Persistence of BCR/ABL mRNA-Expressing Bone-Marrow Cells in Patients with Chronic Myelogenous Leukemia in Complete Cytogenetic Remission Induced by Interferon-alpha Therapy

Eberlé, Frédéric; Toiron, Yves; Camerlo, Jacques; Lafage, Marina; Sainty, D; Arnoulet, Christine; Raineri, Vincent; Gabert, Jean; Maraninchi, D; Mannoni, P

doi:10.3109/10428199509064936

Cited by 4 publications

(3 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…307,[555][556][557][558] A smaller percentage of patients appear to have quite durable complete remissions that persist even after stopping treatment, but using PCR technology or FISH analysis, small numbers of leukemic cells can usually still be detected in the majority of patients having long-term cytogenetic remissions. [559][560][561][562][563] Interferon is not devoid of toxicity, and many patients are unable to tolerate the unpleasant side effects for the long periods of treatment required to obtain durable responses. Some of the clinical trials experienced better results than others; possible explanations include different proportions of patients in higher or lower risk groups or in aggressiveness in continuing therapy despite the unpleasant side effects of interferon.…”

Section: Overall Survival and Prognostic Factorsmentioning

confidence: 99%

Chronic myelogenous leukemia as a paradigm of early cancer and possible curative strategies

et al. 2003

View full text Add to dashboard Cite

The chronological history of the important discoveries leading to our present understanding of the essential clinical, biological, biochemical, and molecular features of chronic myelogenous leukemia (CML) are first reviewed, focusing in particular on abnormalities that are responsible for the massive myeloid expansion. CML is an excellent target for the development of selective treatment because of its highly consistent genetic abnormality and qualitatively different fusion gene product, p210(bcr-abl). It is likely that the multiple signaling pathways dysregulated by p210(bcr-abl) are sufficient to explain all the initial manifestations of the chronic phase of the disease, although understanding of the circuitry is still very incomplete. Evidence is presented that the signaling pathways that are constitutively activated in CML stem cells and primitive progenitors cooperate with cytokines to increase the proportion of stem cells that are activated and thereby increase recruitment into the committed progenitor cell pool, and that this increased activation is probably the primary cause of the massive myeloid expansion in CML. The cooperative interactions between Bcr-Abl and cytokine-activated pathways interfere with the synergistic interactions between multiple cytokines that are normally required for the activation of stem cells, while at the same time causing numerous subtle biochemical and functional abnormalities in the later progenitors and precursor cells. The committed CML progenitors have discordant maturation and reduced proliferative capacity compared to normal committed progenitors, and like them, are destined to die after a limited number of divisions. Thus, the primary goal of any curative strategy must be to eliminate all Philadelphia positive (Ph+) primitive cells that are capable of symmetric division and thereby able to expand the Ph+ stem cell pool and recreate the disease. Several highly potent and moderately selective inhibitors of Bcr-Abl kinase have recently been discovered that are capable of killing the majority of actively proliferating early CML progenitors with minimal effects on normal progenitors. However, like their normal counterparts, most of the CML primitive stem cells are quiescent at any given time and are relatively invulnerable to the Bcr-Abl kinase inhibitors as well as other drugs. We propose that survival of dormant Ph+ stem cells may be the most important reason for the inability to cure the disease during initial treatment, while resistance to the inhibitors and other drugs becomes increasingly important later. An outline of a possible curative strategy is presented that attempts to take advantage of the subtle differences in the proliferative behavior of normal and Ph+ stem cells and the newly discovered selective inhibitors of Bcr-Abl. Leukemia (2003) 17, 1211-1262. doi:10.1038/sj.leu.2402912

show abstract

Section: Overall Survival and Prognostic Factorsmentioning

confidence: 99%

Chronic myelogenous leukemia as a paradigm of early cancer and possible curative strategies

et al. 2003

View full text Add to dashboard Cite

show abstract

“…Thus, the FISH test may be more reliable clinically in the monitoring of the bcr/abl fusion gene in CML. 31,32,[38][39][40][41] Additionally, this peripheral FISH test is very useful in differential diagnosis of CML. Up to now, when patients or healthy individuals with leukocytosis were referred to hematologists, we have had to perform bone marrow aspiration and send the samples for karyotype analysis in order to confirm the diagnosis of CML.…”

Section: Discussionmentioning

confidence: 99%

True

1999

Leukemia

View full text Add to dashboard Cite

Philadelphia (Ph) chromosome or the bcr/abl fusion gene is the hallmark of chronic myeloid leukemia (CML) and serves as a prognostic marker during its treatment. Its detection has been primarily done by karyotype analysis of bone marrow cells. The major limitation of the karyotypic technique is an absolute need for metaphases, often difficult to obtain in an appropriate number in patients under therapy. Fluorescence in situ hybridization (FISH) is a sensitive and quantitative method to detect the bcr/abl fusion gene in cells in both metaphase and interphase. Using M-bcr and abl probes, we performed the interphase FISH in the peripheral blood of 30 healthy volunteers and in 20 hematologically normal bone marrow samples. False-positive cells were detected in 2.7 +/- 0.7% (mean +/- standard deviation) and 2.3 +/- 0.7% among 500 cells, respectively. Then we tested 31 patients with CML at various stages of disease on 50 occasions. Although there was a good correlation between the percentage of FISH-positive cells in the peripheral blood and that in the bone marrow (r = 0.977), between the percentage of FISH-positive cells in the peripheral blood and that of Ph chromosome in the bone marrow (r = 0.841), and between the percentage of FISH-positive cells and that of Ph chromosome in the bone marrow (r = 0.933), the limits of agreement in each group were not small, and thus the peripheral blood FISH test can not be interpreted as the same method with conventional karyotyping. Additionally, we could easily rule out CML in 15 individuals with leukocytosis without performing bone marrow aspiration. The present study indicates that FISH analysis in the peripheral blood is a simple and reliably sensitive test for the detection and quantitative monitoring of the M-bcr/abl fusion gene in CML in routine clinical practice, although this can not entirely replace karyotype analysis of bone marrow cells.

show abstract

Section: Discussionmentioning

confidence: 99%

Simple and reliably sensitive diagnosis and monitoring of Philadelphia chromosome-positive cells in chronic myeloid leukemia by interphase fluorescence in situ hybridization of peripheral blood cells

et al. 1999

View full text Add to dashboard Cite

Persistence of BCR/ABL mRNA-Expressing Bone-Marrow Cells in Patients with Chronic Myelogenous Leukemia in Complete Cytogenetic Remission Induced by Interferon-alpha Therapy

Cited by 4 publications

References 24 publications

Chronic myelogenous leukemia as a paradigm of early cancer and possible curative strategies

Chronic myelogenous leukemia as a paradigm of early cancer and possible curative strategies

True

Simple and reliably sensitive diagnosis and monitoring of Philadelphia chromosome-positive cells in chronic myeloid leukemia by interphase fluorescence in situ hybridization of peripheral blood cells

Contact Info

Product

Resources

About