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PubMed1993

Detection of residual proliferating leukemic cells by fluorescence in situ hybridization in CML patients in complete remission after interferon treatment.

Interferon-alpha produces a complete hematologic and cytogenetic remission in approximately 20% of patients with chronic myelogenous leukemia (CML). In this study, we applied fluorescent in situ hybridization (FISH) methodology to examine the possibility that a low level of proliferating Philadelphia-chromosome-positive (Ph+) cells may be present in interferon-treated CML patients who have achieved complete cytogenetic remission (as defined by the absence of Ph chromosome in 20-25 metaphases analyzed). Ten such patients in remission for 6-35 months were studied by this technique, in which a chromosome-22-specific DNA painting probe was used to detect leukemic cells with the characteristic 9;22 chromosomal translocation. In six of the 10 patients (60%), 3-9% Ph+ metaphases were detected. No Ph+ cells were observed in nine control individuals. Thus, this study demonstrates that FISH technology is more sensitive than conventional cytogenetic analysis for the detection of minimal residual disease in CML.

Cell Division↗

PubMed1993

Autologous transplant for CML revisited.

A chronic myelogenous leukemia (CML)-like disease can be induced in mice by infecting hematopoietic stem cells with a BCR/ABL-containing retrovirus; serial transplantation produces either normal or leukemic animals. In many patients with CML, autografting produces transient Philadelphia chromosome (Ph)-negativity, but Ph-negative hematopoiesis is prolonged in some cases. These and other observations suggest that at diagnosis, CML patients may have substantial numbers of normal stem cells in their marrow, which may in certain circumstances regain a proliferative advantage if leukemic hematopoiesis can be suppressed by intensive chemotherapy. Thus autografting may have the capacity to restore normal hematopoiesis for long periods in patients not eligible for treatment by allogeneic bone marrow transplantation.

Animals↗

PubMed1996

Intensive combination chemotherapy in treatment of CML.

Tumor load reduction has an influence on survival of patients in the chronic phase of chronic myelogenous leukemia (CML). This comprises both reduction of white blood cell (WBC) mass and reduction of the Philadelphia (Ph)-positive clone. Besides drug monotherapy, intensive combination chemotherapy is also very effective in reducing tumor burden in the chronic phase of CML. Therapeutic concepts consisting of combination chemotherapy include intensive chemotherapy alone or in combination with interferon-alpha (IFN-alpha) and preparative regimens before autografting or allografting. All these concepts demonstrate the effectiveness of this treatment form. The high toxicity of combination chemotherapy does not justify its application in unselected patients. However, in suitable patients, possibly in poor interferon-alpha responders (as carried out in the current German CML study) it might be superior with regard to survival.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1996

Interferon therapy, but not busulfan restores normal-sized megakaryopoiesis in CML--a comparative histo- and immunomorphometric study.

To assess possible alterations of megakaryocytes associated with interferon (IFN) and busulfan (BU) therapy of Ph(1+)-CML, an immunohistochemical and morphometric study was performed on trephine biopsies of the bone marrow taken before and at varying intervals during treatment. For the identification of megakaryopoiesis and its endoreduplicative activity the monoclonal antibodies CD61 (anti-platelet glycoprotein IIIa) and PC10 raised against proliferating cell nuclear antigen (PCNA) were used. We compared 60 specimens from 20 patients following IFN alpha-2b administration (in combination with IFN gamma in seven patients) with 57 specimens from 22 patients after monotherapy with BU. A close correlation with clinical follow-up studies revealed that in the IFN-treated group the prevalence of atypical micro-megakaryocytes, usually characterizing CML, was conspicuously reduced in repeatedly taken bone marrow samples. Initially, even an increase in size which was levelled to normal values during maintenance therapy was observed. These features were most prominently expressed in the 13 patients with a complete hematologic and/or partial cytogenetic response. Associated with this phenomenon was a significant enhancement of the PCNA-labelling index which indicated a stimulation of endoreduplicative (endomitotic) activity necessary for achieving normal size and ploidy. In the second group of patients treated by BU these changes were absent. For this reason, our findings are in keeping with the assumption that during IFN treatment, there is at least partial recovery and expansion of a putative normal (Ph1-) megakaryopoiesis. In conclusion, megakaryocyte morphology, i.e. normalization in size, is thought to be a useful indicator to evaluate the response to IFN in CML patients.

Adult↗

PubMedDate not supplied

Tiazofurin effects on IMP-dehydrogenase activity and expression in the leukemia cells of patients with CML blast crisis.

Tricot et al have reported that the nucleoside analog tiazofurin can induce hematologic remissions in patients with chronic myelogenous leukemia in blast crisis (CML-BC). These reports prompted us to begin a derivative, phase II trial of tiazofurin in CML-BC to determine if the promising findings reported by these investigators could be reproduced. In our ongoing trial patients receive tiazofurin by IV infusion (2200-4400 mg/m2 over 1 hr) once every 24-48 hrs for up to 10 days. Each of 3 patients, treated to date on this trial, experienced substantial hematologic responses with normalization of WBC counts and complete or partial clearance of blasts from the blood within 4-11 days of treatment. These responses were relatively brief, in that leukemic blasts reaccumulated in the marrow and blood of patients within 4 weeks following treatment, but were re-induced with subsequent courses of treatment. Of interest, the rates of blast cell reaccumulation appeared to increase progressively following sequential courses of treatment. Tiazofurin, which inhibits IMP-dehydrogenase (IMPDH) and blocks guanine ribonucleotide synthesis, has been shown to increase IMPDH mRNA expression in various cell lines in vitro, as an apparently compensatory response to guanylate deprivation. Studies of IMPDH mRNA expression in the leukemic blasts of CML-BC patients receiving tiazofurin treatment showed that this same phenomenon occurs in vivo. Since IMPDH activity is linked to the proliferative activity of neoplastic cells an amplification of IMPDH message expression induced by tiazofurin may lead to an increased sensitivity of the leukemic clone to cycle active agents.

Aged↗

PubMed1994

[Leukocyte transfusion as therapy of recurrent CML after allogenic bone marrow transplantation].

Eight patients with relapsed chronic myelogenous leukemia (CML) after allogeneic bone marrow transplantation (BMT) were treated with alpha-interferon and leukocyte transfusions of the bone marrow donor. Six patients responded with disappearance of leukemic cells (Ph1, BCR-ABL) and reestablished donor hemopoiesis. All six patients developed bone marrow hypoplasia and graft-versus-host disease (GvHD). Three of the six patients died of cerebral bleeding, infection and GvHD, respectively. The remaining three patients are alive and well at day 418, 677, 818 after leukocyte transfusions. Two patients relapsed with more advanced disease of CML after BMT and failed treatment. Donor leukocyte transfusions provide an effective therapy for patients with relapsed CML after BMT, but are associated with a high mortality due to bone marrow hypoplasia and GvHD.

Antigens, CD↗

PubMed1998

CML and apoptosis: the ceramide pathway.

In patients with Chronic Myeloid Leukemia (CML), the neoplastic (Bcr-Abl+) progenitors are characterised by an increased proliferative activity. These cells appear to become resistant to apoptosis following growth factor withdraw. We demonstrate that despite this property, Bcr-Abl transformed cells (primitive hematopoietic progenitors or cell lines) remains sensitive to apoptosis induced by Ceramides analogues. This effect is dose dependent and occurs faster in transformed cells as compared to their normal counterparts. In addition to the classical features of apoptosis, we observed that Ceramide-treated CML cells display a rapid and sequential activation of the Bcr-Abl and PI3 kinases. We then demonstrated the role of the Bcr-Abl kinase activity in the accelerated response observed in CML cells treated by Ceramide. The PI3 kinase seems to be partly involved in the accelerated Phosphatidyl-Serine exposure observed in Bcr-Abl transformed cells. Finally, we observed that Ceramide-induced apoptosis does not seem to implicate a Bcl2 protein modulation. Taken together these results support the hypothesis of at least two independent signaling pathways initiating programmed cell death: one will be involved in apoptosis mediated by signals such as cytokine-starving is blocked by the Bcr-Abl fusion protein while the other one initiated by Ceramide is accelerated by the Bcr-Abl protein.

Apoptosis↗

PubMed1978

Chromosomes and causation of human cancer and leukemia. XXIX. Further studies on karyotypic progression in CML.

Fifty-seven Ph1-positive cases of chronic myelocytic leukemia (CML) were analyzed with chromosomal banding techniques and their karyotypic progression followed. These cases included 1 without evidence of a Ph1-translocation and 1 new patient with a complex Ph1-translocation involving chromosomes No. 9, No. 17 and No. 22. Of the 57 patients, 28 had the Ph1 as the only karyotypic anomaly, whereas the remaining 29 cases developed and/or were associated with chromosomal changes usually of a hyperdiploid nature, particularly in the blastic phase, in addition to the Ph1. Even though the additional karyotypic changes frequently included chromosomes No. 8, No. 17, No. 19 and No. 21, a large number of others was also involved, although less often. The series included 3 cases with different types of translocations unrelated to the Ph1. The cytogenetic observations have been correlated with some of the clinical parameters. The survival of the patients was evaluated in relation to the karyotypic findings, indicating that the chromosomal changes may not play as important a role in the prognostic and progressive aspects of Ph1-positive CML as that of other as yet undetermined factors.

Adult↗

PubMed2001

Radio fluorination and positron emission tomography (PET) as a new approach to study the in vivo distribution and elimination of the advanced glycation endproducts N epsilon-carboxymethyllysine (CML) and N epsilon-carboxyethyllysine (CEL).

After synthesis of fluorine-18 labelled analogues by [18F]fluorobenzoylation at the alpha-amino group, biodistribution and elimination of individual advanced glycation endproducts, namely N epsilon-carboxymethyllysine and N epsilon-carboxyethyllysine, were studied in comparison to lysine in rats after intravenous injection using positron emission tomography (PET). The [18F]radiofluorinated amino acids were fast distributed via the blood, followed by a rapid excretion through the kidneys. Elimination kinetics were similar for both AGEs and lysine. For CML and CEL, but not for lysine, a temporary liver accumulation could be observed, which was not connected with any metabolisation or enterohepatic circulation. No further accumulation in any tissues was observable, indicating that increased tissue levels of CML or CEL, which have been described for certain disorders, are exclusively derived from endogenous origin and should not depend on a dietary intake. However, under uremic conditions, an impaired kidney function might result in a significant increase of the AGE-load of blood and tissues. PET based on 18F-labelled AGEs proved to be a promising tool to elucidate the physiological fate of post-translationally modified amino acids and to clarify the role of AGEs as possible "glycotoxins".

Animals↗

PubMed2003

Imatinib in Philadelphia chromosome-positive chronic phase CML patients: molecular and cytogenetic response rates and prediction of clinical outcome.

Previous clinical trials with the tyrosine kinase inhibitor imatinib in chronic-phase Philadelphia chromosome-positive chronic myelogenous leukemia (CML) resulted in 95% of hematologic and 60% major cytogenetic remissions in patients who failed a previous interferon-alpha-containing regimen. In an identical clinical trial setting with 39 chronic-phase CML patients we achieved comparable cytogenetic response rates after a median follow up of 30.1 weeks, with an almost identical toxicity profile. In order to identify predictive markers for the therapeutical use of imatinib, we monitored apart from standard hematology parameters bcr/abl fusion transcripts by quantitative real-time fluorescence RT-PCR. As previous investigations demonstrated that the plasma protein alpha-1 acid glycoprotein might inactivate circulating levels of free imatinib by protein binding with high affinity, we assessed plasma alpha-1 acid glycoprotein concentrations in our study cohort as well. Median bcr/abl fusion transcripts declined gradually over the entire treatment period and became significantly lowered at month 3 after initiation of imatinib therapy. Further, we observed elevated pretreatment levels of alpha-1 acid glycoprotein in patients who relapsed with leukemia, whereas initial bcr/abl mRNA copy numbers were not of predictive value. In addition, we provide data showing molecular response to this therapy in the vast majority of patients. Finally, our results support the hypothesis, that initially elevated plasma levels of alpha-1 acid glycoprotein might serve as a predictive marker for the clinical outcome of treatment with imatinib.

Adult↗

PubMed2007

Bone marrow aplasia--a rare complication of imatinib therapy in CML patients.

Imatinib mesylate therapy in CML patients is a generally well tolerated without any significant hematological adverse drug effects. However, complications like anemia and cytopenias have been described in literature. A very few case reports of bone marrow aplasia following imatinib therapy have been reported so far. We here report five patients of CML who developed bone marrow aplasia following imatinib therapy.

Adolescent↗

PubMed1977

Chromosomes and causation of human cancer and leukemia: XXVIII. Value of detailed chromosome studies on large numbers of cells in CML.

Comparison of the chromosome findings obtained on routine examination (10-50 cells) of the marrows from patients with Ph1-positive CML with those based on a large number (110-500 cells) of metaphases in six of these patients, in whom appropriate material was available, revealed the presence of small percentages of aneuploid cells in the marrow during the chronic phase of the disease and not seen with the routine procedure. These aneuploid cells may ultimately constitute the dominant clone during the blastic phase of the chronic myelocytic leukemia (CML). Furthermore, karyotypically abnormal cells, in addition those observed on routine study, were detected in the blastic phase when a large number of cells was examined. The value and implications of these observations are discussed.

Blood Cell Count↗

PubMed1980

Childhood CML in blastic stage: an analysis of cell markers and cell kinetics.

The clinical course of Ph+CML and their terminal blastic stage is described in the following case histories. During blastic phase, cell surface markers, terminal deoxynucleotidyl transferase (TdT) activity, and flow cytometric measurements were used or determination of the blast cell phenotype which was undifferentiated by morphological and cytochemical criteria. A high proportion of blast cells expressed Fc receptors for IgG, TdT activity was normal in both children and RNA measurements of single cells flow cytometry showed a high RNA content in the majority of blasts. These findings are compatible with the phenotype seen in the myelomonocytic leukemias. Flow cytometry appears to be a useful adjunct to immunological methods and TdT activity for the rapid characterization of CML in blastic phase.

Child↗

PubMed1995

Hypertriglyceridemia may be severe in CML patients treated with interferon-alpha.

We analyzed serum triglyceride (TG) levels in 22 chronic myeloid leukemia (CML) patients treated with interferon-alpha (IFN-alpha). Hypertriglyceridemia was present in one-half of patients at diagnosis, and IFN-alpha treatment was associated with a further increase in 90% of the total group of patients. This increase was maximal during the first months of therapy. Four patients (18%) reached levels higher than 1,000 mg/dl. This is the first report describing this secondary effect in CML patients treated with IFN-alpha.

Adolescent↗

PubMed1995

Clinical and histological features retain their prognostic impact under interferon therapy of CML: a pilot study.

In 55 patients with Ph1+ CML under interferon (IFN) monotherapy, an immunohistochemical and morphometric study on pretreatment bone marrow biopsies was performed to evaluate the prognostic impact of clinical as well as histological disease features. For identification of megakaryocytes we used the PAS stain and CD61 to calculate the subfraction of precursors (pro- and megakaryoblasts). Demonstration of macrophages and their different subsets was carried out by PG-M1 (CD68) and the GSA-1 lectin. The erythroid precursors were stained by Ret40f (anti-glycophorin C). Density of argyrophilic (reticulin plus collagen) fibers was determined by applying Gomori's silver impregnation method. Clinical variables like state of hematological response to IFN administration, age, spleen and liver size, myeloblasts plus promyelocytes, basophils as well as basophils and eosinophils exerted a predictive capacity by univariate statistical analysis. However, when entering these factors into previously published risk models, i.e., the so-called Sokal score and its modifications, to assess subgroups with different survival patterns or relative risk groups, a clear-cut discrimination was not feasible. Bone marrow features of prognostic value consisted of megakaryocytes and their precursors, fibers, and pro- and erythroblasts. Only when including histological variables into a formerly reported Cox model, could a significant separation of patients into the different categories or relative risk groups be computated. In conclusion, the present data emphasize the prognostic impact of histological parameters to be considered in all clinical trials on CML.

Adult↗

PubMed1989

Location of breakpoints within the major breakpoint cluster region (bcr) in 33 patients with bcr rearrangement-positive chronic myeloid leukemia (CML) with complex or absent Philadelphia chromosomes.

We report the sublocalization of the breakpoint in chromosome 22 in 33 patients with chronic myeloid leukemia (CML) who also had unusual marrow cytogenetics. In 23 patients, the leukemic clones were characterized by Philadelphia (Ph1) chromosomes that arose through complex translocations that involved three or more chromosomes. In the remaining ten patients, there were no detectable Ph1 chromosomes despite molecular evidence for the presence of rearrangements in the major breakpoint cluster region (bcr) of chromosome 22 in all cases. There was no significant difference between the two groups with respect to location of the breakpoints within the bcr. When these two groups of patients were combined, there was a significant excess of breakpoints in one segment of the bcr when compared to the distribution of breakpoints seen in 119 patients with simple 9;22 translocations. The difference in breakpoint distributions did not appear to be entirely attributable to differences between groups in disease duration at the time of study. These data support the notion that the unusual genetic recombinations that give rise to BCR/ABL fusion genes in CML involve specific DNA sequences of BCR (and possibly ABL) and additional, recombinogenic sequences, at least some of which are present in loci known to be nonrandomly involved in complex Ph1 translocations.

Adult↗

PubMed1997

Adenovirus mediated alpha interferon (IFN-alpha) gene transfer into CD34+ cells and CML mononuclear cells.

Gene transfer or gene therapy has advantages in the treatment of a variety of disorders due to its selective expression within specific mammalian cells. Interferon-alpha (IFN-alpha) has been used in the management of leukemia but its diverse adverse activities with multiple potential side effects, possibly unrelated to therapeutic targets, may negatively influence the ability of IFN-alpha to treat this disorder. Therefore, we examined the ability of adenovirus (Ad)-IFN-alpha gene construct to transfect normal (CD34+ cells) and chronic myelogenous leukemia (CML) bone marrow mononuclear cells (BMMNC) and the transient overexpression of IFN-alpha in these cells. Ad-cytomegalovirus promoter driven IFN-alpha (AdCMV-IFN-alpha) at multiple doses was assessed to transfect highly purified CD34+ cells in liquid culture, and optimal transduction of CD34+ cells was achieved using 120 plaque forming units. Flow cytometric determinations revealed that there was no significant difference in cell viability for the 4 h or 24 h transfection periods. Immunoassay of IFN-alpha produced by CD34+ cells shows that IFN-alpha levels increased several fold in transfected cells. Transient expression of the IFN-alpha gene did not suppress proliferation of CD34+ progenitors as indicated by BFU-E or colony forming units-granulocyte-macrophage (CFU-GM) growth. Reverse transcriptase/polymerase chain reaction analysis of RNA from CD34+ harvested CFU-GM progenitor cells demonstrated transient IFN-alpha mRNA expression. Similarly, CML BMMNC were transfected with AdCMV-IFN-alpha under similar conditions as described for CD34+ cells. BMMNC cells exposed to adenovirus for 24 h and 48 h were found to express IFN-alpha at a substantial level. This in vitro data suggest that Ad-mediated gene transfer of IFN-alpha into hematopoietic stem cells can be achieved and that the IFN-alpha gene can be translated into its specific mRNA in CD34 progenitor cells.

Adenoviridae↗

PubMed1981

Chronic myelogenous leukemia with translocations (3q-;9q+) and (17q-;22q+). Possible crucial cytogenetic events in the genesis of CML.

Two reciprocal translocations involving chromosomes 3, 9, 17, and 22 were found in a patient with seemingly Ph1-negative chronic myelogenous leukemia (CML). The two translocations were t(3;9)(q21;q34) and t(17;22)(q21;q11); the breakage in chromosomes 9 and 22 apparently occurred at the same point as in the usual Ph1 translocation, t(9;22)(q34;11). From the present evidence and a review of the literature it appears that the breakage on both chromosomes 9 and 22 at the special regions and the separation of the fragments are present in practically all standard and variant Ph translocations, even those in which the terminal region of the long arm of chromosome 9 and (9q) does not seem to be involved in the rearrangement; however, a translocation between chromosomes 9 and 22 is not an obligatory result of the rearrangement, as seen in the present case. Thus, we postulate that the breakage on both chromosomes 9 and 22 at the special regions and separation of the fragments are the crucial cytogenetic events in the genesis of CML and stress the importance of paying careful attention to the terminal region of 9q, particularly when chromosome 9 does not seem to be involved in the rearrangement.

Adult↗