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PubMed1986

[Extramedullary manifestations of blast crisis in chronic myeloleukemia].

The paper is concerned with the development of extramedullary blast infiltrates in Ph-positive chronic myeloid leukemia. Two cases are described. In one case during the blastic phase lasting 27 months, a female patient developed by turn skin leukemids, lesions of the soft tissues in the knee joint, lesions of the stomach, lungs and heart. Administration of the treatment according to the "3 + 7" scheme (an anthracycline antibiotic plus cytosar) and to the TRAMPCOL scheme brought about the reverse development of the infiltrates. In the second case a male patient in the 12th year of the disease developed, in the absence of the blastic phase, massive blast lesions of the lymph nodes of the mediastinum followed by neuroleukemia. The lesions were removed by the treatment according to the ACOP scheme and endolumbal injections of methotrexate and cytosar. Ten months after diagnosing the enlargement of the lymph nodes of the mediastinum the picture of the blood and the bone marrow remained typical of the marked stage of the disease. The authors provide brief data on 27 patients with extramedullary blast infiltrates in the terminal stage of chronic myeloid leukemia together with short reported data.

Adult↗
PubMed1993

The methylation status of the major breakpoint cluster region in human leukemia cells, including Philadelphia chromosome-positive cells, is linked to the lineage of hematopoietic cells.

The Philadelphia (Ph) translocation [t(9;22)(q34;q11)] is the most common genetic abnormality in human leukemia; a transposition of the ABL gene to the major-breakpoint cluster region (M-BCR) is associated with the pathogenesis in Ph+ chronic myelogenous leukemia (Ph+ CML) and in some cases of Ph+ acute leukemia (Ph+ AL). Our current understanding of the methylation of human genomes allows us to consider the association between the epigenetic phenomenon and the control of differentiation and proliferation in mammalian cells. In order to determine whether the methylation status of the M-BCR is associated with breakpoint-localization in this region and with the lineage of hematopoietic cells, we have examined 28 patients with Ph+ leukemias, including nine with Ph+ AL, six patients with acute myeloblastic leukemia without Ph (Ph- AML), and five patients with Ph- acute lymphoblastic leukemia (Ph- ALL); using the restriction endonuclease isochizomers, MspI and HpaII. In CML patients in the chronic phase, the hypomethylated status within the normal M-BCR allele is heterogeneous. In contrast, patients with Ph+ CML in the lymphoid blast crisis phase exhibited a 2.5/2.7 kb band with a complete disappearance of the germline M-BCR fragment (type L). This pattern is consistently noted in Ph- ALL cells, and the pattern is quite different from that found in myeloid blast crisis or Ph- AML (type M). In patients with M-BCR-nonrearranged Ph+ ALL, it is suggested that the M-BCR methylation patterns are cell-lineage specific but some Ph+ ALL cells had a hypomethylation pattern that was identical to that observed in Ph- AML, suggesting a distinction of genetic diversity of leukemia cells with the Ph chromosome, especially Ph+ AL.

5-Methylcytosine↗
PubMed2005

Imatinib mesylate in chronic myeloid leukemia: a prospective, single arm, non-randomized study.

Chronic myeloid leukemia (CML) is a hematopoietic stem cell disorder characterized by the balanced reciprocal translocation t (9:22). The resulting fusion gene, the BCR-ABL, is responsible for oncogenesis. Imatinib mesylate is a novel molecule, which inhibits the protein product of this fusion gene and hence has been used in the treatment of CML. The present study evaluates 174 patients with CML treated with imatinib mesylate. Of these 174 patients, 97 were in chronic phase, 47 in accelerated phase and 30 patients had blast crisis. Patients in chronic phase received imatinib mesylate in the dose of 400-mg daily, while those in accelerated phase and blast crisis received 600 to 800 mg daily. Of the 97 patients with chronic phase, 49 patients (50.5%) achieved a major (major + complete) cytogenetic response. Of the 47 patients in accelerated phase, 10 patients (21.3%) achieved a major cytogenetic response and in 30 patients with blast crisis, 7 (23.3%) achieved a major cytogenetic response. Dermatitis, mucositis, neutropenia and thrombocytopenia were some of the major toxicities. Of interest, 121 of the 174 patients (69.5%) developed generalized hypopigmentation. We conclude that imatinib mesylate is a safe and effective first-line therapy for chronic myeloid leukemia.

Adolescent↗
PubMed1992

Frequent p53 gene mutations in blast crisis of chronic myelogenous leukemia, especially in myeloid crisis harboring loss of a chromosome 17p.

We investigated chromosome alterations and mutations of the p53 gene in 118 samples from 92 patients with chronic myelogenous leukemia in various clinical phases, i.e., chronic phase, accelerated phase, and blast crisis (BC). Single-strand conformation polymorphism analysis and subsequent nucleotide sequencing disclosed no alteration of the p53 gene in chronic phase (no mutation in 80 samples), while five of 31 BC samples showed point mutations: four in myeloid and one in lymphoid crisis. One of seven accelerated phase samples also showed a p53 gene mutation. Ten of 31 BC samples showed loss of one of the short arms of chromosome 17 (17p) through the formation of isochromosome 17q, i(17q), or unbalanced translocations. Loss of heterozygosity at the p53 locus in the accelerated phase and BC was detected only in two cases with i(17q) but not in seven cases with normal chromosome 17 homologues, suggesting that loss of one p53 allele is rare without cytogenetically detectable loss of a 17p. Among those six samples with p53 gene mutations, five showed loss of a 17p cytogenetically, and only one lymphoid crisis case exhibited normal chromosome 17 homologues. Thus, mutations of the p53 gene were closely associated with myeloid crisis with loss of a 17p (four mutations in ten samples), in contrast to myeloid crisis with normal chromosome 17 homologues (zero in 13) or lymphoid crisis (one in seven). Our results also suggest that alterations of the p53 gene might occur after loss of a 17p during the course of chronic myelogenous leukemia.

Adult↗
PubMed2004

[Therapeutic efficacy of hematopoietic stem cell transplantation in patients with chronic myelogenous leukemia].

OBJECTIVE: To evaluate the clineffects of autologous and allogeneic hematopoietic stem cell transplantation (HSCT) for chronic myelogenous leukemia (CML). METHODS: Fifty-seven patients with CML were treated by HSCT, including 8 patients treated with autologous transplantation in vivo and vitro purging minimal residual disease (MRD), 39 with related donor allogeneic HSCT (allo-HSCT), and 10 with unrelated donor allo-HSCT. For the conditioning regimen, total-body irradiation with cyclophosphamide (CTX) was given in 32 patients, modified BuCY protocol (hydroxyurea, busulfan, Ara-C, CTX) in 24 patients, and MACC protocol (melphalan, Ara-C, CTX and lomustine) in one patient. Cyclosporine (CsA) and methotrexate (MTX) were used in patients with related donor allo-HSCT, and the combination of CsA, MTX , mycophenolate mofetil (MMF), and antithymocyte globulin (ATG) in unrelated donor all-HSCT to prevent graft versus host disease (GVHD). Kaplan-Meier survival analysis model was used to estimate the overall survival and the disease-free survival (DFS) at 5 years after transplantation. RESULTS: In 8 patients with autologous transplantation, 7 obtained partial or complete cytogenetic remission (CR) within 3 months after transplantation and one died of transplantation-related complication. In 49 patients with allo-HSCT transplantation, all patients obtained CR except for two patients, one of whom failed to obtain CR and the other died of hepatic veno-occlusive disease. The incidence of infection and veno-occlusive disease during transplantation was 33.3% and 7.0%, respectively. The incidence of hemorrhagic cystitis and cytomegalovirus interstitial pneumonia after transplantation was 22.8% and 8.8%, respectively. Veno-occlusive disease, hemorrhagic cystitis or cytomegalovirus interstitial pneumonia did not occur in patients with autologous transplantation. The incidence of acute GVHD was 41.0% and 48.6%, and that of chronic GVHD 40.0% and 42.9% in patients with related and unrelated transplantation, respectively. The rate of relapse was 57.1% and 12.8%, with DFS at 5 years of 25.0% and 61.7%, respectively, in patients with autologous and related donor transplantation. The DFS at 5 years was 70.7% and 34.1%, respectively, in patients with chronic/accelerated phases and blast crisis be fore trans plantation. CONCLUSION: allo-HSCT can produce a higher clinical cure rate in CML patients in chronic phase CsA+MTX+MMF+ ATG protocol is more effective for prevention and alleviation of acute GVHD in patients with unrelated donor transplantation. Autologous transplantation with bone marrow purging helps prolong the patients' survival and even obtain clinical cure of CML.

Adolescent↗
PubMed2005

Quantitative RT-PCR of Wilms tumor gene transcripts (WT1) for the molecular monitoring of patients with accelerated phase bcr/abl + CML.

The tyrosine kinase inhibitor imatinib inhibits the activity of the bcr/abl fusion protein present in patients with chronic myeloid leukemia. Although in chronic phase patients response to therapy can be monitored by quantitative RT-PCR for bcr/abl mRNA transcripts, in advanced disease (accelerated phase or blast crisis) only few patients respond on a molecular level. We investigated Wilms tumor gene (WT1) and bcr/abl mRNA transcripts in 16 accelerated phase CML patients by quantitative real time PCR. In contrast to the bcr/abl mRNA levels the WT1 mRNA levels were indicative for hematologic relapse (n = 6) versus response (n = 10).

Antineoplastic Agents↗
PubMed1998

Phase II study of carboplatin in blast crisis of chronic myeloid leukemia: Eastern Cooperative Oncology Group Study E1992.

This study was a phase II evaluation of the activity of carboplatin in patients with Philadelphia chromosome positive accelerated or blastic phase of CML. Carboplatin, 250 mg/m2/day as an intravenous continuous infusion was given for 5 days, for a total dose of 1250 mg/m2 per course. If necessary, a second induction course could be given, and patients achieving complete remission were to receive an additional consolidation cycle at the same dose. Thirty-six patients were eligible and evaluable. There were five complete and three partial remissions for an overall response rate of 22% (95% CI 10.1-39.1%). The complete remission rate was 13.9% (95% CI 4.7-29.9%). The median remission duration was 3 months (range 1.4-8.94 months) and the median survival on study for all patients was 3.5 months (95% CI, 2.4-11.4 months). The median survival of responders was 12.8 months (95% CI, 3.6-17.2 months). Three eligible patients survived 2.0, 2.5 and 3.5 years following carboplatin therapy. Carboplatin has activity in blast crisis of CML, but responses are brief. Response did allow one patient to proceed to bone marrow transplantation and two other patients to continue therapy for chronic phase disease before returning to blast crisis. Activity in combination regimens should be explored.

Adult↗
PubMed1989

[Parameters of granulocyte proliferation in chronic myeloid leukemia and their prognostic value].

A total of 112 patients with chronic myeloid leukemia were examined over time for the parameters of the proliferation of bone marrow and peripheral blood granulocytes. In the phase of blast crisis, the bone marrow demonstrated a significant rise of the portion of the G2 cells and of the mitotic index. The portion of the cells undergoing DNA synthesis in the chronic phase of the disease was not dependent on its duration. The parameters such as the mitotic index and the portion of the G2 cells in the bone marrow as well as the percentage of the cells in the S-phase in the peripheral blood correlated negatively with the patients' survival.

Adolescent↗
PubMed2001

NUP98 gene rearrangements and the clonal evolution of chronic myelogenous leukemia.

The role of the BCR-ABL fusion gene in the pathogenesis of the chronic phase of chronic myelogenous leukemia (CML) has been well established. Several additional genetic changes have been reported to occur, at varying frequencies, during disease progression to "accelerated" and "blast crisis" phases. The NUP98 gene localized to chromosome band 11p15 has been found at the breakpoints of several distinct chromosomal translocations in patients with both de novo and therapy-related myelodysplastic syndromes (MDS) and acute myelogenous leukemia (AML). Using combined cytogenetic and molecular analyses, we have found rearrangements of the NUP98 gene in the leukemic cells of two patients with Philadelphia chromosome-positive CML, during disease evolution. As expected, analysis of the t(7;11)(p15;p15) from one of the patients showed an in-frame NUP98-HOXA9 fusion. The fusion points were similar to previously reported NUP98-HOXA9 fusion points from patients with MDS/AML. Our results indicate that the NUP98 gene is an additional, albeit infrequent, genetic target during clonal evolution of CML.

Chromosome Breakage↗
PubMed1987

CML patients in blast crisis have breakpoints localized to a specific region of the BCR.

Chronic myelogenous leukemia (CML) is associated with the Philadelphia (Ph) chromosome, which results from a reciprocal translocation between chromosomes 9 and 22. This activates the abl oncogene by moving it from chromosome 9 and combining it with sequence located on chromosome 22. The new fusion gene, with chromosome 22 sequence at its 5' end and chromosome 9-abl sequence at its 3' end, generates a new messenger RNA (mRNA) and protein that are implicated in the pathogenesis of CML. The breakpoint near the c-abl locus on chromosome 9 can occur within a large area. In contrast, the breakpoints on chromosome 22 are concentrated within a 6 kilobase (kb) region termed the breakpoint cluster region (bcr). This study was designed to determine whether chronic-phase and blast crisis patients had identifiable differences in the structure of their Ph chromosomes. Restriction mapping of the chromosome 22 translocation breakpoints performed for 26 patients showed that the breakpoints of eight of the nine patients in blast crisis were in the 3' portion of the bcr, whereas the breakpoints in the 17 patients in the chronic phase were clustered in the 5' portion of the bcr. This suggests a strong correlation between a 3' bcr breakpoint and blast crisis in CML.

Blast Crisis↗
PubMed2002

The usefulness of monitoring WT1 gene transcripts for the prediction and management of relapse following allogeneic stem cell transplantation in acute type leukemia.

In acute-type leukemia, no method for the prediction of relapse following allogeneic stem cell transplantation based on minimal residual disease (MRD) levels is established yet. In the present study, MRD in 72 cases of allogeneic transplantation for acute myeloid leukemia, acute lymphoid leukemia, and chronic myeloid leukemia (accelerated phase or blast crisis) was monitored frequently by quantitating the transcript of WT1 gene, a "panleukemic MRD marker," using reverse transcriptase-polymerase chain reaction. Based on the negativity of expression of chimeric genes, the background level of WT1 transcripts in bone marrow following allogeneic transplantation was significantly decreased compared with the level in healthy volunteers. The probability of relapse occurring within 40 days significantly increased step-by-step according to the increase in WT1 expression level (100% for 1.0 x 10(-2)-5.0 x 10(-2), 44.4% for 4.0 x 10(-3)-1.0 x 10(-2), 10.2% for 4.0 x 10(-4)-4.0 x 10(-3), and 0.8% for < 4.0 x 10(-4)) when WT1 level in K562 was defined as 1.0). WT1 levels in patients having relapse increased exponentially with a constant doubling time. The doubling time of the WT1 level in patients for whom the discontinuation of immunosuppressive agents or donor leukocyte infusion was effective was significantly longer than that for patients in whom it was not (P <.05). No patients with a short doubling time of WT1 transcripts (< 13 days) responded to these immunomodulation therapies. These findings strongly suggest that the WT1 assay is very useful for the prediction and management of relapse following allogeneic stem cell transplantation regardless of the presence of chimeric gene markers.

Acute Disease↗
PubMed1991

Blast crisis in a murine model of chronic myelogenous leukemia.

The P210bcr/abl protein is produced in cells from patients with Philadelphia chromosome-positive chronic myelogenous leukemia (CML). Retroviral transfer of the gene encoding P210bcr/abl into murine bone marrow induces a granulocytic leukemia that models the chronic phase of human CML. We have transferred the leukemic clone to syngeneic animals, albeit with surprising inefficiency, and have observed CML and clonally related acute leukemias of lymphoid or myeloid phenotype in some transplant recipients. These data show that murine CML can result from retroviral transfer of the bcr/abl gene into pluripotent hematopoietic stem cells, that infected clones repopulate poorly after adoptive transfer, and that these clones can give rise to acute leukemia, reflecting evolution to a phase resembling blast crisis in the human disease.

Animals↗
PubMedDate not supplied

[Certain biochemical features of leukocytes in blast crisis of chronic myelogenous leukemia].

The content of nuclear high mobility group (HMG) proteins, activities of ornithine decarboxylase (ODC), adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP) and also glycosaminoglycan (GAG) content and composition were studied in leukocytes of patients with chronic myelogenous leukemia in the phase of blast crisis (BC CML). Myeloid and lymphoid cytochemical variants of BC CML differ by biochemical parameters. It is suggested, that the content of HMG-proteins, activities of ODC and PNP, and electrophoretic patterns of GAGs could be used in diagnostics of two main variants of BC CML.

Blast Crisis↗
PubMedDate not supplied

Tyrosine kinase inhibitors: a cure for chronic myeloid leukemia?

Chronic myeloid leukemia (CML), a malignant transformation of hematopoietic cells, accounts for one-fifth of all leukemias and will be diagnosed in 4,400 individuals in the United States this year. CML has three phases: chronic, accelerated, and blastic. Interferon, hydroxyurea, busulfan, and bone marrow and stem cell transplantation are used to treat CML, but individuals who are in the accelerated phases or blast crisis usually respond poorly to treatment. A new tyrosine kinase inhibitor, STI 571, is being evaluated in clinical trials. STI 571 is highly bioavailable in oral form and produced minimal toxicities in phase I studies. Further research is needed to determine the rate of response and survival data, but STI 571 holds great promise in the treatment of CML.

Benzamides↗
PubMed2002

A case of biphenotypic blast crisis of unclassified myeloproliferative disorder.

We report a first case of biphenotypic blast crisis of unclassified myeloproliferative disorder (MPD). A 20-year-old patient presented with fever, splenomegaly, marked leukocytosis (603 x 10(3)/ micro l), and blasts in the peripheral blood. Since Ph chromosome and bcr-abl gene rearrangement were absent, the diagnosis of an unclassified MPD in the blast crisis phase was established. Immunophenotyping confirmed a biphenotypic crisis of myeloid and T-lymphoid antigens. The patient went into a complete remission after chemotherapy, but marked granulocytic hyperplasia (M:E ratio of 5.7) and 90% cellularity remained. Blast crisis recurred during subsequent intensification chemotherapy and the patient did not go into a complete remission regardless of the intense chemotherapy. The blast crisis transformed from unclassified MPD had a grave prognosis as it responded poorly to chemotherapy. This unique blast crisis is distinguishable from the blast crisis of chronic myelogenous leukemia.

Adult↗
PubMed2005

Survivin expression in the progression of chronic myeloid leukemia: a sequential study in 16 patients.

An increase in the proliferation and resistance to apoptosis of leukemic cells has been found in chronic myeloid leukemia (CML) as the disease evolves from the chronic phase to blast crisis (BC). To contribute to a better knowledge of the molecular mechanisms involved in such biological abnormality, the expression of the survivin gene was studied by quantitative real-time polymerase chain reaction (PCR) in the chronic phase of CML and at BC in 16 patients in whom sequential RNA samples from the 2 phases of the disease were available. Survivin was significantly overexpressed in both the chronic phase and BC as compared with granulocytes from controls. In BC, survivin expression was 7-fold higher than in the chronic phase, with such an increase being more pronounced in the myeloid (17-fold) than in the lymphoid cases (3-fold) (P = 0.03). Cell proliferation was significantly increased at BC, with Ki-67 expression being 2.8-fold higher than in the chronic phase. Despite the overexpression of both survivin and Ki-67 at BC, no significant correlation between their expression levels was observed. These data support a possible role for survivin overexpression in the pathogenesis of the progression of CML. However, further studies are required to elucidate the possible prognostic importance of such biological findings in this disease.

Adolescent↗
PubMed2000

A successful cord blood transplant in a child with second accelerated phase chronic myeloid leukemia following lymphoid blast crisis.

We describe a 5-year-old girl with Ph(+) CML who received a cord blood transplant in a second accelerated phase after a very early lymphoid blast crisis. She was induced into CR by ALL-directed chemotherapy and then maintained with IFN-alpha2b together with weekly rotational chemotherapy. Nineteen months after diagnosis, her mother gave birth to an HLA-compatible sibling, whose cord blood was cryopreserved. The patient's second acceleration occurred 22 months after the CML diagnosis. The subsequent conditioning regimen included busulfan 16 mg/kg, Ara-C 12 g/m2 and melphalan 140 mg/m2. In order to prevent GVHD, CsA alone was administered, 3 mg/kg i.v. per day for a total of 40 days. The total number of nucleated cells infused was 0.8 x 108/kg, with CD34+ cells 1.8 x 106/kg and CFU-GM 1 x 104/kg. Engraftment occurred on day +35. Respiratory distress, severe VOD and grade II acute gastrointestinal GVHD complicated the post-transplant period. No chronic GVHD occurred. The girl is alive 23 months after transplantation with complete donor chimerism; both Ph chromosome and bcr/abl RNA are negative. Bone Marrow Transplantation (2000) 25, 213-215.

Antineoplastic Combined Chemotherapy Protocols↗