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Objective:To investigate the dynamic change and clinical impact of DEK-NUP214 fusion gene in patients with acute myeloid leukemia (AML) receiving allogeneic hematopoietic stem cell transplantation (allo-HSCT).Methods:Real-time quantitative polymerase chain reaction (RQ-PCR) and multicolor flow cytometry (FCM) were used to detect DEK-NUP214 gene expression and leukemia-associated immunophenotype (LAIP) in 15 newly diagnosed patients with positive DEK-NUP214 and receiving allo-HSCT from September 2012 to September 2017 at Peking University People′s Hospital. The clinical outcome was analyzed using Kaplan-Meier survival curves. The impact of DEK-NUP214 expression was analyzed by log-rank test.Results:The subjects were followed-up with a median period of 657 (62-2 212) days. The median DEK-NUP214 expression level at diagnosis was 488% (274%-1 692%). Thirteen patients achieved complete remission before allo-HSCT. Thirteen patients had a residual DEK-NUP214 expression of 0.38% (0.029%-738.9%) before allo-HSCT. After allo-HSCT, DEK-NUP214 expression in 9/13 patients remained positive, which dropped by around 500 folds (5.7-5 663.0 folds) within a month post-transplant. Five patients died and 2 patients relapsed. The 3-year cumulative incidence of relapse in patients with positive DEK-NUP214 before transplant was 17.5%±11.3% and the 3-year overall survival was 60.5%±13.8%. After allo-HSCT, DEK-NUP214-negative patients had a better outcome.Conclusion:Quantitative monitor of DEK-NUP214 fusion gene could be a sensitive indicator of MRD status after allo-HSCT.
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OBJECTIVE@#To trace a rare case of chronic myeloid leukemia (CML) with a four-way Philadelphia chromosome variant by cytogenetic analysis in order to provide a basis for the selection of treatment.@*METHODS@#Bone marrow morphology, chromosomal karyotyping, fluorescence in situ hybridization (FISH) and real-time quantitative PCR (RQ-PCR) were used for the diagnosis and staging of the disease. Point mutations in the tyrosine kinase domain of ABL1 gene were detected by Sanger sequencing.@*RESULTS@#The patient was initially diagnosed as CML in chronic phase (CML-CP) with a chromosomal karyotype of 46,XX,t(5;9;22;6)(q13;q34;q11;q25), while FISH revealed presence of a variant Philadelphia chromosome translocation. Clonal evolution has occurred after 38 months of tyrosine kinase inhibitor (TKI) treatment, when cytogenetic analysis revealed coexisting t(5;9;22;6)(q13;q34;q11;q25) and t(5;9;22;6;17)(q13;q34;q11;q25;q11). After 57 months of TKIs treatment, only the t(5;9;22;6;17) clone was detected. Three months later, hyperdiploidy with additional abnormalities were detected in addition to t(5;9;22;6;17). Three mutations, including p.Tyr253Phe, p.Thr315Ile and p.Gly250Glu, were identified in the tyrosine kinase domain of the ABL1 gene during the course of disease. The patient did not attain cytogenetic and molecular response to TKIs.@*CONCLUSION@#The four-way variant translocation may be genetically unstable. Clonal evolution and genetic mutations are likely to occur during TKIs treatment, resulting in poor response to drug therapy. This observation, however, needs to be confirmed by large-scale studies.
Subject(s)
Female , Humans , Enzyme Inhibitors/therapeutic use , Evolution, Molecular , In Situ Hybridization, Fluorescence , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Mutation/genetics , Philadelphia Chromosome , Translocation, GeneticABSTRACT
Objective@#To explore the efficacy and prognosis of nilotinib or dasatinib as second- or third-line treatment in patients with chronic myeloid leukemia (CML) in the chronic phase (CP) and accelerated phase (AP) .@*Methods@#From January 2008 to November 2018, the data of CML patients who failed first- or second-line tyrosine kinase inhibitor (TKI) -therapy received nilotinib or dasatinib as second-line and third-line therapy were retrospectively reviewed.@*Results@#A total of 226 patients receiving nilotinib or dastinib as second-line (n=183) and third-line (n=43) therapy were included in this study. With a median follow-up of 21 (range, 1-135) months, the cumulative rates of complete hematological response (CHR) , complete cytogenetic response (CCyR) and major molecular response (MMR) were 80.4%, 56.3%and 38.3%, respectively in those receiving TKI as second-line TKI therapy. The 3-year progression-free survival (PFS) and overall survival (OS) rates were 78.7%and 93.1%, respectively. Multivariate analyses showed that Sokal high risk, female gender, the best response achieved <CHR on the first-line TKI-therapy, the interval from diagnosis to switching to second-line TKI ≥18 months, AP or hematologic failure, or non-specific mutation of BCR-ABL kinase domain before second-line TKI therapy, developing severe hematologic toxicity during the second-line TKI therapy were variables associated with poor responses or outcomes on second-line TKI therapy. With a median follow-up of 6 (range, 3-129) months, the cumulative CHR, CCyR and MMR were 95.7%, 29.3%, and 18.6%, respectively in those receiving the third-line TKI therapy. The 2-year PFS and OS rates were 66.8% and 93.8%, respectively. The patients with an interval from diagnosis to starting TKI ≥6 months, achieving no cytogenetic response on the second-line TKI, the interval from diagnosis to starting second-line TKI ≥60 months, and progression to AP before the third-line TKI therapy had lower probabilities of responses and unfavorable outcomes.@*Conclusions@#The efficacy of dasatinib and nilotinib as second- or third-line TKI-therapy were active in the CML patients with TKI-resistance. The best response achieved on previous TKI-therapy, the disease phase before switching TKI, and the severe hematologic toxicity developing on the current TKI-therapy were associated with the responses and outcomes.
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Objective@#To investigate the characteristic and prognostic significance of leukemia stem cells associated antigens expressions including CD34, CD38, CD123, CD96 and TIM-3 in t (8;21) AML.@*Methods@#Bone marrow samples of 47 t (8;21) AML patients were collected at diagnosis from October 2015 to April 2018 in Peking University Peoples’ Hospital, then flow cytometry method was performed to detect the expression frequencies of CD34, CD38, CD123, CD96 and TIM-3 to analyze the relationship between leukemia stem cells associated antigens expressions and relapse.@*Results@#Of 47 t (8;21) AML patients tested, the median percentages of CD34+CD38-, CD34+ CD38-CD123+, CD34+CD38- CD96+ and CD34+ CD38- TIM-3+ cells among nucleated cells were 2.37%, 0.24%, 0.27% and 0.06%, respectively. All the frequencies of CD34+CD38-, CD34+CD38-CD123+, CD34+CD38-CD96+ and CD34+ CD38-TIM-3+ cells had no impact on the achievement of CR after the first course of induction. All higher frequencies of CD34+CD38-, CD34+CD38-CD123+, CD34+CD38-CD96+ cells were related to higher 2-year CIR rate. Whereas, the frequency of CD34+ CD38- TIM-3+ cells had no impact on CIR rate. Both high frequency of CD34+ CD38- cells and the high level of minimal residual diseases (patients with <3-log reduction in the RUNX1-RUNX1T1 transcript level after the second consolidation therapy) were independent poor prognostic factors of CIR[P=0.025, HR=6.9 (95%CI 1.3-37.4) ; P=0.031, HR=11.1 (95%CI 1.2-99.2) ].@*Conclusion@#Different leukemia stem cells associated antigens had distinct prognostic significance in t (8;21) AML. High frequencies of CD34+ CD38-, CD34+ CD38- CD123+ and CD34+CD38-CD96+ cells at diagnosis predicted relapse in patients with t (8;21) AML.
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Objective To investigate the impact of sample typeon the detection of c-KIT exon 17 mutation in acute myeloid leukemia (AML) patients. Methods A retrospective study was conducted on 51 bone marrow samples collected from 37 AML patients [17 maleand 20 female, with a median age of 33 (range from 1 to 82)] at diagnosis or after treatment from June 2016 to August 2018. Of the 37 cases of AML, 24 were t(8; 21) AML, 11 were inv(16)/t(16;16) AML and 2 were non-CBF-AML. RNA and DNA were simultaneously extracted from every sample. PCR followed by Sanger sequencing were used to screen c-KIT exon 17 mutation, and the comparisons were made between paired cDNA and DNAsamples. Results (1) Of the 51 paired samples, 14 pairs were simultaneously detected positive for c-KITmutation in both of cDNA and DNA samples, but 17 pairs were detected negative in both, and the remaining 20 pairswere only detected positive for the mutation in cDNA but not in DNA, with an inconsistency rate of 39.2％. The positive rate of detecting c-KITmutation was significantly higher in cDNA than in DNA samples (66.7％vs 27.5％,P=0.000073). (2)Inconsistent mutation results between paired cDNA and DNA samples occurred in t(8;21)AML, inv(16)AML and non-CBF-AML patients with the inconsistency rate of 36.4％(12/33), 27.2％(3/11) and 71.4％ (5/7), respectively. (3)The inconsistency rate was significantly higher in samples collected after treatment compared with those collected at diagnosis (72.7％vs 13.8％, P=0.00003). (4) All 5 serially monitored patients with c-KITmutation had inconsistency in mutation detection between cDNA and DNA samples during follow up. Conclusion cDNA improves the detection of c-KIT exon 17 mutation in AML patients compared with DNA, which is especially common after treatment.
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Objective@#To compare the clinical features between the 2 cohorts developing myelodysplastic syndrome or acute myeIogenous Ieukemia in Philadelphia chromosome-negative cells (Ph- MDS/AML) and maintaining disease stable in the patients with Philadelphia chromosome-positive chronic myeloid Ieukemia (Ph+ CML) who had clonal chromosomal abnormalities in Philadelphia chromosome-negative metaphases (CCA/Ph-) during tyrosine kinase inhibtor (TKI) - therapy.@*Methods@#We retrospectively analyzed Ph+ CML patients who developed CCA/Ph- during TKI-therapy from May 2001 to December 2017.@*Results@#Data of CCA/Ph- 63 patients, including 7 progressing to Ph- MDS/AML and 56 remaining disease stable were collected. Compared with those with stable disease, patients with Ph-MDS/AML had lower hemoglobin (P=0.007) and platelet (P=0.006) counts, and higher proportion of peripheral blasts (P<0.001) when the first time CCA/Ph- was detected, and more mosonomy 7 abnormality (5/7, 71.4%) when MDS or AML was diagnosed; meanwhile, trisomy 8 (32/56, 57.1%) was more common in those with stable disease. Outcome of the patients with Ph- MDS/AML were poor. However, most of those with CCA/Ph- and stable disease had optimal response on TKI-therapy.@*Conclusions@#A few patients with Ph+ CML developed CCA/Ph- during TKI-therapy, most of them had stable disease, but very few patients developed Ph- MDS/AML with more common occurrence of monosomy 7 or unknown cytopenia. Our data suggested the significance of monitoring of peripheral blood smear, bone marrow morphology and cytogenetic analysis once monosomy 7 or unknown cytopenia occurred.
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Objectives@#To explore the incidence and factors of severe leukopenia and/or thrombocytopenia in newly diagnosed patients with chronic myeloid leukemia (CML) to probe their impacts on cytogenetic and molecular responses, progression free survival (PFS) and overall survival (OS) .@*Methods@#Data of newly diagnosed patients with CML in the chronic phase (CP) and/or accelerated phase (AP) were retrospectively collected and analyzed.@*Results@#855 CML patients [including 744 (87%) in the CP and 111 (13.0%) in the AP] were included in this study. 523 (61.2%) patients were male with a median age of 39 years (range, 14-87 years) . 749 (87.6%) patients received imatinib, 93 (10.9%) nilotinib, and 13 (1.5%) dasatinib, respectively as front-line therapy. At a median treatment of 1 month (range, 0.1-7.0 months) , 137 (16.0%) developed ≥grade 3 leukopenia and/or thrombocytopenia and recovered 0.6 month (range, 0.3-6.5 months) . Multivariate analysis showed that female gender (OR=1.5, 95%CI 1.0-2.2, P=0.033) , WBC ≥100×109/L (OR=1.9, 95%CI 1.3-2.8, P=0.001) , CP in Sokal high-risk (OR=2.2, 95%CI 1.2-3.9, P=0.005) , AP with ≥15% blast cells in blood or bone marrow (OR=5.1, 95%CI 1.9-13.3, P=0.001) were factors associated with higher incidence of ≥grade 3 leukopenia and/or thrombocytopenia. Severe leukopenia and/or thrombocytopenia with time of drug discontinuance >2 weeks was associated with lower probabilities of achieving complete cytogenetic (OR=0.4, 95%CI 0.3-0.6, P<0.001) , severe leukopenia and/or thrombocytopenia, no matter the time of drug discontinuance >2 weeks or ≤2 weeks, were associated with lower probabilities of achieving major molecular responses (OR=0.3, 95%CI 0.2-0.5, P<0.001; OR=0.7, 95%CI 0.5-1.0, P=0.036) and MR4.5 (OR=0.2, 95%CI 0.1-0.5, P=0.002; OR=0.7, 95%CI 0.4-1.1, P=0.110) ; however, those had no impacts on PFS and OS.@*Conclusions@#Severe leukopenia and/or thrombocytopenia were common adverse events during TKI therapy. Female patients, WBC ≥100×109/L at diagnosed, CP in Sokal high-risk, CML-AP with ≥15% blast cells in blood or bone marrow were at high risk for higher incidence of severe leukopenia and/or thrombocytopenia. Those severe adverse events had impacts on lower cytogenetic and molecular response.
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Objective@#To analyze the characteristics of myeloid neoplasms with t (3;21) (q26;q22) .@*Methods@#Clinical data of patients with t (3; 21) (q26; q22) , diagnosed as hematologic malignancies in Peking University people's hospital from January 2011 to March 2018, were collected retrospectively. 19 patients in our hospital and forty-eight patients bearing t (3;21) (q26;q22) with detailed survival data reported in literature were summarized. Kaplan- Meier method was used for survival analysis.@*Results@#Among 19 patients, including 15 males and 4 females with a median age of 36 years (22-68 years) , 4 cases was diagnosed as de novo acute myeloid leukemia (AML) , 4 as myelodysplastic syndromes (MDS) , 3 as MDS-AML and 8 as chronic myelogenous leukemia (CML) in myeloid blast transformation. All of the 19 patients were detected to have t (3;21) (q26;q22) by G-banding technique and 13 carried additional cytogenetic aberrations. 9 of the 19 patients were detected for positive AML1-MDS1 fusion genes. In the 9 patients with detailed follow-up data, 6 patients received chemotherapy and only 2 achieved complete remission (CR) while 4 with no response. During the follow-up period, 8 patients died and the median overall survival (OS) was 6 months (4.5 to 22 months) . Survival analysis of the present 9 patients together with the literature data showed that the prognosis was poor and the median OS was 7 months. In particular, AML/t-AML had the worst prognosis. Hematopoietic stem cell transplantation (HSCT) could significantly improve survival, the median OS in HSCT group and non-HSCT group were 20.9 and 4.7 months respectively (P<0.001) .@*Conclusions@#t (3; 21) (q26; q22) is a rare recurrent chromosomal abnormality which is detected mainly in myeloid neoplasm and confer to poor clinical prognosis. HSCT should be recommended to improve the outcomes.
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Objectives@#To compare the efficacy and safety of Chinese generic imatinib with branded imatinib as frontline therapy in adults with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) (Frontline group) , and to explore the efficacy and safety of Chinese generic imatinib in CML-CP patients switching from branded imatinib (Switching group) .@*Methods@#Frontline group: Data of adults with newly diagnosed CML-CP receiving Chinese generic imatinib (Xinwei®) or branded imatinib (Glivec®) between October 2013 and August 2018 were retrospectively collected and analyzed. Switching group: Data of adults diagnosed with CML-CP who received branded imatinib and then switched to Chinese generic imatinib after achieving at least complete cytogenetic response (CCyR) were retrospectively collected and analyzed.@*Results@#Frontline group: In total, 409 adult patients receiving Chinese generic imatinib (n=201) or Glivec (n=208) were included in this study. Median age was 42 years (range, 18-83 years) . Comparison of baseline showed significant difference on demographic characteristics among two cohorts: lower education level (P<0.001) , and divorced or widowed status (P=0.004) and rural household registration (P<0.001) were more common in the generic imatinib cohort than those in the Glivec cohort. There was no significant difference on age, gender, Sokal risk score, WBC and HGB between the 2 cohorts. With a median follow-up of 25 months (range, 3-62 months) , there was no significant difference on the 3-year cumulative incidence of achieving CCyR (97.5% vs 94.5%, P=0.592) , major molecular response (MMR) (84.3% vs 93.1%, P=0.208) , molecular response4.0 (MR4.0) (42.7% vs 41.7%, P=0.277) , molecular response4.5 (MR4.5) (25.4% vs 33.0%, P=0.306) as well as the 3-year probabilities of failure free survival (FFS) (76.7% vs 81.0%, P=0.448) , progression free survival (PFS) (91.8% vs 96.3%, P=0.325) and overall survival (OS) (95.8% vs 98.5%, P=0.167) between the generic and branded imatinib cohorts. Multivariate analysis showed the type of imatinib was not associated with treatment responses and outcomes. The incidences of adverse effects were comparable in the 2 cohorts. Switching group: In total, 39 patients switching from branded imatinib to Chinese generic imatinib after achieving at least CCyR were included in this study. Median age was 42 years (range, 23-80 years) . With a median follow-up of 39 months (range, 6-63 months) , molecular responses were maintained in 23 (58.9%) patients and improved in 12 (39.8%) patients. Adverse effects were tolerable.@*Conclusion@#Demographic characteristics might influence the choice of the type of TKI used in CML-CP patients. There was a comparable efficacy and safety between the Chinese generic imatinib and the branded imatinib in adults with newly diagnosed CML-CP under standard management and closely monitoring. Patients could safely switch from the branded imatinib to the Chinese generic imatinib.
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Objective@#To investigate the current status and real performance of the detection of RUNX1-RUNX1T1 fusion transcript levels and WT1 transcript levels in China through interlaboratory comparison.@*Methods@#Peking University People’s Hospital (PKUPH) prepared the samples for comparison. That is, the fresh RUNX1-RUNX1T1 positive (+) bone morrow nucleated cells were serially diluted with RUNX1-RUNX1T1 negative (-) nucleated cells from different patients. Totally 23 sets with 14 different samples per set were prepared. TRIzol reagent was added in each tube and thoroughly mixed with cells for homogenization. Each laboratory simultaneously tested RUNX1-RUNX1T1 and WT1 transcript levels of one set of samples by real-time quantitative PCR method. All transcript levels were reported as the percentage of RUNX1-RUNX1T1 or WT1 transcript copies/ABL copies. Spearman correlation coefficient between the reported transcript levels of each participated laboratory and those of PKUPH was calculated.@*Results@#①RUNX1-RUNX1T1 comparison: 9 samples were (+) and 5 were (-) , the false negative and positive rates of the 20 participated laboratories were 0 (0/180) and 5% (5/100) , respectively. The reported transcript levels of all 9 positive samples were different among laboratories. The median reported transcript levels of 9 positive samples were from 0.060% to 176.7%, which covered 3.5-log. The ratios of each sample’s highest to the lowest reported transcript levels were from 5.5 to 12.3 (one result which obviously deviated from other laboratories’ results was not included) , 85% (17/20) of the laboratories had correlation coefficient ≥0.98. ②WT1 comparison: The median reported transcript levels of all 14 samples were from 0.17% to 67.6%, which covered 2.6-log. The ratios of each sample’s highest to the lowest reported transcript levels were from 5.3-13.7, 62% (13/21) of the laboratories had correlation coefficient ≥0.98. ③ The relative relationship of the reported RUNX1-RUNX1T1 transcript levels between the participants and PKUPH was not always consistent with that of WT1 transcript levels. Both RUNX1-RUNX1T1 and WT1 transcript levels from 2 and 7 laboratories were individually lower than and higher than those of PKUPH, whereas for the rest 11 laboratories, one transcript level was higher than and the other was lower than that of PKUPH.@*Conclusion@#The reported RUNX1-RUNX1T1 and WT1 transcript levels were different among laboratories for the same sample. Most of the participated laboratories reported highly consistent result with that of PKUPH. The relationship between laboratories of the different transcript levels may not be the same.
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Objective@#To compare the cytogenetic and molecular responses, outcomes and severe hematologic toxicity of nilotinib and imatinib as frontline therapy in newly diagnosed patients with chronic myeloid leukemia in chronic phase (CML-CP) .@*Methods@#Newly diagnosed CML-CP patients were consecutively recruited from January 2006 to December 2018 who received nilotinib and imatinib as first-line treatment. Clinical data were retrospectively analyzed.@*Results@#A total of 524 patients were classified into 439 (83.8%) receiving imatinib and 85 (16.2%) receiving nilotinib. Comparing with imatinib group, patients in nilotinib group were much younger (P=0.019) and more with intermediate and high Sokal risks (P<0.001) , WBC ≥100×109/L (P<0.001) , HGB<120 g/L (P<0.001) , blast cells in bone marrow (P=0.026) , splenomegaly (P<0.001) by physical examination at diagnosis, and longer interval from diagnosis to TKI treatment (P=0.003) . With a median TKI duration of 57 (range 3-153) months, the probabilities of complete cytogenetic response (CCyR) (P=0.011) , major molecular response (MMR) (P=0.001) and MR4.5 (P=0.046) were much higher in nilotinib group than those in imatnib according to each risk group. There is no statistical significance on probabilities of failure free survival (FFS) , progression free survival (PFS) and overall survival (OS) at 6 years between the two groups. Multivariate analyses showed that imatinib was an adverse factor associated with achieving CCyR (OR=0.6, 95% CI 0.5-0.8, P=0.001) , MMR (OR=0.6, 95% CI 0.5-0.9, P=0.032) and MR4.5 (OR=0.6, 95%CI 0.5-0.9, P=0.032) and poor FFS (OR=1.9, 95%CI 1.0-3.4, P=0.041) . In addition, Sokal score was an independent factor affecting cytogenetic and molecular responses, treatment failure, disease progression and survival. Male, WBC ≥100×109/L or HGB<120 g/L at diagnosis were significantly associated with lower cytogenetic and molecular response rates and/or poor FFS. The severe hematologic adverse events were not associated with different TKIs.@*Conclusions@#Nilotinib reaches to the faster and deeper cytogenetic and molecular responses and significantly improves FFS than imatinib in newly diagnosed patients with CML-CP.
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Objective@#To explore Fertility and disease outcomes in patients with chronic myeloid leukemia (CML) .@*Methods@#Clinical and fertility outcomes of male (from Jul. 1998 to Feb. 2018) and female CML (from Sep. 2009 to Feb. 2018) patients were retrospectively analyzed at Peking University People’s Hospital.@*Results@#A total of 49 male CML patients and their spouses were enrolled. Before their spouses conceived, 34 patients were receiving tyrosine kinase inhibitor (TKI) imatinib, 9 with nilotinib, and 6 with dasatinib. At the time of conception, the median age of these male patients was 32 years (range, 25-48 years) , and the median TKI treatment duration was 36 months (range, 0.2-198 months) . One male patient having achieved complete hematologic response yet discontinuing TKI for a year developed a disease progression to blast crisis. The other 48 patients sustained stable disease. The total conception times were 61 and finally 55 infants were born including one with premature birth, two with low birth weight, and one with hypospadias receiving surgery. The other 18 female patients after pregnancy were enrolled. Two patients developed spontaneous abortions. Two received induced abortions. Fourteen gave birth to healthy infants without congenital malformation. The interval from diagnosis of CML to initiation of TKI was 4 months (range, 0.3-16 months) . During a median follow-up of 45 months (range from 7-114 months) , the estimated complete cytogenetic response (CCyR) rate, major molecular response (MMR) rate and molecular response4.5 (MR4.5) rate by 5 years were 88.9%, 85.3% and 35.1%, respectively. The estimated failure-free survival, progression-free survival and overall survival were 64.2%, 90.9% and 90.9%, respectively. All 14 babies developed as normal.@*Conclusions@#It seems that TKIs do not affect pregnancy outcome in the spouses of male CML patients, suggesting that withdrawal of TKIs is not necessary. Female CML patients have good pregnancy and disease outcomes in the TKI era.
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Objective@#To investigate the clinical significance of minimal residual disease (MRD) monitoring by using WT1 gene and flow cytometry (FCM) in patients with myelodysplastic syndrome (MDS) who receiving allogeneic stem cell transplantation (allo-HSCT).@*Methods@#WT1 gene and MDS-related abnormal immunophenotype were examined by real-time quantitative polymerase chain reaction (RQ-PCR) and FCM, respectively. The bone marrow samples were collected from patients with MDS who received allo-HSCT from Feb, 2011 to Oct, 2015 in Peking University People’s Hospital before and after transplantation.@*Results@#Among 92 MDS patients, 40 (48.2%) patients were positive for WT1 (WT1+) and 9 (10.8%) patients were positive for flow cytometry (FCM+). 27 patients (29.3%) met the criteria of our combinative standard, MRDco (MRDco+). Only FCM+ post-transplant (P<0.001) and MRDco+ (P=0.017) were associated with relapse. The cumulative incidence of relapse (CIR) at 2 years were 66.7% and 1.2% (P<0.001) in FCM+ and FCM- groups. MRDco+ group had a 2-year CIR of 23.0% while MRDco- group had a 2-year CIR of 1.6% (P=0.004). The specificity of post-transplant WT1, FCM and MRDco to predict relapse was 59.0%, 96.4% and 74.7%, respectively. The sensitivity of these three MRD parameters to predict relapse was 66.7%.@*Conclusion@#Post-transplant FCM and MRDco are useful tools to monitor MRD for MDS after transplantation. The preemptive intervention based on MRDco is able to reduce the relapse rate.
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<p><b>OBJECTIVE</b>To report on a case of therapy-related acute monocytic leukemia(t-AML) with t(11;17) (q23;q21)/MLL-AF17q after successful treatment for acute promyelocytic leukemia(APL) with t(15;17) (q22;q21)/PML-RARα.</p><p><b>METHODS</b>A MICM method (bone marrow morphology(M), immunophenotype(I), cytogenetics(C), and molecular biology(M)) was used for the diagnosis and classification of the disease at the time of onset and transformation.</p><p><b>RESULTS</b>The patient was initially identified with typical morphology and immunophenotype of APL. She has carried t(15;17)(q22;q21) and PML-RARα fusion gene but was without t(11;17)(q23;q21) or MLL gene abnormalities. After 13 months of successful treatment, she has transformed to AML with typical morphology and immunophenotype. t(11;17)(q23;q21) and MLL-AF17q fusion gene were detected in her bone marrow sample, while no PLZF-RARα fusion gene was detected by real-time quantitative reverse-transcription PCR(RQ-PCR) and fluorescence in situ hybridization(FISH).</p><p><b>CONCLUSION</b>t-AML is a serious complication after successful treatment of APL. t(11;17)(q23;q21) is not specific for the diagnosis of variant APL and can also be detected in t-AML. RQ-PCR and FISH are essential for the diagnosis of such patients.</p>
Subject(s)
Female , Humans , Middle Aged , Chromosomes, Human, Pair 11 , Chromosomes, Human, Pair 15 , Chromosomes, Human, Pair 17 , In Situ Hybridization, Fluorescence , Leukemia, Monocytic, Acute , Genetics , Leukemia, Promyelocytic, Acute , Genetics , Neoplasms, Second Primary , GeneticsABSTRACT
Acute myeloid leukemia (AML) is a highly heterogeneous hematologic malignancy. The precise prognostic stratification is the premise of the individualized treatment. The serial monitoring of minimal residual disease (MRD) has become the important stratification marker at present. The newly developed next generation sequencing (NGS) technique has been gradually used in AML patients for gene mutation screen in clinical routine. The characteristics of NGS technique implies its availability for MDS monitoring, and the preliminary data on its application in MRD monitoring have demonstrated its clinical significance. Therefore, NGS technique has the great potential for MRD monitoring in clinical practice. However, some key points remain to be solved.
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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.
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Objective@#To explore status of tyrosine kinase inhibitor (TKI) discontinuation in patients with chronic myeloid leukemia (CML) in the chronic phase (CP) in the real world, to analyze causes, factors and outcomes associated with TKI discontinuation and the possibility of pursuit treatment-free remission (TFR) in China.@*Methods@#From January 2013 to August 2016, data of CML-CP patients in Peking University People’s Hospital which were not enrolled in clinical trials were retrospectively collected and analyzed.@*Results@#Data of 662 CML-CP patients were collected. With a median follow-up after TKI-therapy of 26 months (range, 3-187 months) , 187 patients (28.2%) experienced TKI cessation of at least 2 weeks. Causes of TKI discontinuation included hematologic adverse events 57.8% (n=108) , non-hematologic adverse events 30.4% (n=57) , financial burden 25.1% (n=47) , and others 7.0% (n= 13) . Multivariate analyses showed female, ≥40 years, no co-morbidity, and interval from diagnosis to TKI initiation ≥6 months, TKI switch and patients from other hospitals were factors associated with TKI discontinuation because of hematologic adverse effects. Female and patients from other hospitals were factors associated with TKI discontinuation because of non-hematologic adverse effect. TKI switch, generic TKI used and patients from other hospitals were factors associated with TKI discontinuation because of financial toxicity. Patients TKI discontinuation because of hematologic, non-hematologic or financial toxicity achieved a lower complete cytogenetic response or complete molecular response (CMR) than those with uninterrupted TKI-therapy. Patients with TKI discontinuation because of hematologic or financial toxicity had a shorter progression-free survival than those with uninterrupted TKI-therapy. 5 of 7 patients who obtained sustained CMR and discontinued TKI-therapy experienced disease recurrence with a median duration of 3 months (range, 2-32 months) . In 39 patients from other hospitals who aimed to confirm their optimal response of sustained CMR in Peking University People’s Hospital, 21 (53.8%) were BCR-ABL positive.@*Conclusion@#In the real world in China, half of CML-CP patients who discontinued TKI-therapy were incurred to TKI-related hematologic adverse effect, and both a quarter of them, TKI-related non-hematologic toxicities and financial toxicity, respectively. Discontinued TKI-therapy due to hematologic adverse events or financial toxicity was associated with lower TKI-therapy response rates. Nowadays, based on the Chinese situation, it is too early to talk about TFR.
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Objective@#To investigate the clinical significance of monitoring ETV6-RUNX1 fusion gene in children with acute lymphoblastic leukemia (ALL) after allogeneic stem cell transplantation (allo-HSCT) .@*Methods@#Clinical data of 13 children received allo-HSCT in Peking University Institute of Hematology from May 2009 to March 2016 were retrospectively collected. The ETV6-RUNX1 gene was examined by real-time quantitative polymerase chain reaction (RQ-PCR) . The correlation between its expression level and the disease status was analyzed.@*Results@#Of 13 enrolled ALL cases, the ETV6-RUNX1 expression of 7 patients converted to positive after transplant at a median time of 137 days (range, 28-270 days) . The expression level of the first positive sample was 0.034% (range, 0.004%-0.061%) . The duration from ETV6-RUNX1 positive to hematological relapse was 196 days (range, 28-666 days) . Four patients experienced relapse at a median time of 294 days (range, 104-803 days) after allo-HSCT. The ETV6-RUNX1 expression converted to positive prior to MRD. Patients with positive ETV6-RUNX1 gene expression pre-transplantation would be more likely to relapse.@*Conclusion@#Monitoring ETV6-RUNX1 by RQ-PCR could be used to evaluate MRD status after allo-HSCT. Patients with positive ETV6-RUNX1 after transplant had a poor prognosis.
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Objective To compare the efficacy and safety between Chinese generic imatinib (Xinwei(R),Jiansu Hansoh Pharmaceutical Group Co.,Ltd.) versus branded imatinib (Glivec(R),Novartis) in patients with newly-diagnosed chronic myeloid leukemia in chronic phase (CML-CP).Methods Patients with newly diagnosed CML-CP were enrolled and assigned to receive either Xinwei or Glivec at an initial dose of 400 mg/d according to patients' financial capability.The efficacy and adverse effects were evaluated.Results From January 2014 to September 2015,145 eligible patients were assigned to Xinwei (n =89) or Glivec (n =56) group.All patients were treated and followed up at least 3 months.At 3 months,the complete response rates were 95.5％ (85/89) and 100％ (56/56),major cytogenetic response rates were 74.2％ (66/89) and 80.4％ (45/56),and the proportions of achieving BCR-ALBIS ≤ 10％ were 76.1％ (67/88) and 82.1％ (46/56) in Xinwei and Glivec groups respectively (all P ＞0.05).With a median follow-up of 12 months,2 patients in each group progressed to accelerate or blast phase.Hematologic and non-hematologic side effects were similar between the 2 groups.Conclusions Early hematological,cytogenetic and molecular responses between Xinwei and Glivec are comparable in newly-diagnosed CML-CP patients.The progression rate and side effects are also similar between the 2 groups.
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<p><b>OBJECTIVE</b>To 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.</p><p><b>METHODS</b>122 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.</p><p><b>RESULTS</b>In 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).</p><p><b>CONCLUSIONS</b>Dasatinib 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.</p>