Clinical Implications of Discordant Early Molecular Responses in CML Patients Treated with Imatinib

Stella, Stefania; Zammit, Valentina; Vitale, Silvia Rita; Pennisi, Maria Stella; Massimino, Michele; Tirrò, Elena; Forte, Stefano; Spitaleri, A.; Antolino, Agostino; Siracusa, Sergio; Accurso, Vincenzo; Mannina, Donato; Impera, Stefana; Musolino, Caterina; Russo, Salvatore; Malato, Alessandra; Mineo, Giuseppe; Musso, Maurizio; Porretto, Ferdinando; Martino, Bruno; Raimondo, Francesco Di; Manzella, Livia; Vigneri, Paolo; Stagno, Fabio

doi:10.3390/ijms20092226

Cited by 16 publications

(11 citation statements)

References 38 publications

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“…Only individuals with the common e13a2 and/or e14a2 BCR-ABL1 transcripts were included in our analysis. BCR-ABL1 values were converted to the IS as previously described (24, 25). MR 3.0 and MR 4.0 were defined by BCR-ABL1/ABL1 IS values ≤0.1% and ≤0.01%, respectively, with no <10,000 ABL1 copies (26).…”

Section: Methodsmentioning

confidence: 99%

BCR-ABL1 Doubling-Times and Halving-Times May Predict CML Response to Tyrosine Kinase Inhibitors

et al. 2019

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In Chronic Myeloid Leukemia (CML), successful treatment requires accurate molecular monitoring to evaluate disease response and provide timely interventions for patients failing to achieve the desired outcomes. We wanted to determine whether measuring BCR-ABL1 mRNA doubling-times (DTs) could distinguish inconsequential rises in the oncogene's expression from resistance to tyrosine kinase inhibitors (TKIs). Thus, we retrospectively examined BCR-ABL1 evolution in 305 chronic-phase CML patients receiving imatinib mesylate (IM) as a first line treatment. Patients were subdivided in two groups: those with a confirmed rise in BCR-ABL1 transcripts without MR 3.0 loss and those failing IM. We found that the DTs of the former patients were significantly longer than those of patients developing IM resistance (57.80 vs. 41.45 days, p = 0.0114). Interestingly, the DT values of individuals failing second-generation (2G) TKIs after developing IM resistance were considerably shorter than those observed at the time of IM failure (27.20 vs. 41.45 days; p = 0.0035). We next wanted to establish if decreases in BCR-ABL1 transcripts would identify subjects likely to obtain deep molecular responses. We therefore analyzed the BCR-ABL1 halving-times (HTs) of a different cohort comprising 174 individuals receiving IM in first line and observed that, regardless of the time point selected for our analyses (6, 12, or 18 months), HTs were significantly shorter in subjects achieving superior molecular responses ( p = 0.002 at 6 months; p < 0.001 at 12 months; p = 0.0099 at 18 months). Moreover, 50 patients receiving 2G TKIs as first line therapy and obtaining an MR 3.0 (after 6 months; p = 0.003) or an MR 4.0 (after 12 months; p = 0.019) displayed significantly shorter HTs than individuals lacking these molecular responses. Our findings suggest that BCR-ABL1 DTs and HTs are reliable tools to, respectively, identify subjects in MR 3.0 that are failing their assigned TKI or to recognize patients likely to achieve deep molecular responses that should be considered for treatment discontinuation.

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Section: Methodsmentioning

confidence: 99%

BCR-ABL1 Doubling-Times and Halving-Times May Predict CML Response to Tyrosine Kinase Inhibitors

et al. 2019

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“…The introduction of imatinib mesylate dramatically improved the outcome of patients with CML in the chronic phase (8)(9)(10)(11)(12)(13). Nevertheless, clinical evidence suggests that patients treated with imatinib mesylate may develop BCR-ABL-dependent or BCR-ABL-independent resistance to therapy (14)(15)(16)(17)(18)(19)(20).…”

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confidence: 99%

Optimal Response in a Patient With CML Expressing BCR–ABL1 E6A2 Fusion Transcript With Nilotinib Therapy: A Case Report

Manzella

Tirrò

Vitale

et al. 2020

In Vivo

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Background/Aim: The Philadelphia chromosome is considered the hallmark of chronic myeloid leukemia (CML). However, although most patients with CML are diagnosed with the e13a2 or e14a2 breakpoint cluster region (BCR)-Abelson 1 (ABL1) fusion transcripts, about 5% of them carry rare BCR-ABL1 fusion transcripts, such as e19a2, e8a2, e13a3, e14a3, e1a3 and e6a2. In particular, the e6a2 fusion transcript has been associated with clinically aggressive disease frequently presenting in accelerated or blast crisis phases; there is limited evidence on the efficacy of front-line second-generation tyrosine kinase inhibitors for this genotype. Case Report: We describe a case of atypical BCR-ABL1 e6a2 fusion transcript in a 46-year-old woman with CML. Results: The use of primers recognizing more distant exons from the common BCR-ABL1 breakpoint region correctly identified the atypical BCR-ABL1 e16a2 fusion transcript. Treatment with second-generation tyrosine kinase inhibitor nilotinib was effective in this patient expressing the atypical e6a2 BCR-ABL1 fusion transcript.Chronic myeloid leukemia (CML), is a myeloproliferative disorder characterized by the presence of the Philadelphia 1481 This article is freely accessible online.

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“…Similar to these reports, MDR1 and ABCG2 variants were associated with better EMR/MMR in the present study. Higher plasma imatinib levels 16,60 , attainment of EMR (at 3 or 6 months) [61][62][63] & MMR at 12 months 64,65 have been reported to result in better FFS in patients with CML on imatinib therapy. In the present study, MDR1 variants, day29 plasma imatinib level of > 1757 ng/mL, lower ABCA6, ABCC4 RNA expression as well as achieving EMR at 3, 6 months and MMR at 12 months were associated with significantly better FFS.…”

Section: Discussionmentioning

confidence: 99%

Plasma imatinib levels and ABCB1 polymorphism influences early molecular response and failure-free survival in newly diagnosed chronic phase CML patients

Rajamani

Benjamin

Abraham

et al. 2020

Sci Rep

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Achieving early molecular response (EMR) has been shown to be associated with better event free survival in patients with chronic phase chronic myeloid leukemia (CP-CML) on Imatinib therapy. We prospectively evaluated the factors influencing the 2-year failure free survival (FFS) and EMR to imatinib therapy in these patients including day29 plasma Imatinib levels, genetic variants and the gene expression of target genes in imatinib transport and biotransformation. Patients with low and intermediate Sokal score had better 2-year FFS compared to those with high Sokal Score (p = 0.02). Patients carrying ABCB1-C1236T variants had high day29 plasma imatinib levels (P = 0.005), increased EMR at 3 months (P = 0.044) and a better 2 year FFS (P = 0.003) when compared to those with wild type genotype. This translates to patients with lower ABCB1 mRNA expression having a significantly higher intracellular imatinib levels (P = 0.029). Higher day29 plasma imatinib levels was found to be strongly associated with patients achieving EMR at 3 months (P = 0.022), MMR at 12 months (P = 0.041) which essentially resulted in better 2-year FFS (p = 0.05). Also, patients who achieved EMR at 3 months, 6 months and MMR at 12 months had better FFS when compared to those who did not. This study suggests the incorporation of these variables in to the imatinib dosing algorithm as predictive biomarkers of response to Imatinib therapy.

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Clinical Implications of Discordant Early Molecular Responses in CML Patients Treated with Imatinib

Cited by 16 publications

References 38 publications

BCR-ABL1 Doubling-Times and Halving-Times May Predict CML Response to Tyrosine Kinase Inhibitors

BCR-ABL1 Doubling-Times and Halving-Times May Predict CML Response to Tyrosine Kinase Inhibitors

Optimal Response in a Patient With CML Expressing BCR–ABL1 E6A2 Fusion Transcript With Nilotinib Therapy: A Case Report

Plasma imatinib levels and ABCB1 polymorphism influences early molecular response and failure-free survival in newly diagnosed chronic phase CML patients

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