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PubMed1996

Southern technique and cytogenetics are complementary and must be used together in the evaluation of Ph1, M-BCR positive chronic myeloid leukemia (CML) patients treated with alpha interferon (IFN-alpha).

Cytogenetic analysis is the gold standard for the follow-up of CML patients. The sensitivity of cytogenetics is fairly similar to that of Southern detection of M-BCR rearrangement (5%); this last technique has the potential advantage of being independent of cell division and yield of metaphases. IFN alpha treatment can induce lack of growth of hemopoietic precursors and poor yield of metaphases has been observed. For this reason we decided to study the grade of concordance and complementarity between analysis of karyotype and detection of M-BCR rearrangement of Southern blot. We studied 43 Ph1 positive, M-BCR positive pre-BMT CML patients (48 samples) treated with IFN alpha 2a. Karyotype was done on bone marrow cells by direct method, culture, and banding. Southern technique was performed onto DNA from peripheral blood leukocytes treated with BgIII (and Xbal if necessary) and hybridized with the universal probe (Ph1/bcr-3, Transprobe 1) labelled with dCTP32. A highly significant association between both tests was obtained. Of 48 samples analyzed, 34 were evaluable by both methods and 28 gave the same result for both tests. The concordance between the tests was good (kappa index: 0.63). Of total samples 27.1% was not evaluable by cytogenetics; this figure was 31.2% in samples from patients who were previously in complete cytogenetic response. All of the specimens not evaluable by karyotyping were evaluable by Southern. One sample was not analyzable by Southern but it was evaluable by cytogenetic analysis. The information obtained by Southern technique was clinically relevant, and decisions were made according to its results. We conclude that both tests show a significant association and a good concordance, although they are not interchangeable. Cytogenetic and molecular studies are complementary and must be employed together in CML patients treated with alpha-interferon.

Blotting, Southern↗

PubMed1999

Outcome of Chinese patients with chronic myeloid leukaemia (CML) underwent allogeneic bone-marrow transplantation (BMT).

UNLABELLED: Clinical studies have shown that patients with chronic myeloid leukaemia (CML) treated with allogeneic bone-marrow transplantation (BMT) experience not only prolonged disease-free survival but also complete cure in some. Therefore, we followed a cohort of 81 Chinese patients who received allogeneic BMT. PATIENTS AND METHODS: The donors were either relatives (65 siblings, 1 parent) or unrelated volunteers (15). BMT was performed at a median interval of 11.6 months from diagnosis of CML, and the stages of disease before BMT were: first chronic phase (60 patients), accelerated or second chronic phase in (10 patients), and blastic crisis (11 patients). Three conditioning regimens were employed: Bu-Cy, Cy-TBI, or Bu-Cy-TBI. Standard cyclosporin and short methotrexate protocol were used for acute graft-versus-host disease (GvHD) prophylaxis. RESULTS: There were five graft failures with three after related BMT. Patients after related or unrelated BMT had a comparable rate of neutrophil recovery (median = 22 days), but significant delay in platelet recovery occurred after unrelated BMT (median = 34 vs. 20 days, P < 0.05). The latter also had higher incidence of acute GvHD (73% vs. 41%, P < 0.05), although the incidence of chronic GvHD was not different between groups. At a median follow-up of 43.5 months, patients after related BMT had a significantly better rate of disease-free survival (68% vs. 37.3%, P < 0.05) and overall survival (81% vs. 38.9%, P < 0.05) at 4 years. Subgroup analysis of patients after related BMT showed the outcome was better when they were transplanted at first chronic phase. Multivariate analysis showed that advanced disease (RR = 2.01, 95% CI = 1.48-2.73) significantly worsened the outcome of BMT, whereas the presence of chronic GvHD had a protective effect against relapse and survival (RR = 0.09, 95% CI = 0.02-0.38). CONCLUSION: Allogeneic BMT is a curative form of treatment for patients with CML. Treatment outcome is best for those who undergo transplants from HLA-matched siblings during the first chronic phase.

Acute Disease↗

PubMed1998

Fluorescence in situ hybridization (FISH) on peripheral blood smears for monitoring Philadelphia chromosome-positive chronic myeloid leukemia (CML) during interferon treatment: a new strategy for remission assessment.

Interferon-alpha (IFN-alpha) alone or in combination with cytostatic drugs can induce major and durable cytogenetic responses in about 20 to 25% of chronic myeloid leukemia (CML) patients. Since these patients have a significant survival benefit, more frequent follow-up investigations have become clinically important but require bone marrow (BM) aspirates. The aim of our study was to evaluate interphase fluorescence in situ hybridization (IPF) on peripheral blood (PB) smears as a rapid and reliable method to quantify Ph-positive myeloid cells. IPF analysis was performed on 49 PB samples from 36 patients in the chronic phase of CML and at different stages of cytogenetic remission. IPF results of 30 PB samples were compared with those from BM aspirates simultaneously obtained from the same patients to evaluate the correlation of Ph-positive cells. Further, the hypermetaphase FISH (HMF) technique was performed on cultured BM preparations of 31 patients for comparison with IPF results on PB. An excellent correlation was observed between the IPF results obtained on PB and BM samples (r = 0.98, y = x - 0.6, p < 0.0001). The mean difference between HMF from BM, on the one hand, and IPF from PB, on the other hand, was 3.2% (SD = +/- 8.4%). Seventy percent of samples were identically classified in one of the four subgroups of cytogenetic response. Thirty percent were classified in neighbouring response groups. We conclude that FISH performed on PB is a rapid and reliable method for assessing the cytogenetic response of CML patients on IFN-alpha based therapies, allowing more frequent and less invasive follow-up investigations although it is not able entirely to replace routine analysis of BM.

Adult↗

PubMed1976

The chromosomes and causation of human cancer and leukemia. XVIII. The missing Y in acute myeloblastic leukemia (AML) and Ph1-positive chronic myelocytic leukemia (CML).

The occurrence of a missing Y chromosome was investigated in the bone marrow cells of male individuals, i.e., 255 controls, 73 with acute myelocytic leukemia (AML) and 59 with Ph1-positive chronic myelocytic leukemia (CML). The incidence in controls of individuals with 45,X cells increased with age, particularly after the age of 60. In AML, 45,X metaphases were detected in two patients over 70 years of age, but the leukemia seemed to have involved the 46,XY cells rather than the 45,X cells. Four of the six patients with No. 8-No. 21 translocation and two of the 16 with major karyotypic abnormalities (MAKA) exhibited a missing Y in the leukemic cells in addition to other karyotypic aberrations. Four of the Ph1-positive CML patients exhibited a missing Y in all or nearly all the cells in the bone marrow along with the Ph1. In one patient, additional chromosome abnormalities involved the 46,XY,Ph1 rather than the 45,X,Ph1 cells. The genesis of the missing Y in CML cells may be related to the presence of the Ph1, though apparently the patient's age also plays a role. It is our hypothesis that 45,X or 45,X,Ph1 cells are resistant to the development of further chromosomal abnormalities and, thus, reflect their resistance to being involved in an acute leukemic process.

Adolescent↗

PubMed1980

Chromosomes and causation of human cancer and leukemia: XL. The Ph1 and other translocations in CML.

To date, 85 cases with unusual Ph1 translocations have been described and are summarized in the present work. Of the 85 translocations, 41 were simple and 44 complex. Only chromosomes #1, #4, #8, and #20 and the Y have not been found to be involved in simple translocations and #12, #16, #18, #20 and the Y in complex ones. Chromosomes #18, #20, and Y have not been involved to date in either complex or simple Ph1 translocations. Four cases have been reported in whom more tan three chromosomes were involved in the Ph1 translocation and only four cases in whom the #9 was not involved in complex Ph1 translocations. The chromosomal changes, in addition to the Ph1, accompanying unusual Ph1 translocations in CML are not different from those seen in cases with the standard type of Ph1 translocation. Translocations (other than the Ph1) in CML occur in less than 1% of the cases and, to date, have found to involve all the chromosomes except the X and Y. With rare exceptions, in complex Ph1 translocations 1) the distal end of #22 is translocated to a third chromosome (i.e., other than #9), a part of which is translocated to #9, #2) the breaks in the involved chromosomes probably occur concomitantly, and 3) a characteristic PH1 chromosome is present. The survival of patients with CML and unusual or complex Ph1 translocations does not differ significantly from that of patients with the standard Ph1-translocation.

Chromosome Aberrations↗

PubMed1980

Chromosomes and causation of human cancer and leukemia: XXXIX. Usual and unusual findings in Ph1-positive CML.

The chromosomal changes in the leukemic cells of 48 patients with Ph1-positive CML are reported. The karyotypic findings in the chronic phase (CP) and blastic phase (BP) were similar to those reported in the past, with +8, and extra Ph1, and an iso (17q) being the most common anomalies observed in BP. Unusual cytogenetic findings were observed in one patient whose cells (from lymph nodes, bone marrow, and blood) were characterized by very marked hypodiploidy and hypo-haploidy, with some of the cells having less than 20 chromosomes. In each of these very hypodiploid metaphases, conglomerations of darkly stained and condensed chromosomes were seen. These conglomerations consisted of a few to eight chromosomes. The role played by these chromosomes in the genesis of severe hypodiploidy is uncertain. The patient was thought to have "lymphoid" types of leukemic cells in BP, with an extramedullary origin of such cells, particularly in lymph nodes, playing a major role in the genesis of BP. The reported cases of near-haploidy with Ph1-positive CML and those with constitutional translocations with CML have been tabulated and the possible significance of the cytogenetic abnormalities discussed.

Adolescent↗

PubMed2004

Second case of CML with aberrant BCR-ABL fusion transcript (e8/a2) with insertion of an inverted ABL intron 1b sequence.

We found a case of Ph-positive chronic myelogenous leukemia (CML) patient with an atypical BCR-ABL transcript that was undetectable by a routine reverse transcription polymerase chain reaction (RT-PCR) for major BCR-ABL. Additional RT-PCR and sequence analyses have demonstrated that the aberrant transcript consists of a fusion of BCR exon 8 (e8) and ABL exon 2 (a2) with an insertion of a 55-bp inverted sequence of intron 1b between them. The nucleotide sequences of the aberrant transcript were identical to those of a previously reported CML patient. These are the only two CML cases in the literature with identical aberrant BCR-ABL transcripts.

Aged↗

PubMed1985

Differences between labeling index and DNA histograms in assessing S-phase cells from a homogeneous group of chronic phase CML patients.

The reliability of DNA histogram analysis in accurately estimating S-phase cells from human tumors was tested by comparing the results to those of simultaneously obtained tritiated thymidine labeling index (LI) studies. Patients with chronic myelocytic leukemia (CML) during chronic phase were selected for study because the Philadelphia chromosome (Ph) was the only cytogenetic abnormality in each case and, since it is a balanced translocation, the frequently encountered problem of aneuploidy in human neoplastic cells was avoided. Unfortunately, when 30 CML patients were studied simultaneously by DNA histogram analysis and LI studies, the correlation coefficient between the two results was only r = 0.611. A comparison of three different mathematical programs for DNA histogram analysis showed that none was completely satisfactory. We conclude that DNA histogram analysis does not provide the same data as autoradiographically processed labeling index studies even in patients with Ph-positive CML during the chronic phase when the situation is not complicated by additional aneuploidy.

Bone Marrow↗

PubMed2003

Genomic imbalances in CML blast crisis: 8q24.12-q24.13 segment identified as a common region of over-representation.

The acute phase of chronic myeloid leukemia (CML) is accompanied by secondary chromosomal changes. The additional changes have a non-random pattern; however, highly abnormal (marker) chromosomes are reported in some 20% of abnormal karyotypes. These marker chromosomes have proved to be beyond the resolution of conventional G-banding analysis. We used molecular cytogenetic techniques to determine the structure of complex chromosome markers in 10 CML-derived cell lines after our investigations of CML patients in blast crisis. Multicolor fluorescence in situ hybridization identified a multitude of structural chromosome aberrations. In addition, genomic gains identified by comparative genomic hybridization (CGH) were mapped to highly complex marker chromosomes in more than one cell line. The most common genomic loss detected by CGH affected chromosome 9, whereas the most common genomic gains affected, in order of frequency, the sequences of 8q, 6, and 13q. The smallest discrete amplification on 8q was identified in cell line MEG-01. This amplicon contains sequences represented by the marker D8S263/RMC08P029 but did not contain the proximal MYC gene or a more distal marker, D8S256/RMC08P025. We determined the size of the amplicon to be less than the chromosome segment 8q24.12-q24.13. The use of region- and locus-specific probes to analyze the organization of highly complex marker structures aided the identification of preferentially amplified genomic regions. The resultant amplifications could harbor gene(s) driving disease progression.

Allelic Imbalance↗

PubMed2000

Detailed mapping of methylcytosine positions at the CpG island surrounding the Pa promoter at the bcr-abl locus in CML patients and in two cell lines, K562 and BV173.

Chronic myelogenous leukemia (CML) is associated with a translocation of the protooncogene c-abl from chromosome 9 to chromosome 22, where it fuses to proximal exons of the bcr gene. The expression of the hybrid gene bcr-abl is regulated by the bcr promoter and results in a translation product with high tyrosine kinase activity. In most CML cases, one of two abl promoters (Pa) is nested within the bcr-abl transcription unit, but appears to be usually silent. Recently, de novo methylation of the Pa region and its correlation with disease progression were reported. As these previous studies were limited to the use of methylation-sensitive restriction endonucleases, our aim here was to obtain a complete map of methylcytosines and its variants in CML patients and in model cell lines. To achieve this, bisulfite conversion of cytosines (but not methylcytosines) to uracils in genomic DNA was employed. After modification, the region of interest was PCR-amplified and the products were cloned and sequenced. The results show methylation at a high level and in a homogenous pattern in the BV173 cell line, corresponding to the translocated abl alleles. Variant methylation observed in K562 cells correlates with multiple bcr-abl loci and an intact chromosome 9. Patients that were methylation-positive in restriction analysis showed sporadic and heterogenous occurrence of methylcytosines in bisulfite modification assays. Corresponding results were obtained using a quantitative Southern analysis of the extent of methylation. We conclude that restriction analysis combined with PCR is able to find rare cases of hypermethylation, e. g., for diagnostic purposes, but does not reflect the dominating level of methylation in Ph-positive cells.

Base Sequence↗

PubMed2000

Differences in the microtubule organization between normal and cml granulocytes after stimulation with chemotactic peptide.

Chemotaxis of polymorphonuclear leukocytes (PMNL) from chronic myeloid leukemia (CML) patients followed in a gradient of a chemotactic peptide n-formyl-methionyl-leucyl-phenylalanine (fMLP) is consistently defective in all the phases of the disease. Chemoattractant-induced polymerization of cytoskeletal proteins (actin and tubulin) plays a major role in regulation of cell shape and cellular motility. To study the role of microtubules in defective chemotaxis, we have compared fMLP-induced alterations in organization of microtubules in PMNL from CML patients with those from normal subjects by laser confocal microscopy. Our analysis shows differences in microtubule organization between normal and CML PMNL and suggests that both nucleation of new microtubule and elongation of pre-existing microtubules are essential for PMNL chemotaxis.

Humans↗

PubMed1976

[Vitamin B12 metabolism of human granulocytes. Differences in vitamin B12 uptake of normal granulocytes and CML leukocytes].

The total cell B12 level in chronic myelocytic leukaemia (CML) is low. The uptake of 57Co-cyanocobalamin by normal granulocytes, lymphocytes and CML leukocytes was studied. It was found that the uptake of vitamin B12 was dependent on its concentration. The velocity of the uptake by CML leukocytes was decreased. The reaction showed a non-competitive inhibition. Lymphocytes had the lowest uptake. Na2EDTA inhibited the vitamin B12 uptake of normal granulocytes.

Cobalt Radioisotopes↗

PubMed1993

Histological features of prognostic significance in CML--an immunohistochemical and morphometric study (multivariate regression analysis) on trephine biopsies of the bone marrow.

To evaluate the prognostic significance of clinical as well as histological disease features at the time of diagnosis, an immunohistochemical and morphometric study was performed on bone marrow trephine biopsies in 130 patients with Ph(1+)-CML. For identification of all cell elements of the megakaryocytopoiesis we used the monoclonal antibody CD61 (Y2/51) and for the macrophages, the recently characterized antibody PG-M1. Density of argyrophilic fibers was determined per fat cell-free marrow area. Based on a multivariate analysis-derived risk model, the reproducibility of the prognostic score described by Sokal and co-workers was tested, particularly with regard to histological variables. Additionally, we calculated the disease-specific loss in life expectancy. Our prognostic model (Cox model) consisted of the variables: age, spleen size, peripheral erythro-normoblasts, pseudo-Gaucher cells, and fiber density. To assess the validity of this new CML score, a receiver-operating curve (ROC) of sensitivity and specificity was constructed. The improved prognostic efficiency of this newly developed risk model in predicting death within 3 years after diagnosis of CML was demonstrated in comparison with generally accepted staging systems. Immunohistochemistry revealed that not the total number of macrophages, but only the subfraction of pseudo-Gaucher cells exerted a significant impact on survival. Furthermore, it was feasible to calculate the number of atypical micromegakaryocytes and pro- and megakaryoblasts. This abnormal and immature cell population showed a significant correlation with fiber density and prognosis. Finally, the practical value of the Hannover classification was tested. This histological classification enabled a discrimination between two groups with different survival patterns, i.e., granulocyte and/or megakaryocyte-rich subtypes versus subtypes with increase in reticulin and collagen fibers.

Adolescent↗

PubMed2003

Long term follow-up of Asian patients with chronic myeloid leukemia (CML) receiving allogeneic hematopoietic stem cell transplantation (HSCT) from HLA-identical sibling-evaluation of risks and benefits.

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only known curative therapy for patients with chronic myeloid leukemia (CML), but is associated with significant morbidity and mortality. The recent introduction of imatinib mesylate (STI-571) and reduced intensity transplant regimens has made the choice of primary treatment for patients with CML increasingly difficult. We have evaluated the outcome of 53 patients who have received allogeneic HSCT from human leukocyte antigen (HLA)-identical sibling donors between October 1985 and March 2002, determined the variables affecting the outcome, and tried to define indications for this aggressive approach. Successful engraftment occurred in 49 (98%) of evaluable patients. Acute graft-versus-host disease (GVHD) of grade II to IV severity was observed in 63% of the evaluable patients whereas the incidence of chronic GVHD was 57.5%. The Kaplan-Meier estimate of survival at 10 years was 54% [95% confidence interval (CI): 38-70%] and 31% (95% CI: 6-56%) for patients with first chronic phase and more advanced diseases, respectively. Multivariate analysis showed that younger age, absence of grade III-IV GVHD, the use of busulphan and cyclophosphamide (BuCy) as preparative regimen, and transplantation performed after January 1992 were factors associated with improved survival. Patients who were 30 years of age or younger who had transplantation done within 1 year after diagnosis during their first chronic phase of disease had a particularly good prognosis, with a probability of surviving 10 years of 72% (95% CI: 52-92%). We conclude that allogeneic HSCT remains a feasible option for Asian patients with CML. The most favorable outcome is observed in younger patients with early phase of the disease.

Adolescent↗

PubMed2006

Long-term follow-up of allogeneic HSCT for CML reveals significant improvement in the outcome over the last decade.

Allogeneic hematopoetic stem cell transplantation (HSCT) is still the only curative therapeutic option for chronic myelogenous leukemia (CML). To examine the development of allogeneic HSCT at our center over the past two decades (decade 1: 1984-1994; decade 2: 1995-2005), all CML patients transplanted in first chronic phase (n = 234) were analyzed with respect to patient characteristics, overall survival, transplant-related mortality (TRM), and relapse incidence. The median follow up time was 54 months (range 1-218). The incidence of acute graft vs host disease (GvHD) degrees II-IV and extensive chronic GvHD were not different between the two decades (p = 0.894 and p = 0.422, respectively). There was also no difference in the relapse incidence (23 vs 26%, p = 0.869). One-year TRM and overall survival were improved in the later decade (33 vs 18%, p = 0.011 and 62 vs 73% at 5 years, p = 0.063, respectively). The major reason for improved outcome in decade 2 was the improved management of acute GvHD and infections in the early phase after transplantation (p = 0.026). In conclusion, the past decade has seen significant improvement in the performance of allogeneic HSCT for CML.

Acute Disease↗

PubMedDate not supplied

Outcome of peripheral blood stem cell mobilization in advanced phases of CML is dependent on the type of chemotherapy applied.

High-dose chemotherapy with autologous transplantation of in vivo purged PBSC is a novel investigational approach to treating chronic myelogenous leukemia (CML) patients not responsive to conventional therapy with interferon-alpha (IFN-alpha) and not eligible for allogeneic transplantation. PBSC mobilization using either '5+2/7+3'-type chemotherapy or 'mini-ICE/ ICE' chemotherapy was investigated in 43 patients with advanced phases of Philadelphia (Ph)-positive CML. Thirty patients were in late chronic phase (>12 months post diagnosis) and 13 patients in accelerated phase (AP) or blast crisis (BC). Contamination with Ph-positive cells was evaluated in harvests from 37/43 patients. The outcome of PBSC mobilization was dependent on the type of chemotherapy administered: a complete or major cytogenetic response (<35% Ph-positive metaphases) in leukapheresis collections was obtained in ten of 15 patients treated with 'mini-ICE/ICE' but in only three of 28 patients treated with '5 + 2/7 + 3' chemotherapy. One patient (1/43) in blast crisis died during mobilization therapy (2%). Twenty-five patients underwent PBSC transplantation and all of them engrafted successfully. Transplantation-related mortality was 0%. The data show that in advanced phases of CML the chance of harvesting Ph-negative peripheral blood stem cells depends on the type of chemotherapy used for mobilization.

Adult↗

PubMed2000

[Histologic and hematological findings in CML. A comparative immunohistochemical-morphometric and clinical study on bone marrow biopsies from 604 patients derived from two institutes of pathology (Cologne/Freiburg)].

An immunohistochemical and morphometric study was performed on bone marrow biopsies in 604 patients with chronic myelogenous leukemia (CML) to compare morphological and clinical features and to evaluate effects of interferon (IFN) and chemotherapy. Following morphometry significant correlations were calculated between number of CD61(+) megakaryocytes, including their precursors with fiber density. This finding is in line with the close functional relationship between megakaryopoiesis and fibroblasts regarding the complex pathomechanism of myelofibrosis. The latter was observed in about 28% of patients already at diagnosis. In a similar way, the frequency of CD68(+) macrophages was correlated with the amount of Ret40f(+) nucleated erythroid precursors, implicating an involvement of this cell lineage in iron turnover, hemoglobin synthesis, and degradation of the expelled nuclei from normoblasts. The (alpha-D-galactosyl residue-expressing) Pseudo-Gaucher cells were detectable in 30% of pretreatment specimens. Moreover, significant associations were calculable between reduction in erythropoiesis or increase in fibers with clinical features such as hemoglobin level, percentages of myelo- and erythroblasts in the peripheral blood, and spleen size. These variables are in keeping with more advanced stages of CML. Based on our morphometric evaluations, a classification into three different histological subgroups: granulocytic, megakaryocytic, and myelofibrotic was carried out. This simplified staging system was correlated with corresponding sets of hematological data. Sequential biopsies in 173 patients with monotherapy by IFN, hydroxyurea (HU), or busulfan (BU) revealed a fibrogenic effect of IFN in contrast to a fiber-reducing property of HU. The dynamics of myelofibrosis and changes of major cell lineages during treatment were readily demonstrable by calculating corresponding indices. These included the ratios between quantitative differences of corresponding variables at repeated examinations and time. Thus, in patients with complete hematological remission following IFN administration, regeneration of erythropoiesis was found to be accompanied by an increase in the total number of CD68(+) macrophages, including activated subpopulations. Histological subgroups showed a transition from a (nonfibrotic) granulocytic and megakaryocyte pattern to the myelofibrotic subtype in about 40% of patients. This change was opposed to a numerical reduction in the myelofibrotic subtype which occurred in 17 patients (36%), but predominantly in those under HU therapy. In conclusion, the striking heterogeneity of bone marrow features in CML warrants a careful morphological evaluation of trephine biopsies and appropriate means of processing to achieve relevant correlations with clinical data and, thus, allows a more elaborate insight into the dynamics of the disease process.

Biopsy↗

PubMed1985

Cytogenetics and cell surface marker analysis in CML--1. Prediction of phenotype of acute phase transformation.

Thirty-nine patients with Philadelphia chromosome-positive (Ph1) chronic myelocytic leukemia (CML) were monitored using cytofluorometry and cytogenetics. During chronic phase, abnormal populations could be detected using commercially available monoclonal antibodies. Most of these abnormal populations had either an HLA.DR+ or an OKM1+ HLA.DR- phenotype. Thirteen patients progressed to acute phase disease. Five patients with HLA-DR+ abnormal cells during chronic phase showed no clonal evolution detectable using standard cytogenetic techniques and underwent lymphoid transformation. Seven patients with OKM1+-HLA.DR- abnormal cells exhibited chromosomal abnormalities in addition to the Ph1 and progressed to a myeloblastic acute phase. One patient with HLA.DR+ OKM1+ 63D3+ abnormal cells in chronic phase showed clonal evolution and progressed to a myelomonocytic acute phase. These results suggest that cell surface markers on chronic phase cells can be used in conjunction with cytogenetic monitoring to predict the phenotype of cells involved in the acute transformation of CML. B cells (6, 13), but not T cells (18), bearing the Ph1 have been isolated from chronic phase CML patients. Thus cells other than those of myeloid lineage may be involved. Periodic cytogenetic monitoring has been shown to detect clonal evolution (i.e. genetic changes in addition to the PH1) in as many as 75% of patients prior to the acute phase (14, 37). However, neither cytogenetic changes nor morphologic analysis appear to predict the lymphoblastic type of transformation (14). Since fluorescence analysis of cell surface markers has shown reduced numbers of normal cells (28), the identity of the 'abnormal' cells was probed with antibodies recognizing a variety of markers on immature and mature lymphoid and myeloid cells. Not only were significant numbers of abnormal cells detected in the peripheral blood of chronic phase patients, but the phenotype of the abnormal population, in combination with cytogenetic analyses, predicted the type of blasts involved in acute phase disease.

Adult↗