Peripheral blood monitoring of chronic myeloid leukemia during treatment with imatinib, second‐line agents, and beyond

Abstract

BACKGROUND:The current study was conducted to compare simultaneously obtained bone marrow (BM) cytogenetics (CTG), peripheral blood (PB) and BM fluorescence in situ hybridization (FISH), and quantitative real-time polymerase chain reaction (Q-PCR) for BCR-ABL1 in monitoring response to treatment with tyrosine kinase inhibitors and homoharringtonine (HHT) in patients with chronic myeloid leukemia (CML). METHODS: PB and BM FISH (n ¼ 112 samples) and/or Q-PCR (n ¼ 132 samples) for BCR-ABL1 were simultaneously obtained in 70 patients with Philadelphia chromosome-positive (Phþ) CML in chronic (68%), accelerated (16%), and blast phase (16%) before the initiation of therapy and during the course of treatment with imatinib (IM) (n ¼ 40 patients), dasatinib (n ¼ 20 patients), nilotinib (n ¼ 4 patients), bosutinib (n ¼ 18 patients), or HHT (n ¼ 4 patients) for patients with newly diagnosed (n ¼ 13 patients), IM-sensitive (n ¼ 34 patients), IM-resistant (n ¼ 30 patients), or IM-intolerant (n ¼ 9 patients) disease. Eighteen patients were found to have Phþ variants or karyotypic abnormalities in addition to the Phþ. RESULTS: Excellent correlations (r) were observed between PB and BM FISH (r ¼ 0.95) and PB and BM Q-PCR (r ¼ 0.87), as well as BM CTG and PB FISH (r ¼ 0.89) and PB Q-PCR (r ¼ 0.82). This correlation was not affected by the presence of the Phþ variant or additional chromosomal abnormalities, the presence of ABL1 kinase domain mutations, phase of the disease, or treatment. CONCLUSIONS: PB FISH and Q-PCR appear to be reliable methods with which to monitor response to modern therapy in patients with all phases of CML.

Correlations Between Cytogenetic and Molecular Monitoring Among Patients With Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase: Post Hoc Analyses of the Rationale and Insight for Gleevec High-Dose Therapy Study

“…These findings corroborate other work showing that qRT-PCR can be reliably performed using either PB or BM. 17,19 They also support the use of FISH (PB) to confirm diagnosis when karyotyping (BM) is not feasible, as recommended in the NCCN guidelines. 1 Our analysis of the concordance between results by FISH (PB) versus karyotyping (BM) at 12 months (Table 3) supports the concept that FISH using a 500-cell preparation is a more sensitive assay than karyotyping.…”

“…To establish the feasibility of methods that use PB samples for monitoring response to therapy, studies have compared test results obtained by multiple methods, including karyotyping versus FISH [15][16][17] and karyotyping versus qRT-PCR. [17][18][19][20] Although overall findings suggest a high level of concordance between results obtained with methods using PB versus BM, the concordance of results obtained by different testing methods has been inconsistent.…”

“…[17][18][19][20] Although overall findings suggest a high level of concordance between results obtained with methods using PB versus BM, the concordance of results obtained by different testing methods has been inconsistent. [15][16][17][18][19][20] The Rationale and Insight for Gleevec High-Dose Therapy (RIGHT) study evaluated the effect of imatinib 400 mg twice daily on the achievement of molecular and cytogenetic responses in the first 18 months of therapy in 115 patients with newly diagnosed CML in chronic phase.…”

“…[17][18][19][20] Although overall findings suggest a high level of concordance between results obtained with methods using PB versus BM, the concordance of results obtained by different testing methods has been inconsistent. [15][16][17][18][19][20] The Rationale and Insight for Gleevec High-Dose Therapy (RIGHT) study evaluated the effect of imatinib 400 mg twice daily on the achievement of molecular and cytogenetic responses in the first 18 months of therapy in 115 patients with newly diagnosed CML in chronic phase. 21 Patients in this study had a rapid response to treatment; by 18 months, rates of complete cytogenetic response (CCyR), major molecular response (MMR; 3-log reduction in BCR-ABL1 transcript level from a standardized baseline), and complete molecular response (undetectable BCR-ABL1 level using an assay with 4.5-log sensitivity) were 83%, 63%, and 55%, respectively.…”

Chronic Myeloid Leukemia— What Else is there Beyond Protein Kinase Inhibitors?

“…The definition of outcome-associated landmarks during TKI treatment is required to improve the survival of CML patients. 36 The importance of an early MMR for overall survival (OS) has not been fully established, although significantly improved survival rates for patients with BCR transcript levels >9.84 % and 10 % at 3 months have been reported. 37,38 Regular monitoring of MRD enables the identification of those with suboptimal response and enables early therapy switching.…”