Efficacy and safety of flumatinib in treatment of imatinib-resistant or imatinib-intolerant patients with chronic myeloid leukemia / 白血病·淋巴瘤

Objective:To investigate the efficacy and safety of flumatinib in the treatment of imatinib-resistant or imatinib-intolerant patients with chronic phase chronic myelogenous leukemia (CML-CP).Methods:The clinical data of 9 CML-CP patients who received flumatinib after imatinib resistance or intolerance in Jining No. 1 People's Hospital from April 2020 to May 2021 were retrospectively analyzed. Patients were evaluated for the hematologic, cytogenetic and molecular responses, progression-free survival (PFS), event-free survival (EFS), and adverse reactions.Results:Among 9 CML-CP patients, there were 4 imatinib-resistant patients and 5 imatinib-intolerant patients. The median duration of flumatinib exposure was 17 months (1-25 months). Except for 1 case who discontinued flumatinib early due to grade 4 thrombocytopenia and other adverse reactions, 7 of the remaining 8 cases achieved the best response at 3, 6 and 12 months of flumatinib therapy. By the end of follow-up in April 2022, 7, 7 and 6 patients achieved complete cytogenetic response (CCyR), major molecular response (MMR) and molecular response 4.5 (MR4.5), respectively. The median time to achieving CCyR, MMR and MR4.5 was 4.5 months (3-6 months), 12 months (3-12 months) and 15 months (3-21 months), respectively. Within 17 months (11-25 months) of follow-up, 7 of the 9 patients had EFS and 8 patients with continuous flumatinib had PFS. Among 9 patients treated with flumatinib, hematologic adverse reactions were observed in 6 cases, and grade 3-4 hematologic adverse reactions occurred in 2 cases. Non-hematologic reactions events mainly included diarrhea (4 cases), muscle ache (2 cases), fatigue (2 cases) and liver damage (2 cases), which were all grade 1-2.Conclusions:Flumatinib is effective and well tolerated in the treatment of imatinib-resistant or imatinib-intolerant CML-CP patients.

Pediatric chronic myeloid leukemia in myeloid blast crisis

ABSTRACT Chronic myeloid leukemia (CML) accounts for 2-3% of childhood leukemias. About 5% of cases present in a blastic phase of CML which clinically and morphologically mimics more common acute leukemias of childhood. We report a case of a 3-year-old male who presented with gradual onset swelling of the abdomen and extremities along with generalized weakness. Examination revealed massive splenomegaly, pallor, and pedal edema. Initial workup showed anemia, thrombocytopenia, and leukocytosis (120,000/uL) with a blast percentage of 35%. Blasts were positive for CD13, CD33, CD117, CD34 and HLA-DR, and stained negative for Myeloperoxidase and Periodic Acid Schiff. Fluorescence in situ hybridization was positive for b3a2/e14a2 junction BCR-ABL1 transcript and negative for RUNX1-RUNX1T1/t(8;21), clinching the diagnosis of CML in myeloid blast crisis. The patient expired within 17 days of diagnosis and initiation of therapy.

Progress in molecular resistance mechanisms of targeted therapy for chronic myeloid leukemia / 白血病·淋巴瘤

Resistance or drug-resistant recurrence of targeted tumor therapy is a complex and multi-factorial process, with the final result of tumor clones that can evade treatment or have relative proliferation advantages under treatment pressure being selectively retained. The BCR::ABL1 fusion gene is the primary molecular abnormality of chronic myeloid leukemia (CML), and the development and application of tyrosine kinase inhibitors (TKI) targeting the BCR::ABL1 fusion protein pioneered the era of small molecule targeted therapeutics. Several TKI have been approved for clinical application or in development. Although most CML patients manifest an excellent response to TKI treatment, there are still some patients with poor primary response or relapse with drug resistance. With the increase in the number of patients with long-term maintenance therapy and the sequential use of multiple TKI, the resistance of TKI has become more complicated. This article introduces the research progress of CML molecular resistance mechanisms in recent years and shares the relevant cutting-edge reports at the 63rd American Society of Hematology Annual Meeting in 2021.

Progress of immunological surveillance in the treatment-free remission of chronic myelogenous leukemia / 白血病·淋巴瘤

With the wide application of tyrosine kinase inhibitor (TKI), to obtain treatment-free remission (TFR) has gradually become the long-term goal for patients with chronic myelogenous leukemia (CML). Self-renewing leukemia stem cells during disease progression are related with the recurrence, and surveillance of residual leukemic cells is hypothesized to be one of the critical factors in successful TFR. On the way to obtain TFR, many breakthroughs have been made in innate and adaptive immunity of CML cells. This paper reviews the immune function of CML patients, the role of the immune markers in maintaining TFR, and the exploration of TKI combined with new immunomodulator therapy to achieve a greater degree of TFR.

Progress of hematologic malignancy related gene mutations in patients with chronic myelogenous leukemia / 白血病·淋巴瘤

Chronic myelogenous leukemia (CML) is a myeloproliferative disease characterized by heterotopic Ph chromosome. Tyrosine kinase inhibitor (TKI) has significantly improved the prognosis of patients with CML. Cytogenetic and molecular monitoring for assessing the therapeutic efficacy of TKI to guide disease management has become an important component of CML therapy. However, the expanded genomic analysis of the disease diagnosis, transformation and drug resistance has not been fully explored in CML research. The paper reviews the frequency and type of gene mutations at initial diagnosis and the time of treatment failure and transformation, and investigates the relationship between genetic mutations and the prognosis of CML patients in the diagnosis and treatment.

Study on the mechanism of circular permuted tumor necrosis factor-related apoptosis-inducing ligand reversing the resistance to imatinib in chronic myeloid leukemia cells / 白血病·淋巴瘤

Objective:To explore the mechanism of circular permuted tumor necrosis factor-related apoptosis-inducing ligand (CPT) reversing the resistance to imatinib in chronic myeloid leukemia (CML) cells.Methods:Five patients with CML in the Affiliated Hospital of Inner Mongolia Medical University from 2016 to 2020 were selected, and heparinized bone marrow blood samples were collected at the first diagnosis and imatinib resistance phase, and mononuclear cells were isolated. The mononuclear cells collected at the first diagnosis were named A1-E1, and the mononuclear cells collected after imatinib resistance were named A2-E2. Human CML wild-type K562 cell line (K562-W) was given gradually increasing small doses of low-concentration imatinib to obtain imatinib-resistant K562 cells (K562-R). K562-R cells were cultured with 20 μg/L CPT and these cells were set as CPT-K562-R group. The CCK-8 method was used to detect the half inhibitory concentration ( IC50) of cells for imatinib. K562-W and K562-R cells were used to establish CML xenografts nude mice models, then the nude mice were divided into K562-W, K562-R and CPT-K562-R xenograft groups. Imatinib was perfused orally in all three groups, and CPT was injected subcutaneously in the CPT-K562-R group at the same time. The tumor volume of the three groups of nude mice before and 4 weeks after treatment with imatinib, and the survival time of the three groups of nude mice were compared. Western blot was used to detect the changes of tyrosine protein kinase receptor B4 (EphB4) and myeloid cell leukemia protein 1 (Mcl-1) protein levels in bone marrow mononuclear cells, K562 cell line and transplanted tumor tissues of CML patients. Results:The expressions of EphB4 protein in A2-E2 cells of 5 patients with CML were higher than those in A1-E1 cells (all P < 0.01). The IC50 of K562-W, K562-R and CPT-K562-R cells for imatinib were (0.160±0.015) mg/L, (5.450±0.460) mg/L, (0.300±0.035) mg/L, and the difference was statistically significant ( F = 390.65, P < 0.01). In cells of K562-W group, EphB4 and Mcl-1 proteins were expressed at low levels (0.54±0.02 and 0.70±0.08); in cells of K562-R group, the expressions of EphB4 and Mcl-1 proteins were enhanced (3.04±0.11 and 2.88±0.04); in cells of CPT-K562-R group, the expressions of EphB4 and Mcl-1 proteins decreased (0.57±0.03 and 0.38±0.04). Before imatinib treatment, there was no statistically significant difference in the tumor volumes of nude mice among the K562-W, K562-R and CPT-K562-R xenograft groups ( F = 0.39, P = 0.68), suggesting the transplanted tumors formed in nude mice were balanced; after imatinib treatment, the difference in the tumor volumes among the three groups were statistically significant ( F = 26.16, P < 0.01). The survival time of nude mice in the K562-W, K562-R and CPT-K562-R xenograft groups was (18.5±3.3) d, (10.0±2.4) d and (17.5±1.6) d, and the difference was statistically significant ( F = 20.45, P < 0.01). In K562-W xenograft group, both EphB4 and Mcl-1 proteins were expressed at low levels (0.55±0.06 and 0.67±0.06); in K562-R xenograft group, the expressions of EphB4 and Mcl-1 proteins were enhanced (1.95±0.08 and 6.21±0.53); the expressions of EphB4 and Mcl-1 in CPT-K562-R xenograft group decreased (0.59±0.04 and 0.37±0.04) and were close to their expressions in K562-W xenograft group. Conclusion:CPT may enhance the sensitivity of CML to imatinib by inhibiting the expressions of EphB4 and Mcl-1, and this may be a targeted pathway for imatinib therapy.

Myeloid sarcoma: an uncommon presentation of myeloid neoplasms; a case series of 4 rare cases reported in a tertiary care institute

Myeloid sarcoma (MS) is a rare extramedullary neoplasm of myeloid cells, which can arise before, concurrently with, or following hematolymphoid malignancies. We report 04 such cases of MS, diagnosed in this institute over a period of 6 years, during various phases of their respective myeloid neoplasms/leukemias. These cases include MS occurring as a relapse of AML (Case 1), MS occurring as an initial presentation of CML (Case 2), MS occurring during ongoing chemotherapy in APML (Case 3), and MS presenting as a progression of MDS to AML (Case 4). In the absence of relevant clinical history and unemployment of appropriate immunohistochemical (IHC) studies, these cases have a high risk of being frequently misdiagnosed either as Non-Hodgkin's Lymphoma (NHL) or small round cell tumors or undifferentiated carcinomas, which may further delay their management, making an already bad prognosis worse. This case series has been designed to throw light on the varied presentation of MS and the lineage differentiation of its neoplastic cells through the application of relevant IHC markers along with their clinical correlation.

Renal tuberculosis in an imatinib-treated chronic myeloid leukemia / Tuberculose renal em paciente com leucemia mieloide crônica tratado com imatinibe

ABSTRACT Imatinib, which inhibits tyrosine kinase activity of Bcr-Abl protein, is a standard form of treatment for chronic myeloid leukemia (CML). Through its immunomodulatory effect it affects T cell function in a number of ways. It inhibits antigen-induced T cell activation and proliferation. Antigen-specific T-cells and macrophages are vital for protection against Mycobacterium tuberculosis. Here we present a case of renal tuberculosis associated with imatinib therapy in the maintenance phase of CML. With granulomatous interstitial nephritis and positive tubercular DNA on renal biopsy, the condition was successfully treated with anti-tubercular therapy. This case provides support to the hypothesis that imatinib therapy in CML increases the susceptibility to tuberculosis and strict vigilance is required to enable its early detection and treatment.

RESUMO O imatinibe, um inibidor da atividade da tirosina-quinase da proteína BCR-ABL, faz parte do padrão de tratamento para leucemia mieloide crônica (LMC). Por conta de seu efeito imunomodulador, o imatinibe afeta a função dos linfócitos T de várias maneiras ao inibir a sua ativação e proliferação induzidas por antígenos. Linfócitos T e macrófagos antígeno-específicos são vitais para a proteção contra o Mycobacterium tuberculosis. O presente artigo relata um caso de tuberculose renal associada a terapia com imatinibe na fase de manutenção da LMC. Com nefrite intersticial granulomatosa e positividade para DNA de M. tuberculosis na biópsia renal, o paciente foi tratado com sucesso com terapia antituberculínica. O presente caso corrobora a hipótese de que a terapia com imatinibe na LMC aumenta a suscetibilidade à tuberculose, exigindo vigilância rigorosa para permitir sua detecção e tratamento precoces.

Diagnosis and treatment progress of chronic myeloid leukemia / 白血病·淋巴瘤

Chronic myeloid leukemia (CML) has made a milestone progress due to the development of the first generation tyrosine kinase inhibitor(TKI). Nowadays, most clinical trials in CML focus on discontinuation, even the second discontinuation, and the third generation TKI against T315I mutation. The conventional treatments are more focused on decreasing BCR-ABL transcripts rapidly. At the same time, the treatment management of some special patients has been valued.

Treatment progress of chronic myeloid leukemia / 白血病·淋巴瘤

A great progress has been made in the treatment of chronic myeloid leukemia (CML) owing to the first generation tyrosine kinase inhibitor (TKI). Nowadays, more and more hematologists are eager to understand how to rapidly reduce the BCR-ABL transcripts level, and to get the standard therapeutic reactions, which emerges the second generation TKI. However, the first and second generation TKI have the potential of drug resistance, and thus the third and fourth generation TKI may resolve this problem. Imatinib drug discontinuation trial emphasizes the importance of digital polymerase chain reaction (PCR) and the probability of the second treatment-free remission.

Prognosis of clonal chromosomal abnormalities in Philadelphia negative metaphases cells in chronic myeloid leukemia with tyrosine kinase inhibitor therapy / 中华血液学杂志

Objective@#To investigate the characteristics and prognosis of clonal chromosomal abnormalities appearing in Philadelphia negative metaphases (CCA/Ph-) cells in chronic myeloid leukemia (CML) with tyrosine kinase inhibitor (TKI) therapy.@*Methods@#The clinical data of 30 cases with CCA/Ph- during TKI treatment in Henan Cancer Hospital from August 2007 to July 2017 were retrospectively analyzed. The univariate factor was analyzed by Kaplan-Meier method. Multiple-factor was analyzed by Cox proportional risk model.@*Results@#Of the 30 cases, 19 (63.3%) were males. At the first detection of CCA/Ph- the median age was 44 (rang 14-68) years old and the median treatment of TKI was 13 (rang 2-94) months. The clones proportion of first detected CCA/Ph-≥ 50% was found in 18 (60.0%) cases. TKI treatment for 3 months with BCR-ABLIS less than 10% was seen in 14 (46.7%) patients. 63.3% (19/30) of CCA/Ph- was transient (only one time) and 36.7% (11/30) was repeated (≥2 times) . Trisomy 8 dominant accounted for 60.0% (18/30) , -7/7q- for 13.3% (4/30) , loss of chromosome Y 6.7%. With a median of follow-up 50 months, 76.7% (23/30) cases were in complete cytogenetic response (CCyR) ; 63.3% (19/30) in major molecular response (MMR) , 43.3% (13/30) in undetectable minimal residual disease (UMRD) . The median event-free survival rate of (EFS) were 44 months, and 2-year and 5-year EFS were (82.1±7.3) % and (52.4±12.8) %, respectively. The median overall survival (OS) were 50 months, and 2-year and 5-year OS rates were (92.6±5.0) % and (77.2±14.7) %, respectively. Univariate analysis shows that the 2-year EFS of who in males, more than 2 times CCA/Ph-, BCR-ABLIS>10% at 3 months after TKI were significantly lower than women, transient CCA/Ph-, and BCR-ABLIS≤10% (P<0.05) . The 2-year OS rate in whom the occurrence frequency of CCA/Ph- more than twice was significantly lower than those with transient CCA/Ph- (P<0.05) . Multivariate analysis showed that CCA/Ph- was an independent risk factor (RR=4.741, 95%CI 1.21-18.571, P=0.018) for EFS in CML patients.@*Conclusion@#Trisomy 8, -7/7q-, and -Y were the most common CCA/Ph- during TKI treatment, with high clones proportion of ≥50%. CCA/Ph- mainly occurred transiently or was permanent occasionally. CCA/Ph- recurrence (≥2 times) was an independent risk factor for EFS and OS in CML with TKI.

Correlation research of morphology and immunological typing in acceleration phase and blastic phase of chronic myelogenous leukemia / 重庆医学

Objective To explore the characteristics of morphology and immunology in acceleration phase and blastic phase of chronic myelogenous leukemia(CML).Methods Seventy-three cases of CML-BP bone marrow specimens were respectively conducted the morphology and related cell chemical dyeing observation for determining the FAB type.Flow cytometry was used to detect series immunological related antigens.Results Among 73 cases of FAB typing,there were 44 cases of CML-AML,21 cases of ALL and 8 cases.21 cases CML-ALL patients In the immunophenotyping by flow cytometry,among 21 cases of CML-ALL,there were 19 cases of B-ALL,2 cases of T-ALL,moreover 12 cases contained myeloid marker.Among 8 cases CML-HAL,the immunophenotypes were 6 cases of B+-My and 2 cases of T+ My.Among 44 cases CML-AML,15 cases contained T cell marker,and 2cases contained B cell marker,other cases had no cross-lineage expression.Among 73 cases of CML-BP,29 cases conducted the flow cytometry detection in the acceleration phase,in which 16 cases urgently changed to AML,and 13 cases to non-AML(9 cases of ALL and 4 cases of HAL).Among non-AML cases,2 cases had the simultaneous existence of myeloid primitive cells and precursor lymphocyte in the acceleration phase and other 9 cases were myeloid primitive cell or accompanied by lymphocyte marker.Conclusion Flow cytometry has a certain implication role for the direction and differentiation diagnosis of CML-BP.

Dasatinib induces severe hemorrhagic colitis in a patient with accelerated phase of chronic myelogenous leukemia

No abstract available.

Análisis de metilación en pacientes con leucemia mieloide crónica en diferentes instituciones médicas de Medellín / Methylation analysis in patients with chronic myeloid leukemia in different medical institutions in Medellín

Fundamento: la leucemia mieloide crónica es una neoplasia mieloproliferativa crónica que se caracteriza por la presencia del cromosoma filadelfia. Para esta se ha diseñado como tratamiento los inhibidores de tirosin kinasa, que genera en los pacientes una respuesta hematológica, citogenética y molecular. Esta enfermedad se caracteriza por presentar tres fases clínicas que son producto de la acumulación de daños tanto genéticos representados por mutaciones puntuales y alteraciones en el cariotipo; y cambios epigenéticos en genes tales como ABL-1, OSCP1, PDLIM4, NPM2, ER y p15. Objetivo: describir los patrones de metilación de seis genes en pacientes con leucemia mieloide crónica en distintas fases de la enfermedad tratados con algún ITK´s o en su defecto con hidroxiurea en dos hospitales de Medellín. Métodos: se realizó un estudio analítico trasversal, en el que se recolectaron 34 muestras a conveniencia de pacientes con leucemia mieloide crónica. Para hacer el análisis de estas muestras se usó una PCR específica de metilación. Los datos analizados no se distribuyeron de forma normal, por lo que se realizaron pruebas no paramétricas como U de Man Whitney y test exacto de Fischer, con una significancia de 0,05. Resultados: se encontró diferencias de estadísticas significativas en los datos del hemograma de ambas fases de la enfermedad, también se encontró una alta frecuencia de genes metilados en fase acelerada. La metilación de p15, ABL-1, ER son independiente de la fase de la enfermedad. En los pacientes tratados con hidroxiurea se observó una metilación del 100 % para los genes NPM2, OSCP1 y PDLIM4 este comportamiento no se observó en los individuos tratados con ITK´S, no obstante, para aquellos pacientes que desarrollaron resistencia a los ITK´s se observó un porcentaje de metilación mayor en los genes OSCP1, ABL-1 y PDLIM4. Conclusiones: la metilación en los genes PDLIM4 y OSCP1, puede asociarse con pronóstico desfavorable, ya que puede estar relacionado con la progresión de fase crónica a acelerada y el desarrollo de resistencia a los ITK´s.

Background: chronic myeloid leukemia (CML) is a chronic myeloproliferative neoplasm characterized by the presence of the Philadelphia chromosome. A specific treatment is designed as tyrosine kinase inhibitors (ITK's), which induces patients to have a hematologic, cytogenetic and molecular response. This disease is characterized by three clinical phases that result from the accumulation of genetic damage, both represented by point mutations and alterations in the karyotype; and epigenetic changes in genes such as ABL, OSCP1, PDLIM4, Npm2, ER and p15. Objective: to describe the schemes of six gens in patients with chronic myeloid leukemia in different stages of the disease and treated with some ITK in two hospitals in Medellín. Methods: a descriptive transversal study was conducted, in which 34 samples were collected at the convenience of patients with chronic myeloid leukemia (CML). To make the analysis of these samples methylation specific PCR was done. Results: statistical differences in blood count data from both phases of the disease was found, a high frequency of methylated genes in accelerated phase was also found. p15 methylation, ABL, ER are independent of the stage of the disease. In patients treated with hydroxyurea, methylation of 100 % for OSCP1 and PDLIM4 genes was observed and this behavior was not observed in individuals treated with ITK'S. In patients who developed resistance to ITK's however was observed a higher percentage of methylation in genes OSCP1 and PDLIM4. Conclusions: methylation in PDLIM4 and OSCP1 genes could be associated with poor prognosis possibly being associated with progression of chronic to accelerated phase and the development of resistance to ITK's.

Comparative study of cytogenetic response evaluated by conventional banding analysis and fluorescence in situ hybridization in chronic myeloid leukemia patients during tyrosine kinase inhibitor treatment / 中华血液学杂志

Objective@#To compare the cytogenetic response detected by conventional banding analysis (CBA) and fluorescence in situ hybridization (FISH) and to explore the correlation between the cytogenetic and molecular response in chronic myeloid leukemia (CML) patients during tyrosine kinase inhibitor (TKI) treatment.@*Methods@#CBA, FISH and real-time quantitative reverse transcriptase polymerase chain reaction (RQ-PCR) methods were performed to detect the cytogenetic and molecular response simultaneously in 504 bone marrow samples from 367 CML patients who received TKI treatment.@*Results@#Among 504 samples, 344 were detected to reach complete cytogenetic response (CCyR) by CBA, while 297 samples reached CCyR by FISH which were considered to carry BCR-ABL positive cells<1%. When the results of CBA, FISH and RQ-PCR were compared in 493 samples at the same time, it showed that in 337 samples with CBA-CCyR, 273 (81.0%) reached FISH-CCyR and 289 (85.8%) were BCR-ABLIS (International Scale, IS) ≤1% by RQ-PCR, compared to 9.0 (261/290) were BCR-ABLIS ≤1% among 290 samples with FISH-CCyR. There was no significant difference in the median value of BCR-ABLIS between samples in CBA-CCyR and FISH-CCyR (0.21% vs 0.13%, z=-1.875, P=0.061) . Furthermore, when the samples were divided into three groups according to BCR-ABL positive cells (0,>0~<1%, 1%~5%) by FISH, the statistical difference was observed, the proportion of samples with BCR-ABLIS ≤1% in the three groups were 94.1%, 57.6% and 27.7% respectively (χ2=43.499, P<0.001; χ2=9.734, P=0.003) , while the median value of BCR-ABLIS were 0.10%, 0.64% and 1.80% respectively (z=-5.864, P<0.001; z=-4.787, P<0.001) .@*Conclusion@#FISH results were in good concordance with CBA in identify samples in CCyR, FISH was more sensitive and had better correlation with RQ-PCR results than CBA, but how to define FISH-CCyR need further study.

Clinical significance of cytogenetic monitoring in chronic myeloid leukemia / 中华血液学杂志

Objective@#To analyze the association of cytogenetic abnormalities with the prognosis of chronic myeloid leukemia (CML) patients in tyrosine kinase inhibitors (TKI) era.@*Methods@#Karyotype analysis of chromosome G-banding was carried out in 387 newly diagnosed CML patients by short-term culture of bone marrow cells. The correlation of cytogenetic abnormalities and CML progression was explored in combination with ABL tyrosine point mutations.@*Result@#Of 387 patients with positive BCR-ABL fusion gene assayed by fluorescence in situ hybridization (FISH) technique, 94.1% (364/387) patients were Ph positive and 5.9% (23/387) Ph negative; 320 patients (87.9%) had a translocation t (9;22) (q34;q11) and 5 (1.4%) a variant translocation t (v;22) . Additional cytogenetic aberrations (ACA) at diagnosis were found in 10.7% (39/387) Ph+ patients, major route ACA in 22 (56.4%) cases and minor route ACA in 15 (38.5%) cases and 2 patients (5.1%) lacked the Y chromosome (−Y) ; 23.4% (71/303) patients occurred ACA during TKI treatment and the most frequent abnormalities were abnormal chromosome numbersd, which were likely associated with high proportion of disease progression (χ2=168.21, P<0.001) and ABL tyrosine point mutations (χ2=29.04, P<0.001) . Newly diagnosed CML-CP patients with t (9;22) (q34;q11) had a longer event-free survival (EFS) and disease-free survival (DFS) rates than that of patients with ACA (P=0.037; P=0.003) , while the overall survival (OS) had no significant differences (P=0.209) . As for CML-CP patients that occurred ACA during TKI therapy would have a marked low OS, EFS and DFS (all P<0.001) compared with no ACA occurred patients. Survival of advanced patients that occurred ACA were dramatically reduced.@*Conclusion@#ACA often emerged during the disease progress in CML patients, regular and timely detection of chromosomes karyotype and ABL tyrosine point mutations during TKI treatment was important for therapeutic evaluation, progress and prognosis of CML.

Progression and clinical application of tyrosine kinase inhibitors for the treatment of chronic myelogenous leukemia / 中国医师杂志

Chronic myelogenous leukemia (CML) has a high proportion in hematologic malignancy.Past decade,the appearance and development of tyrosine kinase inhibitors (TKIs) is the milestone of the treatment of CML.TKIs have antitumor effect with inhibition of the phosphorylation of kinases and the downstream signal transduction.In recent years,many large medical institutions at home and abroad worked on clinical experiment researches to investigate the mechanism of TKIs and how to choose TKIs in CML patients.This work is of great significance to the clinic.

BCR-ABL₁ transcripts (MR(4.5)) at post-transplant 3 months as an early predictor for long-term outcomes in chronic myeloid leukemia

BACKGROUND/AIMS: The aim of this study was to identify the role of BCR-ABL1 transcript level as a predictor for post-transplant relapse and outcome in patients who underwent allogeneic stem cell transplantation (SCT) for chronic phase (CP) chronic myeloid leukemia (CML). METHODS: Of 101 patients receiving allograft in CML CP, 85 had available quantitative reverse transcriptase polymerase chain reaction data at post-transplant 3 months. These patients were divided into two groups according to molecular response (MR(4.5)), defined as a BCR-ABL₁ transcript level ≤ 0.0032% on the international scale, at 3 months based on receiver operating characteristic curve analysis of relapse. RESULTS: The 4-year overall survival and event-free survival (EFS) were 80.6% and 57.3%, respectively, and the cumulative incidence of relapse at 4 years was 29.6% after a median follow-up of 126.4 months. We performed multivariate analyses including potential variables to evaluate the early predictive role of MR(4.5) at 3 months and found that MR(4.5) at 3 months was associated with a higher EFS (p = 0.028) and showed a trend for a lower relapse rate (p = 0.089). CONCLUSIONS: our results imply that frequent molecular monitoring and immune suppressive therapy modulation are required for patients without reduction of BCR-ABL1 transcripts to this level after SCT.

Effect of triptolide on the proliferation and apoptosis and on Wnt/β-catenin pathway in imatanib resistant CML cell / 中国医师杂志

Objective To investigate the impact of triptolide (TP) on proliferation and apoptosis of imatanib resistant CML cell (K562/G01) and its regulating effect on Wnt/β3-catenin signal pathway.Methods A series of 10,20,40,and 80 nmol/L of triptolide were used in CML cells K562/G01 for 12,24,and 48 hours.The cell proliferation was detected with methyl thiazolyl tetrazolium (MTT) test.The apoptosis was assessed with flow cytometry (FCM).The mRNA expressions of breakpoint cluster region-c-abl (BCR-ABL),β-catenin and its down-stream targets Lef-1,and cyclinD1 were analyzed with real-time quantitative polymerase chain reaction (RT-PCR),respectively.Results Triptolide significantly inhibited K562/G01 cell growth ability and induced apoptosis in a dose-dependent manner.Mter being treated with 20,40 nmol/L TP for 24 hours,the cell growth inhibition rates were (22.62 ± 1.33) ％,and (51.41 ±1.39) ％,respectively.The late apuptosis rates were (6.91 ± 0.14) ％,and (7.64 ± 0.47) ％,respectively.Meanwhile,PCR data showed that the mRNA levels of BCR-ABL were decreased,compared to the control group,the mRNA levels of β-catenin,Lef-1,and cyclinD1 were also decreased obviously after treatment.Conclusions Our data indicated that the triptolide could inhibit the proliferation and induce the apoptosis of K562/G01,and the mechanism might be related to the blockade of Wnt/β-catenin signal pathway.

Patients' perceptions about diagnosis and treatment of chronic myeloid leukemia: a cross-sectional study among Brazilian patients / Percepções dos pacientes sobre diagnóstico e tratamento da leucemia mieloide crônica: estudo transversal entre pacientes brasileiros

CONTEXT AND OBJECTIVES: Chronic myeloid leukemia (CML) requires strict daily compliance with oral medication and regular blood and bone marrow control tests. The objective was to evaluate CML patients' perceptions about the disease, their access to information regarding the diagnosis, monitoring and treatment, adverse effects and associations of these variables with patients' demographics, region and healthcare access. DESIGN AND SETTING: Prospective cross-sectional study among CML patients registered with the Brazilian Lymphoma and Leukemia Association (ABRALE). METHODS: CML patients receiving treatment through the public healthcare system were interviewed by telephone. RESULTS: Among 1,102 patients interviewed, the symptoms most frequently leading them to seek medical care were weakness or fatigue. One third were diagnosed by means of routine tests. The time that elapsed between first symptoms and seeking medical care was 42.28 ± 154.21 days. Most patients had been tested at least once for Philadelphia chromosome, but 43.2% did not know the results. 64.8% had had polymerase chain reaction testing for the BCR/ABL gene every three months. 47% believed that CML could be controlled, but 33.1% believed that there was no treatment. About 24% reported occasionally stopping their medication. Imatinib was associated with nausea, cramps and muscle pain. Self-reported treatment adherence was significantly associated with normalized blood count, and positively associated with imatinib. CONCLUSIONS: There is a lack of information or understanding about disease monitoring tools among Brazilian CML patients; they are diagnosed quickly and have good access to treatment. Correct comprehension of CML control tools is impaired in Brazilian patients.

CONTEXTO E OBJETIVOS: Leucemia mieloide crônica (CML) exige estrita adesão à medicação oral e ao monitoramento do sangue e da medula. O objetivo foi avaliar percepções de pacientes com leucemia mieloide crônica (LMC) sobre a doença, seu acesso à informação sobre diagnóstico, monitoramento e tratamento, efeitos adversos e a associação destes com dados demográficos, geográficos e de acesso a tratamento. DESENHO E LOCAL: Estudo prospectivo transversal realizado com pacientes de LMC cadastrados na Associação Brasileira de Leucemia e Linfoma (Abrale). MÉTODOS: Pacientes com LMC recebendo tratamento do sistema público de saúde foram entrevistados por telefone. RESULTADOS: Entre os 1.102 pacientes entrevistados, os sintomas mais frequentemente levando à busca de consulta foram fraqueza e fadiga. Um terço foi diagnosticado por exames de rotina. O tempo entre sintoma inicial e procura por ajuda foi de 42,28 ± 154,21 dias. A maioria foi testada pelo menos uma vez para o cromossomo Filadélfia, mas 43,2% não sabiam os resultados. 64,8% fizeram exame de reação em cadeia da polimerase para o gene BCR/ABL a cada três meses. 47% acreditavam que LMC pode ser controlada, mas 33,1% acham que não há tratamento. Cerca de 24% disseram que ocasionalmente interrompem o tratamento. Imatinibe associou-se com náusea, câimbra e dor muscular. Aderência auto-reportada associou-se significativamente com hemograma normal e positivamente com uso de imatinibe. CONCLUSÕES: Falta informação ou compreensão sobre monitoramento entre pacientes com LMC; eles recebem diagnóstico rapidamente e têm bom acesso ao tratamento. A correta compreensão das ferramentas de controle em LMC está prejudicada entre eles.