Limited clinical value of regular bone marrow cytogenetic analysis in imatinib-treated chronic phase CML patients monitored by RQ-PCR for BCR-ABL

Ross, David M.; Branford, Susan; Moore, Sarah; Hughes, Timothy P.

doi:10.1038/sj.leu.2404139

Cited by 72 publications

(66 citation statements)

References 46 publications

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“…24,25 Loss of MMR was defined as a >2-fold rise to a level above BCR-ABL/BCR% of 0.08%. 26 Cytogenetic response was determined in at least 20 metaphases by the percentage of Ph-positive cells in the bone marrow and was categorized as: complete (CCR; 0%), near-complete (1-10%), major (11-35%), minor (36-65%), minimal (66-95%), or none (96-100%). Loss of CCR was defined as >0% Ph-positive cells that was confirmed by repeat analysis 1 month later.…”

Section: Efficacy Outcomes and Statistical Analysismentioning

confidence: 99%

Efficacy and safety of imatinib in patients with chronic myeloid leukemia and complete or near‐complete cytogenetic response to interferon‐α

Branford

Hughes

Milner

et al. 2007

Cancer

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The photoluminescence (PL) spectra of poly[2,5‐bis‐(tri‐ethoxy)‐1,4‐phenylene vinylene] (BTEO–PPV) films are blue‐shifted with increasing thermal annealing temperature. It is known from the UV–vis absorption spectra that thermal annealing decreases the conjugation length of the polymer. For BTEO–PPV films, unlike with MEH–PPV films, the symmetric triethoxy side groups further block aggregation of the polymer chains. The absorption Fourier transfer infrared spectra showed that thermal annealing in atmosphere destroyed the chain structure of BTEO–PPV film by thermal oxidation to form aldehyde groups, which resulted in low PL efficiency of the annealed films. © 2005 Wiley Periodicals, Inc. J Appl Polym Sci, 2006

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Section: Efficacy Outcomes and Statistical Analysismentioning

confidence: 99%

Efficacy and safety of imatinib in patients with chronic myeloid leukemia and complete or near‐complete cytogenetic response to interferon‐α

Branford

Hughes

Milner

et al. 2007

Cancer

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“…BCR-ABL values lower than 10% IS are approximately equivalent to the achievement of an MCR. 7,13 We found the highest incidence of mutations occurred in patients failing to achieve an MCR by 6 months. 19 Furthermore, patients who have a significant rise in BCR-ABL and have a confirmed loss of an MMR should have mutation screens unless there is a clear association between the rising BCR-ABL level and a dose reduction or interruption.…”

Section: When To Do Mutation Screeningmentioning

confidence: 88%

Monitoring disease response to tyrosine kinase inhibitor therapy in CML

Hughes¹,

Branford²

2009

Hematology

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The remarkable progress made in the treatment of chronic myeloid leukemia (CML) over the past decade has been accompanied by steady improvements in our capacity to accurately and sensitively monitor response to therapy. After the initial target of therapy, complete cytogenetic response (CCR), is achieved, peripheral blood BCR-ABL transcript levels measured by real-time quantitative reverse transcriptase PCR (RQ-PCR) define the subsequent response targets, major and complete molecular response (MMR and CMR). The majority of patients on first-line imatinib therapy achieve a "safe haven" defined as a confirmed MMR, but 20% to 30% stop imatinib due to intolerance and/or resistance. Many imatinib-resistant patients can be effectively treated with second generation tyrosine kinase inhibitors (TKIs), but the actual drug selected should be based on the resistance profile of each inhibitor, in addition to issues of tolerance and disease phase. The main purpose of monitoring response with cytogenetics and RQ-PCR is to identify patients likely to achieve better long-term outcome if they are switched early to second-line therapy, either another TKI or an allograft. Mutation screening is most valuable in cases of loss of response to imatinib or a second-line TKI, but there are other settings where a high yield of mutations may justify regular mutation screening.

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“…In a comparison of cytogenetics and RQ-PCR, 98% of patients who had achieved a 1-2 log reduction were in a MCR and 91% of patients who had achieved 2-3 log reduction were in CCR. 29 Therefore, at early time points the molecular response is a good indicator of the level of leukemia reduction and correlates strongly with cytogenetic status. While RQ-PCR can substitute quite well as an early response indicator, only cytogenetic studies can identify the emergence of additional chromosomal abnormalities in the leukemic clone.…”

Section: Cytogenetic Responsementioning

confidence: 99%

“…No Ph-positive cells were observed in any of the patients who achieved and maintained a MMR. 29 A reasonable monitoring policy would be to conduct cytogenetic analysis of the bone marrow at baseline and at 6 months and then 6 monthly until a patient achieves MMR. Patients who subsequently lose MMR with a significant rise in BCR-ABL level should recommence marrow cytogenetic studies.…”

Section: Cytogenetic Responsementioning

confidence: 99%

ABL Kinase Inhibitor Therapy for CML: Baseline Assessments and Response Monitoring

Hughes

2006

Hematology

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For chronic phase chronic myeloid leukemia (CML) patients treated with imatinib, the essential pretherapy assessments include bone marrow morphology and cytogenetics as well as a baseline real-time quantitative PCR (RQ-PCR) for BCR-ABL. Baseline assessments of clinical relevance include Sokal and Hasford prognostic scores. Several other baseline assays are likely to be predictive of response, including IC50 imatinib , organic cation transporter-1 (OCT-1) mRNA level, and gene expression profiles, but further confirmation is required. RQ-PCR assays of blood at least every 3 months once patients have commenced imatinib is recommended. This will facilitate early identification of suboptimal responders who may benefit from higher doses of imatinib or alternative therapy, and identify at an early stage patients with acquired resistance. Management of the latter group can be further guided by the findings from cytogenetics and BCR-ABL kinase domain mutation screening. Bone marrow cytogenetics is indicated at least every 6 months until the patient achieves major molecular response. RQ-PCR is only clinically useful if it is conducted under a rigorous quality control regimen so that fluctuations in the BCR-ABL level can be confidently attributed to a biological cause rather than assay variation. To further improve the clinical value of RQ-PCR monitoring, expression of results on an international scale is needed. This will facilitate a more uniform and rational approach to management of suboptimal response and loss of response.

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Limited clinical value of regular bone marrow cytogenetic analysis in imatinib-treated chronic phase CML patients monitored by RQ-PCR for BCR-ABL

Cited by 72 publications

References 46 publications

Efficacy and safety of imatinib in patients with chronic myeloid leukemia and complete or near‐complete cytogenetic response to interferon‐α

Efficacy and safety of imatinib in patients with chronic myeloid leukemia and complete or near‐complete cytogenetic response to interferon‐α

Monitoring disease response to tyrosine kinase inhibitor therapy in CML

ABL Kinase Inhibitor Therapy for CML: Baseline Assessments and Response Monitoring

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