Molecular studies in patients with chronic myeloid leukaemia in remission 5 years after allogeneic stem cell transplant define the risk of subsequent relapse

Mughal, Tariq I.; Yong, Agnes S. M.; Szydlo, Richard; Dazzi, Francesco; Olavarría, Eduardo; Rhee, Frits van; Kaeda, Jaspal; Cross, Nicholas C. P.; Craddock, Charles; Kanfer, Edward; Apperley, Jane; Goldman, John M.

doi:10.1046/j.1365-2141.2001.03155.x

Cited by 68 publications

(31 citation statements)

References 33 publications

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“…12 A stable complete molecular response (CMR) is associated with a much lower risk of relapse after allograft, but even in this population, rare relapses are seen after more than 5 years. 13 These observations have implications for how we interpret the outcome of TKI cessation studies, which currently have much shorter follow-up.…”

Section: Asctmentioning

confidence: 99%

Minimal Residual Disease and Discontinuation of Therapy in Chronic Myeloid Leukemia: Can We Aim at a Cure?

Melo

Ross

2011

Hematology

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Patients with chronic myeloid leukemia (CML) who have achieved a complete molecular response (CMR) defined by no detectable BCR-ABL mRNA on imatinib (IM) treatment often ask whether it is necessary for treatment to continue. We now know that approximately 40% of patients with a stable CMR for at least 2 years are able to stop IM treatment and remain in molecular remission for at least 2 years. This exciting observation has raised hopes that many patients can be cured of CML without the need for transplantation and its attendant risks. One might argue that for many patients maintenance therapy with IM or an alternative kinase inhibitor is so well tolerated that there is no imperative to stop treatment; however, chronic medical therapy may be associated with impaired quality of life and reduced compliance. Inferences about the biology of CML in patients responding to kinase inhibitors can be drawn from clinical experience, molecular monitoring data, and experimental observations. We summarize this information herein, and propose 3 possible pathways to "cure" of CML by kinase inhibitors: stem-cell depletion, stem-cell exhaustion, and immunological control.

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Section: Asctmentioning

confidence: 99%

Minimal Residual Disease and Discontinuation of Therapy in Chronic Myeloid Leukemia: Can We Aim at a Cure?

Melo

Ross

2011

Hematology

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“…This information is invaluable to adjust treatment plans and bears important prognostic significance. 10,11 Moreover, it has recently been established that the degree of molecular response at the time of or after achieving complete cytogenetic remission is an independent prognostic factor for progression-free survival. 12 Cepheid recently introduced its GeneXpert-based assay for the identification of leukemia cells harboring the BCR-ABL gene fusion from blood samples.…”

mentioning

confidence: 99%

Evaluation of the Cepheid GeneXpert BCR-ABL Assay

Jobbágy

Atta²,

Murphy

et al. 2007

The Journal of Molecular Diagnostics

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Patients with chronic myeloid leukemia harbor the chromosomal translocation t(9;22), which corresponds to fusion of the BCR and ABL genes at the DNA level. The translated fusion product is an oncogenic protein with increased ABL tyrosine kinase activity causing cell transformation. To date, reverse transcriptase-polymerase chain reaction is considered the most sensitive method available for detecting low copy numbers of the BCR-ABL gene fusion. Recently, Cepheid introduced its GeneXpert-based assay for the identification of the BCR-ABL gene fusion in cells from blood samples. This system comprises a walkaway self-contained instrument that combines cartridge-based microfluidic sample preparation with reverse transcriptase-polymerase chain reaction-based fluorescent signal detection and BCR-ABL and ABL Ct (threshold cycle) determination. The difference between the BCR-ABL Ct and ABL Ct (⌬Ct) is expected to represent the ratio of the two populations of mRNAs and ultimately the percentage of neoplastic cells present. We tested whether this BCR-ABL fusion detection system could be used as a clinical diagnostic tool for monitoring patients with minimal residual disease of chronic myelogenous leukemia. We report similar performance characteristics, including limit of detection, specificity, sensitivity, and precision, of this automated BCR-ABL fusion detection system to those of a manual TaqMan reverse transcriptase-polymerase chain reaction-based test.

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“…Mughal et al presented data on 20 CML patients in molecular relapse who were treated with DLI. 79 After a median follow-up of 42 months, these patients were in continuous molecular remission. Their actuarial probability of survival at 10 years after BMT was 100% and their probability of relapse was 0%.…”

Section: Minimal Residual Disease Detectionmentioning

confidence: 99%

Clinical Applications of BCR-ABL Molecular Testing in Acute Leukemia

Nashed

Rao

Gulley

2003

The Journal of Molecular Diagnostics

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Recent advances in molecular genetics impact the health care and outcome of patients with acute lymphoblastic leukemia (ALL). BCR-ABL, a common molecular defect in adult ALLIn 1960, Nowell and Hungerford 1 reported the discovery of what came to be known as the Philadelphia chromosome (Ph 1 ) in association with chronic myelogenous leukemia (CML). Their short report entitled "Minute chromosome in human chronic granulocytic leukemias" was the first to demonstrate a leukemia-specific genetic abnormality. In the ensuing decades, the pathology of the Ph 1 has been studied and it is now known to represent an abnormally shortened (derivative) chromosome 22 resulting from translocation with chromosome 9.2 The t(9;22) is found in over 90% of CMLs, in a lesser proportion of acute lymphoblastic leukemias (ALL) or biphenotypic acute leukemias, and in rare cases of de novo acute myelogenous leukemia (AML).The break on chromosome 22q11.2 usually occurs in the major breakpoint cluster region (M-BCR), in the minor breakpoint cluster region (m-BCR), or rarely at other nearby sites. The break on chromosome 9q34 involves the ABL gene, named after Abelson murine leukemia virus where a viral version of the ABL gene was first discovered. The translocation brings the 5Ј end of the BCR gene into juxtaposition with the tyrosine kinase domain of the ABL gene to produce a hybrid gene retaining tyrosine kinase activity. 3Depending on whether the M-BCR or m-bcr breakpoint is involved in the translocation, transcription of the hybrid gene results in chimeric mRNA encoding a 210 kd BCR-ABL fusion protein or a 190 kd BCR-ABL fusion protein, respectively. The reciprocal ABL-BCR translocation also forms a chimeric gene that is capable of being transcribed, but the pathological significance of this reciprocal chimeric gene product is uncertain. Laboratory Tests for t(9;22)Conventional cytogenetics is the recommended test for detecting t(9;22) in newly diagnosed leukemia patients. Chromosome banding analysis has the advantage of high specificity and an ability to detect alternate or additional cytogenetic defects that are valuable in diagnosis and prognosis. However, cytogenetic analysis requires viable marrow cells or more than 10% blasts in the peripheral blood to reliably culture the cells and visualize metaphases. Occasionally fibrosis interferes with marrow aspiration, yielding few analyzable metaphase cells. The number of cells examined determines the sensitivity of karyotyping. A typical examination of 20 cells carries a sensitivity of one in 20, or 5%. Cryptic t(9;22) occurs in about 5% of CML cases and also in a small proportion of ALLs, resulting in false negative karyotypic interpretation in metaphase spreads of cells that actually contain the translocation at the molecular level.

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Molecular studies in patients with chronic myeloid leukaemia in remission 5 years after allogeneic stem cell transplant define the risk of subsequent relapse

Cited by 68 publications

References 33 publications

Minimal Residual Disease and Discontinuation of Therapy in Chronic Myeloid Leukemia: Can We Aim at a Cure?

Minimal Residual Disease and Discontinuation of Therapy in Chronic Myeloid Leukemia: Can We Aim at a Cure?

Evaluation of the Cepheid GeneXpert BCR-ABL Assay

Clinical Applications of BCR-ABL Molecular Testing in Acute Leukemia

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