The treatment of chronic myeloid leukemia (CML) was revolutionized with the advent of the first-generation tyrosine kinase inhibitors (TKIs), but drug resistance developed during treatment, leading to the development of the second-generation (dasatinib, nilotinib, and bosutinib) and third-generation (ponatinib) TKI. Compared with previous treatment regimens, specific TKI can significantly improve the response rate, overall survival rate and prognosis of CML. Only a few patients with BCR-ABL mutation are insensitive to the second-generation TKIs, so it is suggested to select the second-generation TKIs for patients with specific mutations. For patients with other mutations and without mutations, the second-generation TKI should be selected according to the patient's medical history, while the third-generation TKIs should be selected for mutations that are insensitive to the second-generation TKIs, such as T315I mutation that is sensitive to ponatinib. Due to different BCR-ABL mutations in patients with different sensitivity to the second and third-generation TKIs, this paper will review the latest research progress of the efficacy of the second and third-generation TKIs in CML patients with BCR-ABL mutations.
Humans ; Antineoplastic Agents/pharmacology* ; Dasatinib/pharmacology* ; Drug Resistance, Neoplasm/genetics* ; Fusion Proteins, bcr-abl/genetics* ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy* ; Mutation ; Protein Kinase Inhibitors/therapeutic use*

OBJECTIVE: To explore the genetic basis for a rare case of acute B-lymphocytic leukemia (B-ALL) with double Philadelphia chromosomes (Ph) and double derivative chromosome 9s [der(9)]. METHODS: A patient with double Ph and double der(9) B-ALL who presented at Shanghai Zhaxin Intergrated Traditional Chinese and Western Medicine Hospital in June 2020 was selected as the subject. Bone marrow morphology, flow cytometry, G-banding karyotyping, fluorescence in situ hybridization (FISH), genetic testing and chromosomal microarray analysis (CMA) were used to analyze bone marrow samples from the patient at various stages. RESULTS: At initial diagnosis, the patient's bone marrow morphology and flow immunotyping have both supported the diagnosis of B-ALL. G-banded karyotyping of the patient indicated double Ph, in addition with hyperdiploid chromosomes involving translocations between chromosomes 9 and 22. BCR-ABL1 fusion gene was positive. Genetic testing at the time of recurrence revealed presence of a heterozyous c.944C>T variant in the kinase region of the ABL1 gene. FISH showed a signal for ABL1-BCR fusion on both chromosome 9s. CMA showed that the mosaicism homozygosity ratio of chromosome 9 was about 40%, and the mosaicism duplication ratio of chromosome 22 was about 43%. CONCLUSION Since both der(9) homologs were seen in 40% of cells, the possible mechanism for the double der(9) in this patient may be similar to that of double Ph, which might have resulted from non-disjunction during mitosis in the Ph chromosome-positive cell clone.
Humans ; Philadelphia Chromosome ; In Situ Hybridization, Fluorescence/methods* ; China ; Chromosome Aberrations ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics* ; Translocation, Genetic ; Fusion Proteins, bcr-abl/genetics* ; Chromosomes, Human, Pair 9/genetics*

OBJECTIVE: To analyze 43 leukemia genes in children with acute lymphoblastic leukemia (ALL) in Yunnan province, and provide the basis for the diagnosis and treatment of children with ALL in this area. METHODS: The clinical data of 428 children with newly diagnosed ALL in Yunnan area from January 2015 to December 2020 were retrospectively analyzed. Multiple nested PCR technology was used to detect 43 common leukemia genes. RESULTS: Among the 428 children with ALL, 159 were positive for leukemia genes, with a positive rate of 37.15% (159/428), and a total of 15 leukemia genes were detected. Among the 159 leukemia gene-positive children, ETV6-RUNX1⁺ accounted for 25.79% (41/159), followed by E2A-PBX1⁺ and BCR-ABL⁺, accounting for 24.53% (39/159) and 23.27% (37/159) respectively. MLL⁺ accounted for 6.29% (10/159), WT1⁺ accounted for 4.40% (7/159), IKZF1 gene deletion and CRLF2⁺ accounted for 3.77% (6/159) respectively. The positive rate of MLL (46.15%) was the highest in ＜1-year old group, the positive rate of ETV6-RUNX1 (10.56%) was the highest in 1-10-year old group, and BCR-ABL⁺ rate (23.65%) was the highest in >10-year old group. The distribution of leukemia genes in different age groups was statistically significant (P <0.05). CONCLUSION The most common fusion gene of children with ALL in Yunnan is ETV6-RUNX1, followed by E2A-PBX1 and BCR-ABL.
Child ; Humans ; Infant ; Child, Preschool ; Oncogene Proteins, Fusion/genetics* ; Fusion Proteins, bcr-abl/genetics* ; Core Binding Factor Alpha 2 Subunit/genetics* ; Retrospective Studies ; China ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy* ; Genotype

BCR-ABL^T315I mutation is the main mechanism of resistance to the first and second generation tyrosine kinase inhibitor (TKI) for patients with chronic myeloid leukemia (CML). Ponatinib as the third generation TKI has been found that can significantly improve the prognosis of CML patients with T315I mutation. However, the latest report has discovered that the T315I compound mutant is even resistant to ponatinib, which aroused the enthusiasm of research on the mechanism of CML resistance and targeted therapy once again. Previous studies have shown that TKI combined with other targeted drugs is effective to CML patients with drug resistance or relapse due to T315I mutation. The latest research has found that the allosteric inhibitor asciminib combined with TKI therapy is equally effective to CML patients with T315I compound mutant, but the specific mechanism is not yet clarified. This review will focus on the latest research progress of therapy for CML with BCR-ABL^T315I mutation, hoping to provide reference for researching new drugs and improve therapy for treating CML with T315I mutation.
Humans ; Drug Resistance, Neoplasm/genetics* ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics* ; Fusion Proteins, bcr-abl/genetics* ; Protein Kinase Inhibitors/therapeutic use* ; Mutation ; Antineoplastic Agents/pharmacology*

OBJECTIVE: To establish a new digital polymerase chain reaction (dPCR) system for the detection of BCR-ABL fusion gene in patients with chronic myeloid leukemia (CML), and explore its analytical performance and clinical applicability in the detection of BCR-ABL^p190/210/230. METHODS: A new dPCR system for detecting BCR-ABL^p190/210/230 was successfully developed, and its sensitivity difference with qPCR and improvement of drug side effects in patients with CML during drug reduction or withdrawal were compared. RESULTS: Among 176 samples, qPCR and dPCR showed high consistency in the sensitivity of detecting BCR-ABL (82.39%), and the positive rate of dPCR was about 5 times higher that of qPCR (20.45% vs 3.98%). During follow-up, blood routine (25% vs 10%), kidney/liver/stomach (25% vs 20%) and cardiac function (10% vs 0) were significantly improved after drug reduction or withdrawal in patients with initial dPCR negative compared with before drug reduction or withdrawal. CONCLUSIONS This new dPCR detection system can be applied to the detection of BCR-ABL^p190/210/230. It has better consistency and higher positive detection rate than qPCR. Drug withdrawal or dose reduction guided by dPCR has a certain effect on improving drug side effects.
Humans ; Fusion Proteins, bcr-abl/genetics* ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/diagnosis* ; Polymerase Chain Reaction ; Drug-Related Side Effects and Adverse Reactions ; Reverse Transcriptase Polymerase Chain Reaction

OBJECTIVE: To analyze the comprehensive laboratory test data of BCR-ABL1 fusion gene and JAK2 V617F mutation co-expressed in myeloproliferative neoplasm (MPN) patients, and investigate its relative clinical significance. METHODS: Data of 1 332 MPN patients were comprehensively analyzed, BCR-ABL1 (P190/P210/P230) fusion gene and JAK2 V617F mutation were detected by real time-polymerase chain reaction (RT-PCR) technique, the CALR, MPL, JAK2 12 and 13 exon mutations were detected by the First Generation Sequencing, the bone marrow cell morphology and pathological characteristics were evaluated by bone marrow smear and biopsy technique, the immune phenotypes of bone marrow cells were evaluated by flow cytometry, the chromosome karyotypes of bone marrow cells were analyzed by chromosome G banding technique. RESULTS: Four of the 1 332 patients were found to have the co-existence of BCR-ABL1 fusion gene and the JAK2 V617F mutation, with a 0.3% incidence and a median age of 70 years old, including 2 cases of polycythemia vera, 1 case of primary myelofibrosis, and 1 case of chronic myeloid leukemia-accelerated phase. The clues of double positive genes of such patients at the time of initial diagnose could not be cued only by age, physical signs and cell morphology, they should be analyzed by comprehensive test data. CONCLUSION The co-existence of BCR-ABL1 fusion gene and JAK2 V617F mutation in the same case is a kind of disease with special clinical significance. The application of multiple detection methods can improve the detection of this disease, which is conducive to early detection, reasonable diagnosis and treatment by clinicians.
Aged ; Fusion Proteins, bcr-abl/genetics* ; Humans ; Janus Kinase 2/genetics* ; Laboratories ; Mutation ; Myeloproliferative Disorders/genetics* ; Polycythemia Vera

OBJECTIVE: To explore the expression level of ETV6-ABL fusion gene in different cell populations in patients with myeloproliferative neoplasm (MPN) and therapeutic effect of tyrosine kinase inhibitor (TKI). METHODS: A 42-year-old man who presented with fever, marked leukocytosis and chronic myelogenous leukemia (CML) like MPN was reported. ETV6-ABL fusion gene was detected by real-time PCR and confirmed by direct sequencing. ETV6-ABL mRNA expression in each cell population sorted from peripheral blood by flow cytometry was detected by real-time PCR. RESULTS: ETV6-ABL fusion gene was found out in bone marrow cells and confirmed as type A by direct sequencing. ETV6-ABL fusion gene transcript level in polymorphonuclear cells was nearly 3.6-fold relative to that in total cells, which was significantly higher than that in T cell, B cell and monocyte subsets. The complete blood count (CBC) returned to normal level after treatment with imatinib (400 mg) daily for three months. After TKI treatment for 6 months, the ratio of ETV6-ABL/ABL decreased from 174.1% to 1.9%. CONCLUSION ETV6-ABL fusion gene positive MPN may have a CML clinical presentation and is sensitive to TKI. ETV6-ABL fusion gene is specifically expressed in polymorphonuclear cells.
Adult ; Fusion Proteins, bcr-abl/genetics* ; Genes, abl ; Hematopoietic Stem Cell Transplantation ; Humans ; Imatinib Mesylate ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics* ; Male ; Myeloproliferative Disorders/genetics*

OBJECTIVE: To evaluate the clinical efficacy and safety of domestic imatinib (made in China) in patients with newly diagnosed chronic myeloid leukemia chronic phase(CML-CP). METHODS: Fifty-seven newly diagnosed CML-CP patients who did not receive any other anti-CML treatment were treated by domestic imatinib 400 mg once a day. The hematological, cytogenetic and molecular reactions and safety were observed and evaluated after 3, 6 and 12 months of treatment. RESULTS: Fifty-six patients were treated for ≥3 and 6 months, among which 50 patients were treated for ≥12 months. After 3 months of treatment, 49 patients underwent hematological examination, 47 patients (95.9%) achieved complete hematological response (CHR), 49 patients underwent cytogenetic examination, 39 patients (79.6%) achieved major cytogenetic response (MCyR), and 12 patients (24.5%) achieved complete cytogenetic response (CCyR). 49 patients underwent the level of BCR-ABL test, including 41 patients (83.7%) with BCR-ABL CONCLUSION In the real world, Domestics imatinib mesylate is effective and safe in the treatment of newly diagnosed CML-CP patients, but long-term follow-up data are still necessary to verify its long-term efficacy.
Antineoplastic Agents/therapeutic use* ; Benzamides/therapeutic use* ; China ; Fusion Proteins, bcr-abl/genetics* ; Humans ; Imatinib Mesylate/therapeutic use* ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy* ; Piperazines ; Pyrimidines/therapeutic use* ; Treatment Outcome

OBJECTIVE: To analyze the disease types, clinical manifestations, efficacy and outcome of JAK2 V617F and BCR-ABL double-mutant myeloproliferative neoplasms (MPN), and provide a reference for the diagnosis, treatment and prognosis of MPN. METHODS: The clinical characteristics, diagnosis, therapeutic efficacy and outcome of JAK2 V617F and BCR-ABL double-mutant MPN were analyzed comprehensitively by combining a clinical case diagnosed and treated in our hospital with literature cases from CNKI and PubMed databases. RESULTS: A total of 38 related literatures were retrieved from the two databases by searching "JAK2 V617F" and "BCR-ABL" as key words from 1990 to 2019, and 59 cases were involved. Among all the 60 cases, 41 were males (68.3%) with a median age of 61 (32-77) years old, while 19 were females (31.7%) with a median age of 58 (21-82) years old. The BCR-ABL fusion gene and JAK2 V617F mutation were found simultaneously in 21 cases (35%), 19 cases (31.7%) with JAK2 V617F mutation were found during the treatment of Philadelphia chromosome (Ph)-positive chronic myelogenous leukemia (CML). Ph CONCLUSION As cases of BCR-ABL and JAK2 V617F double-mutant MPN are reported, simultaneous detection of JAK2 V617F mutation and BCR-ABL fusion gene in MPN patients is necessary to avoid misdiagnosis and missed diagnosis.
Adult ; Aged ; Aged, 80 and over ; Female ; Fusion Proteins, bcr-abl/genetics* ; Humans ; Janus Kinase 2/genetics* ; Male ; Middle Aged ; Myeloproliferative Disorders/genetics* ; Polycythemia Vera ; Thrombocythemia, Essential ; Young Adult

OBJECTIVE: To observe the curative efficacy of tyrosine kinase inhibitors (TKIs) in the treatment of e19a2 transcript (P230) CML chronic phase (CML-CP) patients. METHODS: The clinical data of 11 P230 CML-CP patients were collected from July 2008 to December 2019. Blood routine examination, bone marrow cytology, chromosome, and BCR-ABL qualitative and quantitative tests were performed at initial diagnosis. After TKIs treatment, BCR-ABL (P230)/ABL in peripheral blood was regularly detected to evaluate molecular response by real-time quantitative PCR. RESULTS: There were 11 patients (7 males and 4 females) in chronic phase from 6 domestic hospitals enrolled, their median age was 46 years old (range from 19 to 56 years old). Among 4 patients treated with imatinib (400 mg, qd) firstly, 3 cases switched to nilotinib (400 mg, bid) and 1 case switched to dasatinib (100 mg, qd) due to failure to achieve best molecular response at the landmark time or mutation of ABL kinase. Then major molecular response (MMR) was obtained within 1 year. In addition, 5 patients were treated with nilotinib (300 mg, bid) and 2 patients with dasatinib (100 mg, qd) as first-line treatment, all of them got MMR within 6 months. CONCLUSION For intolerance or resistance to imatinib, second-generation TKIs can enable P230 CML patients to achieve deeper molecular response, and MMR in a short time.
Adult ; Dasatinib ; Female ; Fusion Proteins, bcr-abl/genetics* ; Humans ; Imatinib Mesylate ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy* ; Male ; Middle Aged ; Protein Kinase Inhibitors ; Young Adult