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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↗
PubMed1983

Chronic myelocytic leukaemia: cytogenetical studies on haemopoietic colonies and diffusion chamber cultures.

In 20 patients with chronic myelocytic leukaemia in the chronic phase or in blast crisis, several in vitro (CFU-C, BFU-E) and in vivo (diffusion chamber) culture techniques were used to demonstrate the existence of a still diploid cell clone. In 4 out of 12 patients in the chronic phase, Ph1-negative metaphases were found in the various cultures for haemopoietic progenitor cells but not in the standard suspension cultures used for cytogenetics. However, all the 8 patients investigated during blast crisis had only Ph1-positive and other abnormal clones, indicating the loss of the diploid clone during progression of the disease.

Acute Disease↗
PubMed1994

Antisense oligodeoxynucleotides for IL-2, c-myc and transferrin receptor synchronize mitogen-activated lymphocytes in the G1 phase.

In order to clarify the role and interrelationship of c-myc, interleukin-2 (IL-2), and transferrin receptor (TfR) expressions on PHA-stimulated lymphocyte proliferation, we examined the effects of antisense oligodeoxynucleotides directed against c-myc, TfR, and IL-2 mRNAs on DNA synthesis and cell-cycle phase. Exposure of PHA-stimulated lymphocytes to each antisense oligomer resulted in approximately 75-80% inhibition of DNA synthesis. TfR expression was not inhibited in PHA-stimulated lymphocytes by c-myc or IL-2 antisense oligonucleotides, suggesting that the expression of c-myc, TfR, and of IL-2 is regulated by an independent mechanism. All three antisense oligonucleotides for c-myc, TfR and IL-2 synchronized mitogen-activated lymphocytes to the G1 phase as assessed by morphologic blast formation and cell-cycle phase analysis.

Base Sequence↗
PubMed1979

Megakaryoblastic leukaemia (acute myelofibrosis): a report of three cases.

Three patients with megakaryoblastic leukaemia are described. All three presented with pancytopenia, a few blast cells in the peripheral blood and absence of overt hepatosplenomegaly. In two of them bone marrow aspiration yielded a dry tap. Histological investigation of the bone marrow indicated that the megakaryocytic cell line was the dominant proliferating lineage. Cytochemical and EM investigation supported these findings. The isomorphic isoenzyme pattern of the elevated serum lactic dehydrogenase might be of diagnostic importance. Despite chemotherapy, there was a rapidly fatal terminal leukaemic phase with high blast cell counts. The differentiation from other haematological malignancies, especially acute (aleukaemic) leukaemias and the accelerated phase of primary (chronic) myelofibrosis, is discussed. The picture appears to be identical with acute (malignant) myelofibrosis.

Acute Disease↗
PubMed2006

Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias.

BACKGROUND: The BCR-ABL tyrosine kinase inhibitor imatinib is effective in Philadelphia chromosome-positive (Ph-positive) leukemias, but relapse occurs, mainly as a result of the outgrowth of leukemic subclones with imatinib-resistant BCR-ABL mutations. We evaluated dasatinib, a BCR-ABL inhibitor that targets most imatinib-resistant BCR-ABL mutations, in patients with chronic myelogenous leukemia (CML) or Ph-positive acute lymphoblastic leukemia (ALL). METHODS: Patients with various phases of CML or with Ph-positive ALL who could not tolerate or were resistant to imatinib were enrolled in a phase 1 dose-escalation study. Dasatinib (15 to 240 mg per day) was administered orally in four-week treatment cycles, once or twice daily. RESULTS: A complete hematologic response was achieved in 37 of 40 patients with chronic-phase CML, and major hematologic responses were seen in 31 of 44 patients with accelerated-phase CML, CML with blast crisis, or Ph-positive ALL. In these two phases, the rates of major cytogenetic response were 45 percent and 25 percent, respectively. Responses were maintained in 95 percent of patients with chronic-phase disease and in 82 percent of patients with accelerated-phase disease, with a median follow-up more than 12 months and 5 months, respectively. Nearly all patients with lymphoid blast crisis and Ph-positive ALL had a relapse within six months. Responses occurred among all BCR-ABL genotypes, with the exception of the T315I mutation, which confers resistance to both dasatinib and imatinib in vitro. Myelosuppression was common but not dose-limiting. CONCLUSIONS: Dasatinib induces hematologic and cytogenetic responses in patients with CML or Ph-positive ALL who cannot tolerate or are resistant to imatinib. (ClinicalTrials.gov number, NCT00064233 [ClinicalTrials.gov].).

Adolescent↗
PubMed1969

Reentry of nondividing leukemic cells into a proliferative phase in acute childhood leukemia.

Reentry of small leukemic blast cells into a proliferative phase was demonstrated in a 3 yr old girl with untreated acute lymphoblastic leukemia. Since the proliferating leukemic cell compartment in this disease is not self-maintaining, continual entry of cells into this compartment is necessary to prevent depletion of proliferating cells. In order to identify the source of replacement cells, the rate of change of tritiated thymidine-labeled cells in the proliferating compartment was observed by means of serial bone marrow samples under two conditions. In the first study period only 10% of small leukemic blast cells were labeled, and in the second study period 72% of this population had become lebeled. During the first period the proliferating blast cells were rapidly replaced by unlabeled cells, while during the second period the replacement cells were coming largely from a labeled cell source. The only identifiable source of cells for maintenance of the proliferating population which was virtually unlabeled during the first period and largely labeled during the second period was the population of small leukemic blast cells. The finding that the small blast cells are only temporarily nonproliferative could account for effectiveness of therapy directed primarily against a dividing cell population. Persistence of some cells with longer resting times into remission could provide a focus for subsequent relapse.

Bone Marrow↗
PubMedDate not supplied

Involvement of Akt kinase in the action of STI571 on chronic myelogenous leukemia cells.

To elucidate the role of mitogen-activated protein kinases (MAPKs) and Akt kinase in leukemogenesis caused by the breakpoint cluster region (BCR)-Abelson (ABL) tyrosine kinase oncoprotein, we examined the activities of MAPKs and Akt kinase and their roles in the action of STI571, a specific inhibitor of BCR-ABL tyrosine kinase, in chronic myelogenous leukemia (CML) cells. We found that extracellular signal-regulated kinase (ERK) 1/2 and Akt kinase are constitutively active in the chronic phase of CML, blast crisis of CML, and the CML-derived K562 cell line. Both interferon-alpha and STI571 suppressed ERK1/2 activity in K562 cells. In contrast, Akt kinase activity was inhibited only by STI571. K562 cell proliferation was markedly suppressed by LY294002, a specific inhibitor of PI3K/Akt kinase, and STI571 but not by PD98059, a specific inhibitor of MEK1/2. In addition, caspase-3 was activated by treatment of cells with STI571 and LY294002 but not with PD98059. These data indicate that Akt kinase may play a role in the proliferation of CML leukemia cells and the action of STI571. Primary leukemia cells from patients with CML blast crisis did not show inhibition of ERK1/2 or Akt kinase activity and were resistant to caspase-3-associated apoptosis after treatment with STI571. These findings suggest that STI571 does not effectively block signaling molecules downstream of the BCR-ABL tyrosine kinase in some cases of CML blast crisis.

Adult↗
PubMed1997

Chronic eosinophilic leukaemia (CEL): a distinct myeloproliferative disease.

Chronic eosinophilic leukaemia has not yet been clearly defined, mainly due to the fact that it has not been conclusively shown as a monoclonal disease which should be separated from chronic myelogenous leukaemia, acute myelogenous leukaemia with eosinophilia (AML, FAB M4Eo), and the idiopathic hypereosinophilic syndrome. We report a patient with a white blood cell count of 17.6 x 10(9)/l with 74% eosinophils, normal platelet count and haemoglobin. No blasts were seen in the peripheral blood and the percentage of blasts in the bone marrow was < 3%. A diagnosis of chronic eosinophilic leukaemia was made. Chromosome analysis of a bone marrow aspirate disclosed a trisomy 15 together with loss of the Y chromosome. Moreover, FISH analysis on May-Grünwald-Giemsa-stained peripheral blood smears demonstrated trisomy 15 in the eosinophils. 3 months after initial diagnosis the patient went into blast crisis and died. The blast cells exhibited trisomy 15 and loss of the Y chromosome in a complex, aberrant karyotype. In conclusion, the case shows that chronic eosinophilic leukaemia is a monoclonal, myeloproliferative disease with eosinophils as part of the malignant clone. Clinically, chronic eosinophilic leukaemia can be separated into a chronic phase and a blast crisis.

Blast Crisis↗
PubMed1990

Chromosome and bcr rearrangement in chronic myelogenous leukaemia and their correlation with clinical states and prognosis of the disease.

Among 77 unselected patients with chronic myelogenous leukaemia (CML), 70 had Philadelphia chromosome (Ph1) in blood cells. Extra chromosomal abnormalities were noted in 4%, 55% and 78% of Ph1-positive patients in chronic phase, accelerated phase and acute blast crisis, respectively. Rearrangement of the bcr was detected in 46 of 47 Ph1-positive patients studied and also in three of five Ph1-negative ones. The locations of the breakpoints were mapped to one of four zones of the bcr in 45 patients. The median duration from diagnosis of CML to onset of acute blast crisis was not significantly different between the two groups of patients with breakpoints in the 5' portion (34 months), and in the 3' portion (39 months) of the bcr. In addition, the locations of the breakpoints within the bcr did not change as the disease progressed in the six patients who had DNA analysed both in the chronic phase and subsequently in transformation. In one of them, an additional aberrant band which was not present in the beginning of the acute phase was detected in blood cells taken 2 months later. It is suggested from the studies that transformation of CML may not be related to alterations within the bcr.

Adolescent↗
PubMed2002

Acquired gain of an X chromosome as the sole abnormality in the blast crisis of chronic neutrophilic leukemia.

Chronic neutrophilic leukemia (CNL) is a rare myeloproliferative disorder characterized by sustained neutrophilic leukocytosis and absence of the Philadelphia chromosome. Most patients with CNL have normal karyotypes, and no specific cytogenetic abnormality has been identified. We report here a patient with CNL that evolved to myeloid blast crisis. A 73-year-old man was admitted to the hospital because of marked leukocytosis (leukocyte count 112.5 x 10(9)/L with 91% segmented neutrophils) and massive hepatosplenomegaly that was diagnosed as CNL with a normal karyotype. After treatment with hydroxyurea for 7 months, the disease progressed to a blast crisis. Bone marrow showed myeloid hyperplasia with 21% myeloblasts, 15% promyelocytes, and marked dysplastic changes of neutrophils. Blastic cells were positive for CD10, CD13, CD14, CD33, CD34, and HLA-DR. Chromosome analysis of the bone marrow cells showed 46,XY,+X in all 20 metaphase spreads. We reviewed 15 cases of CNL terminating in the blast crisis and confirmed that all cases transformed into myeloid crises and had poor prognoses. Furthermore, to our knowledge, this is the first case showing the acquired gain of an extra X chromosome as a sole abnormality in CNL. The gain of an extra X chromosome may play an important role in the progression from chronic phase to the blast crisis of CNL.

Aged↗
PubMed2000

Blockade of the Bcr-Abl kinase activity induces apoptosis of chronic myelogenous leukemia cells by suppressing signal transducer and activator of transcription 5-dependent expression of Bcl-xL.

Bcr-Abl-expressing leukemic cells are highly resistant to apoptosis induced by chemotherapeutic drugs. Although a number of signaling molecules have been shown to be activated by the Bcr-Abl kinase, the antiapoptotic pathway triggered by this oncogene has not been elucidated. Here, we show that the interleukin 3-independent expression of the antiapoptotic protein, Bcl-xL, is induced by Bcr-Abl through activation of signal transducer and activator of transcription (Stat)5. Inhibition of the Bcr-Abl kinase activity in Bcr-Abl-expressing cell lines and CD34(+) cells from chronic myelogenous leukemia (CML) patients induces apoptosis by suppressing the capacity of Stat5 to interact with the bcl-x promoter. Interestingly, after inhibition of the Bcr-Abl kinase, the expression of Bcl-xL is downregulated more rapidly in chronic phase than in blast crisis CML cells, suggesting an involvement of this protein in disease progression. Overall, we describe a novel antiapoptotic pathway triggered by Bcr-Abl that may contribute to the resistance of CML cells to undergo apoptosis.

Apoptosis↗
PubMed1986

Megakaryoblastic transformation of myelofibrosis with expression of the c-sis oncogene.

We describe a case of primary myelofibrosis which terminated in an acute megakaryoblastic leukaemia with massive marrow fibrosis and osteosclerosis. The megakaryocyte lineage of the terminal phase was confirmed by ultrastructural and surface marker studies of the blast cells. The leukaemic phase was associated with the presence of large numbers of progressively more immature megakaryocyte progenitors in the peripheral blood. The expression of c-sis mRNA in these blast cells was significantly higher than in normal mononuclear cells. Activation of the c-sis protooncogene leading to increased production of platelet-derived growth factor could be related to the progressive fibrosis observed.

Adult↗
PubMed1973

Mode of action of chemotherapy in vivo on human acute leukemia. I. Daunomycin.

The leukocytes of 16 adult patients with acute myeloblastic leukemia were studied by autoradiographic methods to elucidate the mode of action of daunomycin. It was shown that daunomycin, at clinically useful doses, exhibits a cytolytic effect on all leukemic blasts whatever their cell-cycle phase. This cytolytic action affects, however, preferentially S-phase cells. It was shown also that blasts of patients less sensitive to daunomycin or receiving a lesser dose of the drug are temporarily blocked in G(2) phase (delayed mitosis) or in G(2) phase (prolonged generation time). Finally daunomycin appeared to hamper the passage of G(2)-blocked blasts from the bone marrow to the blood, while G(2)-phase cells crossed freely.

Autoradiography↗
PubMed1996

Induction of interferon regulatory factors 2'-5' oligoadenylate synthetase, P68 kinase and RNase L in chronic myelogenous leukaemia cells and its relationship to clinical responsiveness.

The genes crucially determining the therapeutic response of chronic myelogenous leukaemia (CML) to interferon-alpha (IFN-alpha) are unknown. Recently, two independent IFN-alpha signalling pathways were identified: the classic pathway mediates induction of 2'-5' oligoadenylate synthetase (2-5 OAS), p68 kinase and IFN regulatory factor-2 (IRF-2), whereas the alternate pathway leads to activation of IFN regulatory factor-1 (IRF-1). We investigated whether deficient or imbalanced expression of components of these two pathways is associated with resistance of CML cells to antiproliferative action of IFN alpha/beta. Constitutive and IFN-induced transcript levels of IFN-dependent genes in mononuclear cells, granulocytes, monocytes, lymphocytes and CD34+ cells of chronic-phase CML and blast crisis patients were assessed by Northern blot techniques and were correlated with subsequent clinical responses to IFN therapy. Our results demonstrated that IFN-alpha or -beta treatment in vitro and in vivo leads to an enhanced expression of IRF-1, IRF-2. RNase L, p68 and 2-5 OAS which was independent of the degree of cellular differentiation and clonal evolution of CML. Neither the magnitude of induction of these genes nor the IRF-1/IRF-2 mRNA balance differed between chronic-phase CML patients responding or failing IFN-alpha therapy. These results indicate that failure of IFN-alpha treatment is not due to defects in mRNA induction of the above-mentioned candidate genes for the direct antiproliferative response to IFN type I.

2',5'-Oligoadenylate Synthetase↗
PubMed1980

Cytokinetic changes in the peripheral blood of leukemic patients during cytostatic therapy. VI. Effect of arabinosylcytosine.

Flow and conventional DNA-cytofluorometry and in vitro tritiated thymidine cytoautoradiography were employed in the study of the cytokinetic changes induced by Ara-c on the peripheral blood blast cells of six patients with acute non-lymphoblastic leukemias. Nine courses of therapy were studied, in 5 of which Ara-c was administered in low pulse doses (20-60 mg/sqm) repeated every 12 hrs and in the other 4 it was administered in continuous infusion (90-150 mg/sqm) lasting 24 hrs. Low repeated pulse doses have little cytocidal effect and increase the 2n-4n cell percentage and, less markedly, the LI, while the median grain count is reduced. Many U-like cells and accumulation of 3H-TdR labeled blasts in early S phase were observed during therapy. The continuous infusion of Ara-c induces striking cytoreduction and concomitantly decreases the 2n-4n percentage and LI. Progressive recovery of 2n-4n percentage and LI over pretreatment values was observed 24-48 hrs after stopping infusion in one case and was probably due to cell recruitment following tumor mass reduction. Our data agree with the literature, which is briefly reviewed, in that they indicate that Ara-c in a low intravenous pulse frequently dose synchronizes the blasts in S phase while higher doses of the drug are more often cytocidal in S phase and cell recruitment can follow cytoreduction.

Adult↗
PubMed1985

Incidence of involvement of the B and T lymphocyte lineages in chronic myelogenous leukemia.

Peripheral blood specimens were obtained from 22 patients with Philadelphia chromosome (Ph1) positive chronic myelogenous leukemia (CML) (16 in chronic phase, 2 in an accelerated phase, and 4 in blast crisis). Studies were performed to determine the frequency of the presence of the Ph1 chromosome in cells of lymphoid lineages. Rosetted (E+) lymphocytes (T lymphocytes) from nine patients in chronic phase and one patient in blast crisis were stimulated with T cell growth factor interleukin 2 (IL-2) and/or phytohemagglutinin (PHA). All ten patients had sufficient T lymphocyte metaphases for analysis and of a total of 461 metaphases examined, only one contained the Ph1 chromosome. Nucleated cells of density less than 1.077 g/mL were infected with Epstein-Barr virus (EBV). Following infection, cell lines were established from individual colonies attached to egg albumin-coated Lab-Tek slide chambers (clonal cell lines) or from suspension culture in 96-well tissue culture cluster dishes (nonclonal cell lines). Cell surface and intracellular marker analysis confirmed the B lymphocyte phenotype of all the cell lines examined. B lymphoblastoid cell lines were established from 16 of the 22 patients. All lines from 12 patients were Ph1-negative. From two chronic phase patients, both Ph1-positive and Ph1-negative lines were established. From one patient in an accelerated phase, only Ph1-positive lines were established. From another patient in blast crisis (of myeloblastic phenotype), only Ph1-positive lines were established initially; however, five months later, after the patient had been treated with mitoxantrone, only Ph1-negative lines were derived from this patient. Based on these results, it appears that most B cells and mature T cells in most CML patients are Ph1-negative, but that about 25% of patients have predominantly Ph1-positive B cells or a mixture of Ph1-positive and Ph1-negative B cells that are capable of growing as established cell lines after transformation with EBV.

Adolescent↗
PubMed1993

[Chronic myeloid leukemia: cytogenetic and molecular study and its relationship with the disease course].

The aim of this study was to perform a cytogenetic and molecular study in patients with chronic myelogenous leukemia and to seek a possible relation between bcr gene break points and the clinical evolution of the disease. The cytogenetic study allowed to establish the presence of Ph chromosome and the molecular study localized the break point in bcr region of chromosome 22 using the Southern technique, hybridizing with bcr fragment derived probes bcr1 and bcr2. Forty eight patients were studied, 27 male (aged 46.5 years) and 21 female (aged 56). Forty seven patients were Ph +. A rearrangement in 3' bcr region was found in 25 patients and in 5' region in 23. During the follow up period 20 patients developed a blast crisis or accelerated phase. In 11 of these the rearrangement was in region'3 and their chronic phase lasted a mean of 33.1 months; in 9 the rearrangement was in region 5' and their chronic phase lasted 44.1 months. There were no differences in event-free survival between those with rearrangement in region 3' or 5', however these was a tendency towards a longer chronic phase duration in those with 5' breaks. The lack of correlation between the location of break points and the evolution of the disease may be due to a selection of patients with a better evolution and the exclusion of those with a rapid progression to blast crisis or accelerated phase.

Adult↗
PubMed1976

Significance of PHA induced clonogenic cells in chronic myeloid leukemia and early acute myeloid leukemia.

A technique for cloning myeloblastic leukemic cells in semi-solid agar, after prior PHA stimulation, was studied in all phases of chronic myeloid leukemia. Phytohemagglutinin responsive cells were found in blast crisis and accelerated phase. In a small number of patients in the benign phase of their disease, colony growth with PHA was detected. A group of patients with early acute leukemia was also examined by this technique. The incidence of PHA colonies appeared to correlate with the progression of the disease. The potential application of this assay for early detection of leukemic clones and possible prediction of the rapidity of progression of the leukemic process is discussed.

Bone Marrow↗