OBJECTIVE: To explore the efficacy of tyrosine kinase inhibitor (TKI) combined with decitabine, homoharringtonine, and interferon regimen as maintenance therapy for blast phase chronic myeloid leukemia (CML-BP). METHODS: The clinical data of CML-BP patients who received the first major hematological response after induction therapy at The Affiliated Cancer Hospital of Zhengzhou University from June 2015 to December 2021 were analyzed retrospectively. The event-free survival, duration of remission, and overall survival of patients in TKI combined with decitabine, homoharringtonine, interferon group(n=18) and TKI combined with conventional chemotherapy group(n=10) were compared by log-rank test. RESULTS: A total of 28 patients were included, with a median age of 46 (24-58) years old. Kaplan-Meier survival analysis showed that patients in TKI combined with decitabine, homoharringtonine, interferon group had longer event-free survival (7.4 vs 4.3 months, P=0.043, HR＝0.44, 95% CI: 0.17-1.14), duration of overall remission (16.1 vs 6.6 months, P=0.005, HR＝0.32, 95% CI: 0.11-0.89), overall survival (34.3 vs 13.5 months, P=0.006, HR＝0.29, 95% CI: 0.10-0.82) compared with patients in TKI combined with conventional chemotherapy group. CONCLUSION The TKI combined with decitabine, homoharringtonine and interferon regimen can significantly prolong the survival of CML-BP patients who obtained the major hematological response compared with TKI combined with conventional chemotherapy regimen.
Humans ; Middle Aged ; Blast Crisis/drug therapy* ; Homoharringtonine/therapeutic use* ; Decitabine/therapeutic use* ; Interferons/therapeutic use* ; Tyrosine Protein Kinase Inhibitors ; Retrospective Studies ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Protein Kinase Inhibitors/therapeutic use* ; Treatment Outcome

Objective: To evaluate the clinical characteristics and prognostic factors of patients with Philadelphia-negative myeloproliferative neoplasm-accelerated phase/blast phase (MPN-AP/BP) . Methods: A total of 67 patients with MPN-AP/BP were enrolled from February 2014 to December 2021 at the Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences. Their clinical features and prognostic factors were analyzed retrospectively. Results: ① Sixty-seven patients with MPN-AP/BP with a median age of 60 (range, 33-75) years, including 31 males (46.3% ) and 36 females (53.7% ) , were analyzed. Forty-eight patients progressed from primary myelofibrosis (PMF) , and 19 progressed from other myeloproliferative neoplasms (MPNs) , which included polycythemia vera, essential thrombocythemia, and MPN unclassifiable. Patients who progressed from PMF had higher lactate dehydrogenase (LDH) levels than those who progressed from other MPNs (925.95 vs. 576.2 U/L, P=0.011) , and there were higher proportions of patients who progressed from PMF with splenomegaly (81.4% vs. 57.9% , P=0.05) , a myelofibrosis grade of ≥2 (93.6% vs. 63.2% , P=0.004) , and a shorter duration from diagnosis to the transformation to AP/BP (28.7 vs. 81 months, P=0.001) . ② JAK2V617F, CALR, and MPLW515 were detected in 41 (61.2% ) , 13 (19.4% ) , and 3 (4.5% ) patients, respectively, whereas 10 (14.9% ) patients did not have any driver mutations (triple-negative) . Other than driver mutations, the most frequently mutated genes were ASXL1 (42.2% , n=27) , SRSF2 (25% , n=16) , SETBP1 (22.6% , n=15) , TET2 (20.3% , n=13) , RUNX1 (20.3% , n=13) , and TP53 (17.2% , n=11) . The ASXL1 mutation was more enriched (51.1% vs. 21.1% , P=0.03) , and the median variant allele fraction (VAF) of the SRSF2 mutation (median VAF, 48.8% vs. 39.6% ; P=0.008) was higher in patients who progressed from PMF than those who progressed from other MPNs. ③ In the multivariate analysis, the complex karyotype (hazard ratio, 2.53; 95% confidence interval, 1.06-6.05; P=0.036) was independently associated with worse overall survival (OS) . Patients who received allogeneic stem cell transplantation (allo-HSCT) (median OS, 21.3 vs. 3 months; P=0.05) or acute myeloid leukemia-like (AML-like) therapy (median OS, 13 vs. 3 months; P=0.011) had significantly better OS than those who received supportive therapy. Conclusion: The proportions of patients with PMF-AP/BP with splenomegaly, myelofibrosis grade ≥2, a higher LDH level, and a shorter duration from diagnosis to the transformation to AP/BP were higher than those of patients with other Philadelphia-negative MPN-AP/BP. The complex karyotype was an independent prognostic factor for OS. Compared with supportive therapy, AML-like therapy and allo-HSCT could prolong the OS of patients with MPN-AP/BP.
Male ; Female ; Humans ; Adult ; Middle Aged ; Aged ; Blast Crisis/drug therapy* ; Primary Myelofibrosis/genetics* ; Prognosis ; Splenomegaly ; Retrospective Studies ; Myeloproliferative Disorders/genetics* ; Mutation ; Leukemia, Myeloid, Acute ; Janus Kinase 2/genetics*

OBJECTIVETo investigate the characteristics and clinical outcome of T315I mutation in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+) ALL) and chronic myeloid leukemia (CML).

METHODSThe clinical data of 118 tyrosine kinase inhibitors (TKIs) resistant Ph(+) ALL and CML cases who were detected ABL kinase domain mutation in Affiliated Tumor Hospital of Zhengzhou University from March 2014 to June 2015 were collected. Karyotypes and BCR-ABL fusion gene were analyzed respectively by R-banding, real-time quantitative polymerase chain reaction (PCR). Total RNA was extracted by TRIzol reagent and ABL kinase domain mutation was detected by direct sequencing.

RESULTSIn 23 TKIs resistant Ph(+) ALL and 95 CML cases, the rate of ABL kinase domain mutation was 60.9% (14/23) and 41.1% (39/95), respectively, and the rate of T315I mutation was respectively 34. 8% vs 5.3%, the difference was significant (χ(2)=13.586, P<0.01). The rate of mutations in chronic phase/accelerate phase /blast crisis CML patients was 38.8% (19/49), 47.1% (8/17) and 41.4% (12/29), respectively, and there was no significant difference (χ(2)=0.360, P=0.835). In Ph (+) ALL and CML patients, the median time from the beginning of TKI therapy to appearance of T315I mutation was 10 months and 19 months, the median time from the appearance of T315I to death/deadline was 2 months and 3 months, the median time of persistent hematologic response was 10 months and 16 months and the median time of overall survival (OS) was 13 months and 42 months.

CONCLUSIONT315I mutation was more easily occurred in Ph(+) ALL than CML, but two diseases are similar in the median time from the beginning of TKI therapy to appearance of T315I, the median time of persistent hematologic response and OS.

Acute Disease ; Blast Crisis ; Drug Resistance, Neoplasm ; Fusion Proteins, bcr-abl ; genetics ; Humans ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive ; drug therapy ; genetics ; Mutation ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; drug therapy ; genetics ; Protein Kinase Inhibitors ; therapeutic use

OBJECTIVETo evaluate the efficiency of dasatinib as the second- or third-line tyrosine kinase inhibitor (TKI)in imatinib-resistant patients with chronic myeloid leukemia (CML)based on BCR-ABL mutation detection.

METHODS122 CML patients received dasatinib treatment, including 83 with imatinib-resistance and 39 with both imatinib- and nilotinib-resistance, 55 in the chronic-phase (CP), 21 in the accelerated- phase (AP)and 46 in the blast- phase (BP). Those harboring dasatinib highly- resistant mutations (T315I/A, F317L/V/C and V299L)were excluded based on BCR-ABL kinase domain mutation screening by Sanger sequencing at baseline. Hematologic, cytogenetic and molecular responses were evaluated regularly, and rates of progression-free-survival (PFS)and overall survival (OS)were analyzed. BCR- ABL mutation detection was performed once the patients failed on dasatinib.

RESULTSIn the CP patients, the rates of complete hematological response (CHR), complete cytogenetic response (CCyR), major molecular response (MMR)and molecular response 4.5 (MR4.5)were 92.7%, 53.7%, 29.6% and 14.8%, respectively. 4-year PFS and OS rates were 84.4% and 89.5%, respectively. In the AP patients, HR and CCyR rates were 81.0% and 35.0%; and 3-year PFS and OS rates were 56.1% and 59.3%, respectively. In the BP patients, HR and CCyR rates were 63.0% and 21.4%; and 1-year PFS and OS rates were 43.6% and 61.8%, respectively. Outcomes were similar when dasatinib was used as the second- line TKI or the third-line TKI. Of the 75 patients who were resistant to dasatinib, 37 (48.7%)developed new mutation(s), and T315I (59.5%)was the most common mutation type. The patients who already harbored mutation(s)before dasatinib therapy achieved similar responses and outcomes to those with no mutation at baseline. However, they had higher likelihood of developing additional mutations associated with resistance to dasatinib (65.7%vs 34.1%,P=0.006).

CONCLUSIONSDasatinib was proved to be effective in the treatment of imatinib- or/and nilotinib-resistant CML patients, especially in both CP and AP cohorts. The significance of BCR-ABL mutation screening and monitoring should be highlighted before and during dasatinib therapy.

Blast Crisis ; Cytogenetics ; Dasatinib ; therapeutic use ; Disease-Free Survival ; Drug Resistance, Neoplasm ; Fusion Proteins, bcr-abl ; metabolism ; Humans ; Imatinib Mesylate ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive ; drug therapy ; Mutation ; Protein Kinase Inhibitors ; therapeutic use ; Pyrimidines

BACKGROUNDRapid clearance of peripheral blood blasts (PBBs) predicts complete remission (CR) and survival in patients with acute myeloid leukemia (AML). We aimed to explore the correlation between induction therapy response, outcome, and the PBB percentage.

METHODSForty-six consecutive patients with de novo AML (excluding acute promyelocytic leukemia) were enrolled in this study. Flow cytometry was performed to identify cells with a leukemia-associated aberrant immunophenotype in the initial bone marrow aspirate and in peripheral blood on day 7 of induction therapy.

RESULTSThe PBB percentage on day 7 (D7PBBP) was significantly lower in patients who achieved CR (0.03% (0.0%, 0.45%)) than in those who did not (10.85% (1.13%, 19.38%); u = -3.92, P < 0.001). The CR rate was significantly higher among patients with a D7PBBP of <0.945% (84.62%, 22/26) than among those with a D7PBBP of = 0.945% (25.0%, 5/20; χ2 = 16.571, P < 0.001). D7PBBP was significantly correlated with overall survival (OS; r = -0.437, P = 0.003) and relapsefree survival (RFS; r = -0.388, P = 0.007). OS and RFS were significantly higher in patients with a D7PBBP of <0.43% than in those with a D7PBBP of ≥ 0.43% (P < 0.001 and P = 0.039, respectively). D7PBBP was also found to be an independent prognostic indicator in multivariate analysis for both OS (P = 0.036) and RFS (P = 0.035).

CONCLUSIOND7PBBP may be an important risk factor for the achievement of complete remission, for overall survival, and for relapse-free survival.

Adolescent ; Adult ; Aged ; Aged, 80 and over ; Antineoplastic Agents ; Antineoplastic Combined Chemotherapy Protocols ; Blast Crisis ; complications ; drug therapy ; Child ; Cytarabine ; therapeutic use ; Female ; Flow Cytometry ; Humans ; Idarubicin ; therapeutic use ; Immunophenotyping ; Induction Chemotherapy ; Leukemia, Myeloid, Acute ; drug therapy ; mortality ; Male ; Middle Aged ; Neoplasm Recurrence, Local ; drug therapy ; Young Adult

This study was purposed to investigate the difference of morphology, immunophenotype, cytogenetic features and prognosis between myeloid blast crisis and lymphoid blast crisis of chronic myelogenous leukemia (CML). A total of 31 patients with CML in blastic crisis in Department of Hematology, the First Affiliated Hospital of Xi'an Jiaotong University school of Medicine from 2009 January to 2014 January were enrolled in this study. Out of 31 CML patients, 24 cases were patients with myeloid blast crisis and other 7 cases were patients with lymphoblastic crisis. The clinical data, blast cell percentage in peripheral blood and bone marrow, eosinophil and basophil percentage, immunophenotype, cytogenetic characteristics and prognosis were analyzed. The results indicated that there was no significant difference of blastic cell percentage in peripheral blood and bone marrow of CML with myeloid blast crisis, and the eosinophil and basophil cells could be easily detected. The ratio of blastic cells in BM was higher than that in PB in lymphoid blastic crisis of CML, eosinophil and basophil cells were rare. 7 cases of CML with lymphoid blastic crisis were B ALL with CD10, CD19, CD34, HLA-DR expression, and 2 cases with CD13 and CD33 expression. The lymphoid score was in all CML patients with lymphoid blastic crisis was greater than or equal to 1.5;and 2 patients with CD13 and CD33 expression, and with 1 myeloid score.24 cases of myeloid blastic crisis of CML patients mainly expressed CD33, CD13, CD38, CD34, CD11b and HLA-DR, and their myeloid score greater than or equal to 2, among them the lymphoid scores of 2 patients were 0.5 and 1 score, respectively. All the 31 patients showed 100% Ph(+) chromosome, among them 3 cases also showed other new chromosome aberrations. There was no significant difference of overall survival rate between lymphoid and myeloid blastic crisis of CML, but the overall survival rate of patients treated with tyrosine kinase inhibitor (TKI ) was higher than that in the patients without TKI treatment. It is concluded that eosinophil and basophil cells in peripheral blood of lymphoid blastic crisis were less than that of CML patients with myeloid blastic crisis. Lymphoid blastic crisis of CML patients occurred mostly in B ALL cases with expression of CD10 and CD19. Patients with myeloid blastic crisis of CML mainly expressed CD33, CD13, CD38, CD34, CD11b and HLA-DR, and could be accompanied by other lineage antigen expression, but the score was less than 2. New chromosome aberration is easily observed in myeloid blastic crisis of CML. There is no significant difference of overall survival rate of between CML patients with lymphoid and myeloid blastic crisis, but the overall survival rate of patients treated with TKI is higher than the patients without TKI treatment.
Adolescent ; Adult ; Aged ; Blast Crisis ; Bone Marrow Cells ; immunology ; pathology ; Cytogenetic Analysis ; Female ; Humans ; Immunophenotyping ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive ; drug therapy ; pathology ; Male ; Middle Aged ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; drug therapy ; pathology ; Prognosis ; Protein Kinase Inhibitors ; therapeutic use ; Protein-Tyrosine Kinases ; antagonists & inhibitors ; Retrospective Studies ; Survival Rate ; Young Adult

OBJECTIVETo investigate the underlying mechanism and clinical significance of PU.1 down-expression in chronic myeloid leukemia (CML) patients.

METHODSDifferent methylation status of PU.1 promoter region containing 20 CpG islands in normal individuals, CML chronic phase and blast crisis patients, complete cytogenetic remission patients after imatinib treatment, and blast crisis bone marrow K562 CML cells was detected by bisulfite sequencing. Semi-quantitative PCR was used to detect the PU.1 mRNA expression in normal controls, CML chronic phase and blast crisis patients, and blast crisis bone marrow K562 CML cells. Indirect immune fluorescence and Western blot were used to analyze the exprtession of PU.1 protein in normal individuals, CML chronic phase and blast crisis patients, and blast crisis bone marrow K562 CML cells.

RESULTSAberrant methylation in the promoter region of transcription factor PU.1 was found in both CML chronic phase and blast crisis phase bone marrow cells, as well as in CML blast K562 cells. Down-expression of PU.1 mRNA and protein levels was found in above cells. No methylation in the promoter region of PU.1 was observed in normal individuals, and the PU.1 mRNA and protein expressions were not reduced at all. Furthermore, high methylation status of bone marrow cells was even observed in the CML patients who acquired complete cytogenetic remission.

CONCLUSIONSThe results of our study indicate that the epigenetic modification of PU.1 in CML patients and K562 cell line might be responsible for the down-expression of PU.1. The data suggest that aberrant methylation of PU.1 plays a role in CML pathogenesis, therefore, it might serve as a useful biomarker and potential target in therapy for chronic myeloid leukemia.

Antineoplastic Agents ; therapeutic use ; Benzamides ; Blast Crisis ; Bone Marrow Cells ; metabolism ; pathology ; CpG Islands ; genetics ; DNA Methylation ; Down-Regulation ; Epigenesis, Genetic ; Gene Expression Regulation, Leukemic ; Humans ; Imatinib Mesylate ; K562 Cells ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive ; drug therapy ; genetics ; metabolism ; Piperazines ; therapeutic use ; Promoter Regions, Genetic ; genetics ; Proto-Oncogene Proteins ; genetics ; metabolism ; Pyrimidines ; therapeutic use ; RNA, Messenger ; metabolism ; Trans-Activators ; genetics ; metabolism

Adult ; Antibiotics, Antineoplastic ; therapeutic use ; Benzamides ; Blast Crisis ; drug therapy ; Drug Resistance, Neoplasm ; Humans ; Imatinib Mesylate ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive ; drug therapy ; Male ; Piperazines ; pharmacology ; Pyrimidines ; pharmacology ; Sirolimus ; therapeutic use

Adult ; Benzamides ; Blast Crisis ; Humans ; Imatinib Mesylate ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive ; drug therapy ; pathology ; Male ; Piperazines ; therapeutic use ; Pyrimidines ; therapeutic use

OBJECTIVETo investigate the changes in the expression of beta-catenin in patients with chronic myeloid leukemia (CML) in different phases, and explore the relationship between beta-catenin and the cytogenetic response to imatinib mesylate.

METHODSBeta-catenin mRNA and protein expressions were detected by RT-PCR and Western blotting in the bone marrow mononuclear cells (BMMNCs) from 99 CML patients. The expressions of BCR-ABL fusion gene at both the mRNA and protein levels were detected by fluorescence in situ hybridization (FISH) in 94 patients before and during the one-year treatment with imatinib mesylate at the interval of 3 months, and the relationship between beta-catenin and cytogenetic response to imatinib mesylate was analyzed.

RESULTSThe expression of beta-catenin increased significantly in patients with blast crisis and accelerated phase (P<0.001), but showed no significant difference between normal subjects and CML patients in the chronic phase (P>0.05). The main cytogenetic remission rate was significantly higher in patients who were consistently negative for beta-catenin than in those consistently positive for beta-catenin or those with a positive transformation (P<0.001).

CONCLUSIONBeta-catenin overexpression in the progression of CML, consistent high level of beta-catenin or a positive transformation may indicate a poor response to imatinib, and early measures should be taken to increase the remission rate.

Adolescent ; Adult ; Benzamides ; therapeutic use ; Blast Crisis ; drug therapy ; genetics ; metabolism ; Case-Control Studies ; Female ; Humans ; Imatinib Mesylate ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive ; drug therapy ; genetics ; metabolism ; pathology ; Male ; Middle Aged ; Piperazines ; therapeutic use ; Pyrimidines ; therapeutic use ; RNA, Messenger ; genetics ; Young Adult ; beta Catenin ; metabolism