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PubMed1990

[One-year remission of chronic myelogenous leukemia (CML) after discontinuation of interferon-alpha].

A 53-year-old woman was admitted to our hospital on Nov. 16, 1987, because of general fatigue. On admission, she had hepatosplenomegaly and her peripheral blood profile showed a white blood cell count (WBC) of 309 x 10(3)/microliters with immature neutrophils, a hemoglobin level (Hb) of 7.6 g/dl, platelet count (PLT) of 536 x 10(3)/microliters, neutrophilic alkaline phosphatase (NAP) score of 44. Both Vitamin B12 and LDH levels were high. The bone marrow showed marked myeloid hyperplasia. In a cytogenetic study, Ph1 was found in 3 of 8 metaphases and Ph1 with an additional abnormality of 8 trisomy was noted in 5 of 8 metaphases. She was diagnosed as having chronic myelogenous leukemia (CML) and treated by i.m. injection of interferon (IFN)-alpha at a daily dose of 6 x 10(6) U. Administration of IFN-alpha induced fever for a few days. WBC, PLT count and LDH level gradually decreased, and the NAP score and hepatosplenomegaly improved. She achieved remission in February, 1988. Administration of IFN-alpha was stopped in April, 1988, when the bone marrow showed hypocellularity and normal karyotype. She was treated with 20 mg of prednisolone daily from May until August, because of progressive pancytopenia. She had received no treatment until July, 1989. In May, 1989, the bone marrow again showed myeloid hyperplasia and Ph1 was found in all cells analyzed. Therefore, we resumed IFN-alpha treatment. It is interesting that remission of CML continues for more than one year after discontinuation of IFN-alpha in this case.

Female↗

PubMed1990

Biological importance of residual leukaemic cells after BMT for CML: does the polymerase chain reaction help?

The fate of the leukaemic clone after bone marrow transplantation (BMT) for patients with chronic myeloid leukaemia (CML) may determine the long-term prognosis. Several groups have reported the use of the polymerase chain reaction (PCR), a highly sensitive technique for detecting residual leukaemia, to study blood and bone marrow of patients in apparent cytogenetic and clinical remission at various intervals after BMT. The limitations of the technique relate to the need in CML to use mRNA rather than DNA as test material, the undefined sensitivity of the assay, the lack of knowledge of cell lineage when the test is positive and the high risk with present techniques of false positive and false negative findings. These points notwithstanding, the collected data suggest that most longterm survivors have no evidence of leukaemia detectable by PCR; in contrast many of the patients transplanted within the last 5 years do have evidence of residual leukaemia. This suggests that in a significant number of patients the leukaemic clone may survive for several years after BMT before it is eradicated (or falls below the threshold for detection by PCR). If this is confirmed the finding of residual leukaemia by PCR in the first few years post-BMT would have limited prognostic significance.

Antineoplastic Agents↗

PubMed1989

HLA-D/DR identity results in a positive CML reaction.

Investigating HLA-A, HLA-B, HLA-C, and HLA-DR antigens, MLR, CML, and PLT reactivity in two unrelated persons it was found that despite their HLA-D/DR identity cytotoxic T lymphocytes (CTL) could be induced in the CML assay. The HLA-DP antigens proved to provide the necessary proliferative impetus for the generation of CTL.

Cytotoxicity, Immunologic↗

PubMed1989

[Thrombocytosis in chronic myelogenous leukemia (CML) controlled by interferon alpha (IFN-alpha)].

A 39-year-old Japanese female who had been followed as chronic myelogenous leukemia (CML) since 1984 was admitted to our hospital because of dizziness. On admission, platelet count markedly increased (245 X 10(4)/microliters) in spite of daily administration of busulfan 2 mg. She was diagnosed as accelerated phase CML with thrombocytosis. So we tried to use interferon alpha (IFN-alpha) finally given in a dose of 9 X 10(6) U daily by subcutaneous injection. After that, platelet count decreased to 70 X 10(4)/microliters and megakaryocyte count in bone marrow decreased from 887.5/microliters to 395.7/microliters. But we had to stop IFN-alpha because of severe side effects.

Adult↗

PubMed1989

[The changes of mRNAs of both c-myc and MDR1 in CML-bc tumor cells during the clinical course: a case report].

We examined the expressions of both c-myc and MDR1 in four samples isolated from a CML-bc patient in series during the clinical course. A 46-year-old man was diagnosed as chronic phase of CML in june 1985. In February 1987, the diagnosis of blastic transformation was made because of marked increase of blastic cells. He was initially treated with vincristine (V) and prednisolone (P) successfully. However, the effect of VP therapy was gradually attenuated, so that combined chemotherapies including anthracyclines were started. After the treatments of several courses, tumor cells acquired the refractory to both vincristine and adriamycin . He died in January, 1988. Northern blot hybridization studies revealed no expression of MDR1 mRNAs. However, the expression of c-myc was increased in the latest sample. These findings suggest that the expression of c-myc mRNA in tumor cells of this case reflects one characteristic of clinically refractory states to chemotherapies.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1989

[Bone marrow aplasia without blast crisis in a case of CML of 10-year survival].

A case of chronic myelogenous leukemia (CML) of 10-year survival in described. A 44-year old male was admitted to our hospital because of general malaise, abdominal fullness and fever in February, 1977. On physical examination, giant splenomegaly and hepatomegaly were detected. Peripheral blood examination revealed leukocytosis without hiatus leukemia , normochromic macrocytic anemia and thrombocytosis. NAP rate and score were 16% and 22. Cytogenetic analysis of PB without stimulator revealed 46, XY, Ph1. Then he was diagnosed as having a typical type of Ph1-positive CML. He had been successfully treated over 9 years by intermittent administration of busulfan. However, anemia suddenly progressed in February, 1986 followed by leukopenia and thrombocytopenia. Hemorrhage was not detected by the examination. Though he had been received blood transfusion, the anemia progressed rapidly. He was died of cachexia on 4th of August, 1987. The postmortem examination revealed bone marrow aplasia with no signs of blast crisis nor myelofibrosis. Secondary hemochromatosis was seen in the liver, spleen, pancreas and some other organs.

Adult↗

PubMed1986

Frequent and extensive deletion during the 9,22 translocation in CML.

Chromosomal translocation is one mechanism by which cellular oncogenes may be activated during tumorigenesis. The translocation of the abl oncogene to the Philadelphia chromosome in chronic myelogenous leukemia (CML) results in a new RNA transcript that fuses sequence from chromosome 22 to sequence from the abl oncogene. This RNA presumably codes for a new abl-related protein product found in CML, the activity of which is different from the normal abl protein. The molecular structure of the translocation varies from patient to patient, and the individual variation in RNA transcript and protein product remains to be defined. This report describes the frequent occurrence of chromosomal deletion within the 9q+ chromosome during these translocations. The location of the deletions suggests that some mechanism maintains the chromosomal breakpoint on the Philadelphia chromosome within a limited region. These deletions complicate the interpretation of Southern blots as a means of detecting the translocation.

Chromosome Deletion↗

PubMed1988

The site of the breakpoint within the bcr is a prognostic factor in Philadelphia-positive CML patients.

The Philadelphia (Ph1) chromosome, characteristic of chronic myelogenous leukemia (CML), arises from a reciprocal translocation between chromosomes 9 and 22. The site of the breakpoint on chromosome 22 is within a small region called the breakpoint cluster region (bcr). We have mapped the breakpoint within the bcr in peripheral blood leukocyte DNA from 22 Ph1-positive CML patients. No correlation between the site of the breakpoint and the clinical phase of the disease was found. However, a striking correlation between the site of the breakpoint and the length of time between presentation and onset of acute phase was observed: on average, patients with a 5' break-point had a fourfold longer chronic phase (median, 203 weeks) than those with a 3' breakpoint (median, 52 weeks).

Blotting, Southern↗

PubMedDate not supplied

The prognostic implication of clinical and histological features in Ph1+ chronic myelocytic leukaemia (CML).

A study on clinical and histological features of prognostic significance was performed in 45 patients with Ph1+ -CML who showed median survival of 36 months. The histological features were evaluated by morphometry of iliac crest biopsies. Among the variables correlated with prognosis, we eliminated those without primary importance by mutual univariate retrospective stratification. Thus a clinical and a histological set of important prognostic criteria was established. Their influence on prognosis proved to be independent of each other and therefore could be used for separate classifications. Clinical classification yielded two groups with different prognosis: compared to the rest of the patients, the prognosis was much worse for those with a spleen size greater than 10 cm, a liver size greater than 2 cm (below costal margin) and greater than 5% circulating blasts plus promyelocytes. The histomorphological classification consisted of three subgroups: a better than average prognosis was found for patients with pseudo-Gaucher cells in the bone marrow, while in the remaining cases the prognosis was worse in patients with a high number of megakaryocytes (greater than 70/mm2) and a low volume ratio of granulopoiesis: megakaryocytes (less than 15). Since liver size was correlated with the duration of prediagnostic symptoms, the clinical classification probably reflects different disease stages, i.e. a later CML diagnosis. However, the histological set of prognostic factors is independent of the length of the prediagnostic period. Consequently, this morphological classification seems to discriminate different subgroups. Another important prognostic factor, marrow fibrosis, was independent of other histomorphological features, and correlated with duration of symptoms. It obviously also indicates more advanced disease.

Adolescent↗

PubMed1978

Therapy of chronic myeloid leukemia (CML): interim report on protocols CML/73 and CML/74.

Current therapies of chronic myeloid leukemia (CML) do not prevent the progression of the disease towards blastic metamorphosis, and have not resulted in a remarkable prolongation of survival. Splenectomy was proposed with the aim of removing a part of the tumor without cytotoxics and of removing a potentially privileged pool of malignant blast cells. Acute leukemia-like chemotherapy was proposed with the aim of eradicating or better controlling the highly malignant subclones that emerge during the chronic phase. A preliminary analysis of 2 clinical trials these therapeutic measures, suggests that splenectomy does not modify the rate of blastic transformation, during the first 2 to 3 years from diagnosis. Also the rate of blastic transformation is similar for patients receiving hydroxyurea at first, and arabinosyl cytosine (ARA-C), vincristine (VCR) and prednisone (P) thereafter, as for patients receiving from the clinical onset of CML a more intensive chemotherapy with ARA-C, thioguanine (TG) and daunomycin (DAUNO), but not VCR + P.

Antineoplastic Agents↗

PubMed1983

Fetal hemoglobin analysis of erythroid bursts in patients with chronic myelogenous leukemia (CML).

Early erythroid progenitors (BFUE) form colonies of mature progeny in culture. The development of hemoglobinized red cells within multilineage colonies (CFUGEMM) and erythroid bursts is dependent upon exogenously added erythropoietin and molecules released by hemopoietic subpopulations. Mixed colonies and erythroid bursts were grown from 3 patients with Ph' chronic myelogenous leukemia (CML). It was found that some mixed hemopoietic colonies and erythroid bursts did not require exogenously added erythropoietin. An increase of the plating efficiency of BFUE could be observed when erythropoietin was added. Erythroid bursts grown without added Ep from samples of the patients with chronic myelogenous leukemia have a higher probability to contain HbF than clones grown in the presence of Ep. The data support the view of a phenotypical heterogeneity among clonal descendents of a common ancestor as previously postulated for CML.

Adult↗

PubMed1984

"Masked" Ph1 chromosome abnormalities in CML: a report of two unique cases.

Two patients with chronic myeloid leukemia (CML) showed previously undescribed variants of a "masked" Ph1 abnormality. The first patient had the karyotype 46,XY, + 21, -9, -22, +mar9,mar18 at presentation in the chronic phase. The dicentric marker 9 was interpreted as representing the usual translocation of 22q11 to 9q34, followed by translocation of the Ph1 chromosome (the deleted 22) to 9p and probable translocation of 9p to the distal long arm of the marker. The patient developed clones containing 2 and 3 copies of the "Ph1-containing" marker 9 concomitant with the metamorphosis of his disease to a more aggressive phase. The second case presented with the karyotype 46,XY,-9,-22,+two D-group markers. A complex rearrangement of chromosomes 9 and 22 is postulated, with interstitial insertion of either 9p or distal 9q into chromosome 22q11. This patient is still in the chronic phase of his disease 9 mo after presentation. The common denominator in these unusual "masked" cases is the 22q11 breakpoint. The paucity of published reports of duplication of 9q + without concurrent duplication of the Ph1 chromosome, supported by the findings in our first case, leads us to conclude that the amplification of genes on the Ph1 chromosome are more important for the evolution of the abnormal stem cell in CML than the chromosome 9 derivative.

Adult↗

PubMed1984

[Prolonged remission in a patient with chronic myelocytic leukemia (CML) by methyl 6-[3-(2-chloroethyl)-3-deoxy-alpha-D-glucopyranoside (MCNU)].

A 44-year-old woman with Ph1-positive CML achieved a complete remission following small doses of MCNU. She is still in remission after more than 18 months without maintenance therapy. Chromosomal analyses revealed Ph1 chromosomes in 100% of cells before the therapy, and a mosaic of Ph1-positive cells (74%) and negative cells (26%) after the therapy. Leukocyte alkaline phosphatase scores were low before the therapy and became normal after the therapy. MCNU seems to be an effective drug for treating CML producing prolonged remission with reappearance of Ph1-negative normal clones in the present case.

Adult↗

PubMed1981

Cytogenetic observations in chronic myeloid leukemia (CML) correlations of the cytogenetic findings with morphological cytochemical features of blast cells in various types of blastic phase.

Forty-nine cases of chronic myeloid leukemia have been investigated using cytogenic methods. Twenty-six patients were studied in chronic phase, twenty-three during the transformation of the disease. Out of the second group of the patients, nine were myeloid, five myelomonocytic, two promyelocytic, two megakaryoblastic and five lymphoid in their morphological and cytochemical appearance. Some correlation could be observed between the clinical, morphological, cytological and cytogenetic findings of different subgroups of the blastic phase in CML. The results demonstrate the divergent clonal evolution of transformed blast cells, and emphasize the importance of chromosome investigations -- in addition to the early diagnosis of metamorphosis -- in distinguishing the different subgroups of the terminal stage of CML.

Adult↗

PubMed1982

Clonal evolution of karyotype in blastic phase of CML.

A patient with chronic myelocytic leukemia (CML) had a Philadelphia chromosome--Ph1(t(9q +; 22q--)) in all evaluated bone marrow cells at the time of diagnosis. After 29 months of intermittent therapy (chemotherapy and immunotherapy) and 2 months before clinical signs of blastic phase developed, three additional cell lines in bone marrow and peripheral blood appeared: one line with extra chromosome Ph1, another one in which chromosome Y disappeared, and the third line with extra chromosome No. 13, evidently derived from the X-monosomie cell line. Five weeks before death a variable hypodiploidy was found in more than 50% mitoses. The patient died 47 months after the establishment of CML and seven months after the onset of the blastic phase.

Chromosome Aberrations↗

PubMed1993

Methylation of the major breakpoint cluster region (M-bcr) in Philadelphia-positive CML.

It has previously been shown that a cluster of HpaII sites with the potential to be methylated exist around exon b3 of the M-bcr region involved in the formation of the Philadelphia chromosome in chronic myeloid leukemia (CML). The degree of hypermethylation of these sites can be directly correlated with the percentage of immature cells, whilst progressive hypomethylation occurs during the maturation of the granulocyte lineage. We have examined samples obtained from CML patients at diagnosis, during chronic phase, and blast crisis to examine the degree of methylation of this region in the non-rearranged BCR gene and the rearranged BCR-ABL gene. A low degree of methylation of the non-rearranged gene, similar to that observed in normal individuals, was observed in diagnosis and chronic phase samples. Increased methylation was observed during blast crisis indicative of the presence of immature cells in the samples. In contrast, a significantly lower degree of methylation was observed in the rearranged BCR-ABL gene at the onset of blast crisis. Division of the samples into those patients who had lost exon b3 during the formation of the BCR/ABL gene and those that had retained exon b3 produced differing patterns of methylation during disease progression. The former group, who also expressed a b2-a2 mRNA, showed an increase in methylation of the non-rearranged BCR gene prior to and during blast crisis, with a inverse decrease in the methylation of the BCR/ABL gene. Those patients who had retained exon b3, and expressed a b3-a2 mRNA, showed no change in the extent of methylation of the BCR/ABL gene but did exhibit an increase in methylation of the BCR gene during blast crisis. The consequence of the differing degree of methylation during disease progression could affect, to some extent, the specificity of protein binding or RNA expression.

Chromosomes, Human, Pair 22↗

PubMed1994

Mobilisation of Ph-negative peripheral blood stem cells in CML with idarubicin and cytarabine.

Recent interest in autologous transplantation in chronic myeloid leukaemia (CML) has focused on attempts to select out putatively normal Ph-negative progenitor cells for subsequent reinfusion after high dose therapy. One way in which this may be achieved is by collecting peripheral blood stem cells (PBSCs) during the early regenerative phase following chemotherapy when Ph-negative cells seem to have a short term proliferative advantage. Data now suggest that it is possible to collect Ph-negative (and occasionally PCR negative) progenitor cells in a significant number of CML patients, a proportion of whom will go on to achieve a cytogenetic remission post-autografting. The durability of these remissions and the effect on long term survival remain to be established and at present this form of therapy should be reserved for those unsuitable for allogeneic transplantation who have failed to achieve a major cytogenetic response to interferon-alpha.

Cell Separation↗

PubMed1994

The HLA class I-CML association revisited taking into account the two forms of gene fusion in the Philadelphia chromosome. A multicenter study.

CML patients possess either a b3-a2 or a b2-a2 fusion between the BCR and ABL genes. Depending on the type of fusion, two different series of non-self potentially immunogenic peptides may be produced. If they are presented by HLA class I molecules and recognized by cytotoxic CD8 lymphocytes, individuals could be more susceptible or resistant to leukemic cells bearing one or the other form of fusion according to their HLA class I phenotype. To test this point, the frequencies of HLA-A and HLA-B alleles were compared between b3-a2 and the b2-a2 CML patients. In essence, no difference was found whose significance could withstand correction for multiple comparisons.

Base Sequence↗