phase seemed to be shorter in those over 60 irrespective of Ph1 type (P less than 0.01), the questions arose whether non-standard PhI chromosomes were simply occurring in older patients or whether they were affecting prognosis independently. Their independent effect was suggested by the 11 patients under 60 with a non-9/22 Ph1 who still had a significantly shorter benign phase than the 84 of similar age with a standard Ph1 (P less than 0.01). It is concluded that the myeloid karyotype can provide prognostic as well as diagnostic information in patients with CGL.

Defective platelet aggregation and increased platelet turnover in patients with myelofibrosis and other myeloproliferative diseases.

In 9 patients with myeloproliferative diseases (MPD) (6 with myelofibrosis, MF, 1 with Ph1 positive chronic granulocytic leukaemia, CGL, 1 with primary eosinophilia, PE, 1 with pre-leukaemia syndrome, preL) collagen, epinephrine, and ADP-induced aggregation, N-ethylmaleimide-induced malondialdehyde (MDA) production, beta-thromboglobulin (beta-TG) plasma levels, and platelet turnover were studied. Collagen-induced aggregation was found to be normal in 7 patients, absent in 1, and reduced in 1. In all but 3 patients, aggregation with ADP was markedly reduced. Epinephrine-induced aggregation was decreased in 7 patients. No difference was found between mean MDA production in MPD (3.21 +/- 0.50 nmol/10(9) PLTs) and in control group of 21 normal subjects (3.04 +/- 0.26 nmol/10(9) PLTs). Mean beta-TG levels were significantly higher (P less than 0.01) in MPD patients (165.00 +/- 28.29 ng/ml) than in healthy controls (81.76 +/- 14.63 ng/ml). Mean platelet production half-time was significantly shorter in MPD (2.48 +/- 0.24 d) than in the control group (3.43 +/- 0.17 d), after adjustment for age by covariance analysis (P less than 0.005). Our data do not indicate an abnormal prostaglandin synthesis and are consistent with the hypothesis that a disseminated intravascular platelet aggregation might take place in MPD patients.

Significance of Ph1-negative marrow cells in Ph1-positive chronic granulocytic leukemia

Fifty-six of 195 Ph1-positive patients with chronic granulocytic leukemia were found to have Ph1-negative metaphases in marrow aspirates on one or more occasions. In 22 cases, Ph1-negative cells were found prior to initiation of antileukemic therapy. Five patients were in the blastic stage of the disease when Ph1-negative mitoses were seen. The finding of Ph1-negative cells appeared to be related principally to short duration of CGL and to administration of antileukemic therapy (conventional agents and doses, in most cases). Ph1-negative cells were usually not found more than 2 yr after the diagnosis of leukemia, but in a few cases, they were seen as long as 5–10 yr after diagnosis. Only a minority of metaphases analyzed were Ph1-negative, except in the case of 6 patients who transiently had 50% or more Ph1-negative cells after antileukemic therapy. The presence of Ph1-negative cells in marrow was not associated with any survival advantage in this series.

Ph1‐POSITIVE ACUTE LEUKAEMIA AND CHRONIC GRANULOCYTIC LEUKAEMIA: ONE OR TWO DISEASES?

British Journal of HaematologyVolume 42, Issue 4 p. 493-498 Ph1-POSITIVE ACUTE LEUKAEMIA AND CHRONIC GRANULOCYTIC LEUKAEMIA: ONE OR TWO DISEASES? D. Catovsky, Corresponding Author D. Catovsky MRC Leukaemia Unit, Royal Postgraduate Medical School, LondonDr D. Catovsky, MRC Leukaemia Unit, Royal Postgraduate Medical School, Du Cane Road, London W12 0HS.Search for more papers by this author D. Catovsky, Corresponding Author D. Catovsky MRC Leukaemia Unit, Royal Postgraduate Medical School, LondonDr D. Catovsky, MRC Leukaemia Unit, Royal Postgraduate Medical School, Du Cane Road, London W12 0HS.Search for more papers by this author First published: August 1979 https://doi.org/10.1111/j.1365-2141.1979.tb01161.xCitations: 113AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume42, Issue4August 1979Pages 493-498 RelatedInformation

Terminal Ph1-positive monocytic crisis in chronic myeloid leukemia providing evidence for the promyelocytic origin of monocytes

A case of Ph1-positive chronic granulocytic leukemia in described in which a terminal monocytic crisis developed. The case still was Ph1-positive at the time of the monocyte crisis. Bone marrow smears contained promyelocytes and early granulocytes, but most of the cells belonged to the monocyte series as cytochemistry disclosed. No blast cells could be detected. Cytochemically, transitions between promyelocytes and promonocytes could be demonstrated. From these findings and those from the literature it is concluded that the monocytes of the terminal crisis in our case belonged to the leukemic cell strain and that these monocytes developed from non-specific promyelocytes like granulocytes. Our observation does not provide evidence for the existence of a separate monoblast which would implicate disparity of granulocytopoiesis and monocytopoiesis already at the level of undifferentiated blast cells. This, in turn, would be equal to a re-introduction of a modified polyphyletic theory of white blood cell formation.

New Translocations in Chronic Granulocytic Leukaemia: t(X;22) (p22;q11) and t(15;22) (q26;q11)

Two cases of Ph1-positive chronic granulocytic leukaemia with hitherto undescribed translocations are presented. In case 1 the deleted part of chromosome number 22q- was translocated to the short arm of the X chromosome, t(X;22)(p22;q11). Pronounced basophilia, trisomy 19 in the majority of metaphases, and a partial cytogenetic normalization of the bone marrow during busulphan induced remission were additional remarkable features of this case. In case 2 a translocation t(15;22)(q26;q11) was found. In this case the disease was characterized by an increase of unusually small megakaryocytes, thrombocytosis, and an accelerated course.

Non-random chromosome changes in the blastic transformation stage of Ph 1-positive chronic granulocytic leukaemia

The banded chromosomes from the leukaemic cells of 14 patients in the blastic transformation stage of chronic granulocytic leukaemia (C.G.L.) were analysed. All patients had a Philadelphia chromosome (Ph 1) formed by the usual translocation between chromosomes 9 and 22 [t(9;22) (q34;q11)]. Additional chromosome abnormalities were found in 13 of the 14 cases. Nine of the 13 were found to have at least one of the accepted non-random changes, i.e. either trisomy 8, an extra Ph 1 or an isochromosome long arm 17. One patient appeared to lose the Ph 1 chromosome on entering blastic transformation. The findings from this study, together with all published data on chromosome changes in blastic transformation have been collected into a histogram to illustrate the non-random nature of these changes.

The Significance of the Philadelphia Chromosome in Acute Lymphoblastic Leukaemia: a Report of Two Cases

Two cases of Philadelphia chromosome (Ph1) positive acute lymphoblastic leukaemia are reported, both of which lost the Philadelphia chromosome during remission. In one patient remission of the acute lymphoblastic leukaemia continued but classical Ph1 positive chronic granulocytic leukaemia developed. In the other patient relapse of the acute lymphoblastic leukaemia occurred associated with the return of the Ph1 chromosome. The evidence suggests that the chromosome aberration occurred in a pluripotential stem cell, which in one case proliferated along both a lymphoid cell line and a myeloid cell line. Both cases responded well to conventional therapy for acute lymphoblastic leukaemia.

Characteristics of Blast Crisis in Chronic Granulocytic Leukemia

The terminal phase of most patients with Ph1-positive chronic granulocytic leukemia (i.e., blast crisis) resembles acute leukemia. The clinical and hematologic features of blast crisis in 73 patients with chronic granulocytic leukemia have been reviewed. Two major morphological subgroups, lymphoblastic and myeloblastic, were identified. The lymphoblastic group in general had more profound thrombocytopenia and a greater number of blasts, while the myeloblastic group had more severa anemia. Extramedullary leukemia was documented in 27 patients. In 12 patients extramedullary leukemia preceded or occurred simultaneously with blast crisis in the bone marrow and peripheral blood. On the basis of this study we present hematologic criteria for the diagnosis of blast crisis and emphasize the importance of extramedullary leukemia in heralding the onset of blast crisis.