Liberation of anti-heparin activity during platelet aggregation in patients with blastic leukosis and blastic crisis of chronic myelosis]

The activity of platelet factor 4 (FP4) was examined in 37 patients affected with blastic leukaemia, in 16 patients with blastic crisis in chronic myeloid leukaemia and in 2 patients with Willebrand's syndrome. The real activity of FP4 determined by modifying the method according to NIEWIAROWSKI after a complete lysis of granular membrances by means of triton X-100 was found to be lowered in 9 patients affected with blastic leukaemia, in 5 patients with blastic crisis and in two patients with Willebrand's syndrome. Presuming that a maximal FP4 release of the irreversible platelet aggregation must be obtained, which corresponds to the real activity, the author has examined the apparent activity of FP4 released from the aggregated platelets with the help of her own method. In this way the quality of the release reaction from the platelets can indirectly be characterized with their extremely important role for haemostasis. Whereas in exacerbated myeloid leukaemia and Willebrand's syndrome the apparent activity will correspond to the real one, there is a severe specific disturbance of the platelet release response in blastic leukaemia. The platelet aggregation is incomplete caused by the derailment of the energy metabolism and the disturbance of the adenine nucleotides, thus causing an apparent as well as a real FP4 deficiency which can be brought into the same line with pathogenesis of thrombopathy in blastic leukaemia.     

Cytochemical data in chronic monocytic leukemia]

4 cases of chronic monocytic leukemia were observed during several years. In 2 patients there was a final appearance of blastic crisis. During the course of the disease the activity of the naphthylacetate-esterase in the monocytes increased, but the PAS-reaction was lowered. By the help of two cases for comparison - one patient suffering from a chronic myeloid leukemia and intermediate monocytic phase, the other one from a panmyelopathia and monocytic reaction - the morphological resemblance of these phenomena is demonstrated, which cytochemically cannot be separated.     

ATM-dependent DNA damage-response pathway as a determinant in chronic myelogenous leukemia

Chronic myelogenous leukemia (CML) begins with an indolent chronic phase, and subsequently progresses to an accelerated or blastic phase. Although several genes are known to be involved in the progression to blastic phase, molecular mechanisms for the evolution toward blast crisis have not been fully identified. Oncogenic stimuli enforce cell proliferation, which requires DNA replication. Unscheduled DNA replication enforced by oncogenic stimuli leads to double strand breaks on DNA. We found the DNA damage-response pathway is activated in bone marrow of chronic-phase CML patients possibly due to an enforced proliferation signal by BCR-ABL expression. Since ataxia telangiectasia mutated (ATM) is a central player of the DNA damage-response pathway, we studied whether loss of this pathway accelerates blast crisis. We crossed Atm-knockout mice with BCR-ABL transgenic mice to test this hypothesis. Interestingly, the loss of one of the Atm alleles was shown to be enough for the acceleration of the blast crisis, which is supported by the finding of increased genomic instability as assayed by breakage–fusion–bridge (BFB) cycle formation. In light of these findings, the DNA damage-response pathway plays a vital role for determination of susceptibility to blast crisis in CML.     

Blast crisis of Philadelphia chromosome-positive chronic myelocytic leukemia (CML). Treatment results of 69 patients

We have studied the clinical courses of 69 patients with blastic crises of Philadelphia chromosome positive CML to identify parameters that were associated with an increased response rate or survival. Cytogenetic analysis at the time of blastic transformation revealed additional chromosome changes in 70% of the patients tested. Bone marrow fibrosis was detected in 58% of evaluable patients. Lymphoblastic transformation was seen in 28% of the patients tested with cell surface marker analysis. The value of 5'-nucleotidase as a marker for distinguishing lymphoid from non-lymphoid blast crisis was confirmed. Of 57 evaluable patients, 23 (40%) responded to therapy (CR/PR longer than 14 days). Median survival was 75 days. Longer survival was related to the following factors: Ph1-chromosome as the only detectable cytogenetic abnormality; lymphoblastic transformation; no bone marrow fibrosis; high percentage of blasts and promyelocytes in the bone marrow, and response to therapy. No prognostic significance was associated with age, sex, Tdt, LDH, spleen size, duration of the chronic phase of the disease, white blood cell count, Hb, platelet count and percentages of basophils, eosinophils, erythroblasts and blasts and promyelocytes in the peripheral blood. These data confirm the poor prognosis of patients with blastic crisis of CML treated by conventional chemotherapy.     

A new approach to the evolution of the blastic crisis from chronic myelocytic leukemia: dynamic interplay of cellular alterations and a changing microenvironment.

The mechanisms responsible for the massive hyperplasia and for the blastic crisis in chronic myelocytic leukemia are poorly understood. The most generally accepted hypothesis proposes that this progression is due to the development of genetic instability in the leukemic cells. In particular, the two phases of the disease are believed to reflect different, discrete genetic events. Such events remain undefined as yet, and the causal significance of observed genetic aberrations is not clear. An alternative hypothesis is presented here. It is assumed that the feedback interactions adjust the relative probabilities of maturation and replication of the 'committed' as well as the pluripotent cells, and further that mitotic cells at all stages possess considerable phenotypic adaptability; in particular their self-renewal capacity can vary in response to changes in the cellular composition of the tissue even within a conventionally defined compartment. On this basis, it is shown that chronic leukemia can arise and evolve into the blastic crisis from a progressive decline in a single clonal characteristic--inducibility to maturation. It is shown, with the help of mathematical considerations, how an initial hereditable event in an early hemopoietic cell can cause a disturbance of the tissue which feeds back onto the individual members of the clone, resulting in a cascade of dynamic changes which can lead to blast cell dominance.     

Osteolytic lesion in chronic myelogenous leukaemia

Destructive bone lesion of the femur was observed in one patient from a series of 103 patients with CML. Numerous myeloblasts were seen on touch preparations of the fresh surgical specimen obtained by open biopsy of the affected area. Bone marrow and peripheral blood differential count were compatible with chronic phase of CML at this time. 5 months later blastic crisis developed. Local radiotherapy produced effective palliation of pain but did not prevent blastic transformation of CML. The treatment of blastic crisis was unsuccessful and patient died 3 years after diagnosis of CML, 6 months after the first clinical evidence of bone infiltration.     

Nonrandom chromsome rearrangements in 27 cases of human myeloid leukemia

Summary The R-banding pattern of the chromosomes of 31 patients hospitalized in the Hematologic Clinic for myeloid leukemia were studied before chemotherapy. This analysis permitted identification of one unusual 3-chromosome rearrangement t(3;9;22) in addition to 25 classic forms of (22q-;9q+) translocation accompanied by the specific Ph' chromosome in chronic granulocytic leukemia patients, independent of the blastic course of the disease.During blastic crisis observed in 6 patients, extra 8 and 10 chromosomes, monosomy for chromosome 17, isochromosomes 17q, translocation (12q;13q), and additional Ph' were noted.The nonrandomness of these findings is determined from results published by other authors. Their significance for the cellular phenotype is presently unknown.Supported by Grant No.422/VI of the Polish Academy of Sciences.     

Chromosome abnormalities associated with Phl and acturial survivorship curve in chronic myeloid leukemia. Probabilistic interpretation of blastic transformation of CML

Sixty-six patients with chronic myelogenous leukemia, all with Philadelphia chromosome, have been studied for chromosomic abnormalities associated (CAA) to Ph', as well as for actuarial curve of survivorship. Patients dying from another disease were excluded from this study. Frequency of cells with CAA was measured and appeared strongly higher after blastic transformation than during myelocytic state; probability to be a blastic transformation is closely correlated with this frequency. On the other hand, actuarial curve of survivorship is very well represented by an exponential curve. This suggests a constant rate of death during disease evolution, for these patients without intercurrent disease. As a mean survivance after blastic transformation is very shorter than myelocytic duration, a constant rate of blastic transformation could be advanced: it explains possible occurrence of transformation as soon as preclinic state of a chronic myelogenous leukemia. Even if CAA frequency increases after blastic transformation, CAA can occur a long time before it and do not explain it: submicroscopic origin should be searched for the constant rate of blastic transformation would express the risk of a genic transformation at a constant rate during myelocytic state.     

Chromosomal rearrangements with a common breakpoint at 6p23 in five cases of myeloid leukemia

Rearrangement of the short arm of chromosome 6 with a breakpoint at 6p23 was found in five patients with myeloid leukemia. Three of them had different morphological variants of AML (M2, M3, M4) and two blastic crisis of Ph1 negative and Ph1 positive CML. Identical translocation, t(6;9)(p23;q34), was revealed in two patients. One of them had AML (M2), the other blastic crisis of Ph1 negative CML. The blast cells of the last patient were morphologically similar to those in the M2 variant of AML. Translocation (6;9)(p23;q34) was also detected in two AML patients of Rowley and Potter (1976). The role of the breakpoint at 6p23 in myeloid malignancies needs further investigation.     

Detection of B-cell antigen on the blast cells in chronic myeloid leukemia]

The presence of the common antigen on B lymphocytes of healthy donors and myeloblasts of patients with chronic myeloid leukemia in blastic crisis was observed with antimyeloblastic serum in the indirect surface immunofluorescence test. The cytotoxic test showed this antigen in the blastic cells in 27 out of 57 patients with CML BC, in 3 of 11 patients with acute lymphoid leukemia, in 1 of 8 patients with chronic lymphoid leukemia and in 2 of 2 patients with undifferentiated leukemia. The antigen was not found in the peripheral blood cells of healthy donors.     

Identification of a melanoma antigen, PRAME, as a BCR/ABL-inducible gene

In order to elucidate molecular events in BCR/ABL-induced transformation, we adopted a polymerase chain reaction (PCR)-based technique of differential display and compared mRNA expression in human factor-dependent cells, TF-1, with that in factor-independent cells, ID-1, which were established from TF-1 cells by transfection of BCR/ABL. Cloning and sequencing of a gene which was upregulated in ID-1 cells revealed that the gene was identical to a melanoma antigen, PRAME. Our present study demonstrated that PRAME was markedly expressed in primary leukemic cells with chronic myeloid leukemia (CML) in blastic crisis and Philadelphia (Ph)+-acute lymphoblastic leukemia (ALL), in which BCR/ABL played an important role as a pathogenic gene. Moreover, comparison of PRAME expression among CD34+ cells with CML in blastic, accelerated, and chronic phases revealed a higher expression in CML in advanced phases. Thus PRAME was considered to be a good candidate for a marker of Ph+-leukemic blast cells as well as a new target antigen of leukemic blast cells that cytotoxic T cells can recognize.     

Inactive normal X in a female leukaemic patient with an acquired X/autosome translocation

Summary An X;9;22 translocation was detected in bone marrow cells of a female patient with blastic crisis of CML. A dynamic study following 5-BrdU treatment showed that the inactive late-replicating X chromosome was the normal one. This pattern of X-chromosome replication appears to be superimposable on the most usual model found in congenital X/autosome translocations.It is suggested that preferential autosome translocation onto the active X chromosome could be the general rule in acquired X/autosome translocations associated with long survival.     

慢性髓细胞白血病急变期MICM 分型回顾性分析

目的:探讨慢性髓细胞白血病急变期(CML-BC)患者的细胞形态学(M)、免疫学(I)、细胞遗传学(C)和分子生物学(M)的特征及应用价值。方法:对38例CML-BC患者的MICM分型进行回顾性分析。结果:以FAB分型为基础的形态学确诊率达94.7%;免疫分型结果为:38例CML-BC中CML-AML占71.0%,其中37.0%伴淋系表达;CML-ALL占23.7%,均为B细胞性,其中66.67%伴髓系表达;CML-MAL(混合性白血病)占5.3%,均为B系和髓系混合表达;CD34+26例(68.4%),CD7+10例(26.3%),均与CD34共表达。细胞遗传学结果显示:CML特征性Ph染色体检出率为94.3%(36/38),附加异常染色体检出率为60.5%(23/38),发生频率较高的类型是+Ph、+8和i(17q);FISH检测BCR/ABL融合基因阳性率为100%,der(9)缺失占14.7%。RT-PCR检测20例患者BCR/ABL融合基因均为阳性,其中b2a2型(12/20),b3a2型(8/20),1例(1/20),b2a2和b3a2双阳性(1/20)。结论:CML-BC是造血干细胞疾病,原始细胞分化阻滞在早期阶段,预后差。MICM分型对CML-BC的诊断、治疗和预后判断均有重要价值。     

An unusual case of a basophilic variant of chronic myelogenous leukemia

The described basophilic variant of CML in blastic crisis was characterized by a distinct hyperhistaminemia, a moderate hypocoagulation and an insufficiently effective cytostatic therapy. Cell kinetic was characterized by a marked diminution of the whole marketing index (with H3-thymidine) of blasts and immature basophils with simultaneous prolongation of the generation time in comparison to myeloblasts at the chronic stage of the CML. Aneuploid cell clones prevailed in the bone-marrow.     

Single cilium in human leukemic cells heterotransplanted into hamsters

Single cilium formation was studied in two human hematopoietic cell lines, KCL-22 and MT-2, KCL-22, established from a patient with chronic myelogenous leukemia in blastic crisis, and MT-2, a human cord T cell line carrying human T-lymphotropic virus type I, were transplanted into hamsters. Ciliogenesis was observed in both cell lines, only after transplantation into hamsters.     

Repeated, 2-10 fold asparaginase treatments in children with lymphoproliferative diseases]

In 42 children being in the advanced stage of an acute lymphoblastic leukaemia as well in 7 children with lymphosarcoma a total of 83 series of treatment with L-asparaginase were carried out. During the first blastic crisis of acute leukaemia 74% of complete or partial remissions could be obtained by two treatments and 52% by the following ones. The best results were obtained by organ manifestations of acute leukaemia (80% of complete or partial remissions). Less satisfactory results were achieved in treating lymphosarcoma. All remissions were only of a short duration.     

Correlations between the clinical course,characteristics of blast cells,and karyotype patterns in chronic myeloid leukemia

Summary Results of chromosome studies of blood and bone marrow cells from 101 patients with Ph¹ positive chronic myeloid leukemia (CML) confirm the assumption that clinical and morphologic manifestations of the disease correlate with karyotype peculiarities of leukemic cells. Several variants of the clinical course of CML may be distinguished. One is the variant with a short chronic phase and a comparatively long terminal phase. In blastic crisis the blast cells are peroxidase negative and do not possess cytoplasmic inclusions. Acute transformation occurs without any additional chromosome damage. The second, more common form is less severe because of longer chronic phase but it has a short and grave acute stage. The blast cells present definite signs of myeloid differentiation, they have basophilic or neutrophilic cytoplasmic granules and are peroxidase positive. Marker i(17q) often combined with trisomy 8 is a characteristic chromosome abnormality in the terminal stage of this variant. The third type has an extremely long chronic phase but ends in a rapidly progressing severe and resistant to therapy lymphoid blastic crisis. Blast cells have typical lymphoid morphology, they are peroxidase negative and contain granular PAS positive substance. Various additional chromosome changes appear in the terminal stage. Future studies of a larger series of patients may possibly reveal more CML variants.     

Prefinal clinical findings and results of autopsy in 82 children with acute lymphatic leuckemia (ALL) under various courses of therapy]

At present 80...90 % of the patients with acute lymphatic leukaemia die in the blastic crisis. About 10% will come ad finem during full remission caused by side effects of the treatment and their complication. The leukaemic terminal crisis may be accompanied or overlapped by a number of complications, the most frequent among own patients being acute bleeding in the terminal phase. First of all the source of bleeding is to be found in the gastro-intestinal tract (80%). Other authors found infections to be the most frequent final cause of death. It is only under autopsy that leukaemic infiltrates, infections and bleeding are completely recognized to their full extent. After polychemo-therapy the patients showed a significant increase of complications including pulmonary oedema and a marked insufficiency of the bone-marrow with leukocytopenia and granulocytopenia in the peripheral blood. Among the biochemical parameters only a generally significant increase of alpha2 and gamma globulins could be found in the serum. A correlation towards a form of therapy could not be ensured.     

A new case of chronic myelogenous leukemia with 14q+ marker and review of the literature

We report a new case of Ph 1 positive chronic myelogenous leukemia (CML) with 14q+ marker shown during chronic phase (CP) and subsequently in blastic crisis (BC). After a review of the literature, we discuss the biological significance of 14q+ marker in developing lymphoid cellular differentiation, during evolution of CML, that remains still unclear. Besides, we also discuss the prognostic value of this change, concluding that a larger number of cases may clarify this question, as also the unresponsivity to chemotherapy of the patient studies so far, may not be related to 14q+ marker.