Kinase domain mutations of BCR-ABL identified at diagnosis before imatinib-based therapy are associated with progression in patients with high Sokal risk chronic phase chronic myeloid leukemia

Carella, Angelo Michele; Garuti, Anna; Cirmena, Gabriella; Catania, Gioacchino; Rocco, Ilaria; Palermo, Claudia; Pica, Gianmatteo; Pierri, Ivana; Miglino, Maurizio; Ballestrero, Alberto; Gobbi, Marco; Patrone, Franco

doi:10.3109/10428190903503446

Cited by 21 publications

(15 citation statements)

References 19 publications

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“…There are limited data available from imatinib-naive patients in CP-CML regarding the incidence of KD mutations, and the correlation of these mutations with the therapeutic response in unselected patients has not been established [14], [17]–[18]. Although KD mutations are infrequently detected in newly diagnosed CP-CML patients [18], KD mutations were found in a substantial number of patients when CD34 + stem cell were analyzed [19], [20].…”

Section: Introductionmentioning

confidence: 99%

Sensitive Detection of Pre-Existing BCR-ABL Kinase Domain Mutations in CD34+ Cells of Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia Patients Is Associated with Imatinib Resistance: Implications in the Post-Imatinib Era

et al. 2013

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BackgroundBCR-ABL kinase domain mutations are infrequently detected in newly diagnosed chronic-phase chronic myeloid leukemia (CML) patients. Recent studies indicate the presence of pre-existing BCR-ABL mutations in a higher percentage of CML patients when CD34+ stem/progenitor cells are investigated using sensitive techniques, and these mutations are associated with imatinib resistance and disease progression. However, such studies were limited to smaller number of patients.MethodsWe investigated BCR-ABL kinase domain mutations in CD34+ cells from 100 chronic-phase CML patients by multiplex allele-specific PCR and sequencing at diagnosis. Mutations were re-investigated upon manifestation of imatinib resistance using allele-specific PCR and direct sequencing of BCR-ABL kinase domain.ResultsPre-existing BCR-ABL mutations were detected in 32/100 patients and included F311L, M351T, and T315I. After a median follow-up of 30 months (range 8–48), all patients with pre-existing BCR-ABL mutations exhibited imatinib resistance. Of the 68 patients without pre-existing BCR-ABL mutations, 24 developed imatinib resistance; allele-specific PCR and BCR-ABL kinase domain sequencing detected mutations in 22 of these patients. All 32 patients with pre-existing BCR-ABL mutations had the same mutations after manifestation of imatinib-resistance. In imatinib-resistant patients without pre-existing BCR-ABL mutations, we detected F311L, M351T, Y253F, and T315I mutations. All imatinib-resistant patients except T315I and Y253F mutations responded to imatinib dose escalation.ConclusionPre-existing BCR-ABL mutations can be detected in a substantial number of chronic-phase CML patients by sensitive allele-specific PCR technique using CD34+ cells. These mutations are associated with imatinib resistance if affecting drug binding directly or indirectly. After the recent approval of nilotinib, dasatinib, bosutinib and ponatinib for treatment of chronic myeloid leukemia along with imatinib, all of which vary in their effectiveness against mutated BCR-ABL forms, detection of pre-existing BCR-ABL mutations can help in selection of appropriate first-line drug therapy. Thus, mutation testing using CD34+ cells may facilitate improved, patient-tailored treatment.

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Section: Introductionmentioning

confidence: 99%

Sensitive Detection of Pre-Existing BCR-ABL Kinase Domain Mutations in CD34+ Cells of Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia Patients Is Associated with Imatinib Resistance: Implications in the Post-Imatinib Era

et al. 2013

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“…In line with previous studies, ABL1 KD mutations were exclusive to pattern 2. 20,48,49 However, there were 3 patients with pattern 2 mutations that lacked ABL1 KD mutations. Interestingly, there were also 8 TKIresistant patients among the mutation-free group (pattern 0).…”

Section: Discussionmentioning

confidence: 99%

Spectrum of somatic mutation dynamics in chronic myeloid leukemia following tyrosine kinase inhibitor therapy

Kim

Tyndel

Kim

et al. 2017

Blood

120

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“…99,100 Preexisting and evolving Bcr-Abl mutations could be identified at diagnosis (pre-TKI) using sensitive sequencing techniques, 101,102 However, pre-TKI KD mutations appear to be more prevalent in Sokal high-risk patients and accelerated/blast phase CML. 103,104 For example, KD mutations prior to initiation of TKI were identifiable by direct sequencing in 8 of 13 (62%) Sokal high-risk, 1 of 6 Sokal intermediate-risk, and 0 of 24 Sokal low-risk patients. 102 Willis et al 104 did not detect Bcr-Abl KD mutations in unselected, imatinib naïve CML-CP patients; however, ;30% of accelerated phase (CML-AP) and 25% of blast phase CML (CML-BP) imatinib-naïve patients harbored mutations.…”

Section: 96mentioning

confidence: 99%

Secondary mutations as mediators of resistance to targeted therapy in leukemia

Daver¹,

Cortes²,

Ravandi³

et al. 2015

Blood

120

110

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The advent of small molecule-based targeted therapy has improved the treatment of both acute and chronic leukemias. Resistance to small molecule inhibitors has emerged as a common theme. The most frequent mode of acquired resistance is the acquisition of point mutations in the kinase domain. FLT3 inhibitors have improved response rates in FLT3-mutated acute myeloid leukemia (AML). The occurrence of the ATP-binding site and activation loop mutations confers varying degrees of resistance to the individual FLT3 inhibitors. Second-generation FLT3 inhibitors such as crenolanib may overcome the resistance of these mutations. Furthermore, nonmutational mechanisms of resistance such as prosurvival pathways and bone marrow signaling may be upregulated in FLT3 inhibitor-resistant AML with secondary kinase domain mutations. More recently, point mutations conferring resistance to the Bruton tyrosine kinase inhibitor ibrutinib in chronic lymphocytic leukemia, arsenic trioxide in acute promyelocytic leukemia, and the BH3-mimetic ABT199 in lymphoma have been identified. In chronic myeloid leukemia, the emergence of tyrosine kinase domain mutations has historically been the dominant mechanism of resistance. The early identification of secondary point mutations and their downstream effects along with the development of second- or third-generation inhibitors and rationally designed small molecule combinations are potential strategies to overcome mutation-mediated resistance.

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Kinase domain mutations of BCR-ABL identified at diagnosis before imatinib-based therapy are associated with progression in patients with high Sokal risk chronic phase chronic myeloid leukemia

Cited by 21 publications

References 19 publications

Sensitive Detection of Pre-Existing BCR-ABL Kinase Domain Mutations in CD34+ Cells of Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia Patients Is Associated with Imatinib Resistance: Implications in the Post-Imatinib Era

Sensitive Detection of Pre-Existing BCR-ABL Kinase Domain Mutations in CD34+ Cells of Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia Patients Is Associated with Imatinib Resistance: Implications in the Post-Imatinib Era

Spectrum of somatic mutation dynamics in chronic myeloid leukemia following tyrosine kinase inhibitor therapy

Secondary mutations as mediators of resistance to targeted therapy in leukemia

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