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Objective:To investigate the value of minimal residual disease (MRD) in prediction of prognosis in acute lymphoblastic leukemia (ALL) patients with or above complete remission 2 (CR2) underwent.Methods:A retrospective analysis was performed on 201 ALL patients who received allogeneic stem cell transplantation (allo-SCT) and pretransplant disease status ≥CR2 in Peking University People′s Hospital from January 2009 to December 2018. MRD was measured by multi-parameter flow cytometry at 1 month before transplantation and 1 month, 2 months, 3 months, 4 months, 6 months, 9 months or 12 months after transplantation. To investigate the influence of dynamic changes of MRD before and after transplantation on prognosis.Results:201 ALL patients, including 126 males and 75 females, with a median age of 18 years. The 3-year cumulative incidence of relapse (CIR), non-relapse mortality (NRM), leukemia-free survival (LFS) and overall survival (OS) of all cases were 34%, 16%, 50%, and 56%, respectively. Positive pre-SCT MRD patients with higher 3-year CIR (47% vs 26%, P=0.003), lower 3-year LFS (40% vs 55%, P=0.047) and OS (42% vs 60%, P=0.065) than those with negative one. Subjects with positive post-MRD had higher 3-year CIR (73% vs 22%, P<0.001) and lower 3-year LFS (28% vs 56%, P=0.005) and OS (32% vs 60%, P=0.040) compared with those with negative one. Multivariate analysis showed that both pre-MRD and post-MRD were associated with higher CIR ( HR=1.823, P=0.018; HR=3.474, P<0.001), lower LFS ( HR=1.779, P=0.007; HR=2.185, P=0.001) and OS ( HR=1.609, P=0.034; HR=1.970, P=0.001). Negative pre-and post-SCT MRD group had lower 3-year CIR (17%, 42%, 82%; P<0.001) and higher 3-year LFS (61%, 44%, 18%; P<0.001) and OS (63%, 47%, 27%; P<0.001) compared with those unrisen post-SCT MRD group, and increased post-SCT MRD group. Multivariate analysis showed that pre-and post-SCT MRD dynamics were associated with CIR, LFS and OS ( P<0.01 for all) independently. The pre-and post-SCT MRD dynamics could better distinguish CIR (C=0.669) from that of pre-SCT MRD (C=0.587) and post-SCT MRD (C=0.629). Conclusion:Our data suggest that pre-SCT MRD, post-SCT MRD and the dynamic peri-SCT MRD could be used to predict transplant outcome of ALLpatients with or above CR2 who underwent allo-SCT.
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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 explore the significance of minimal residual disease (MRD) in predicting prognosis and guiding therapy of adults with Philadelphia-chromosome negative acute lymphoblastic leukemia (Ph- ALL) in high-risk.@*Methods@#Data of newly diagnosed adults with Ph- ALL in high-risk who achieved CR were reviewed. Variables associated with outcome were identified by COX regression model and Landmark analysis.@*Results@#A total of 177 patients, 99 (56%) cases male with a median age of 40 years (range, 16-65 years) were included in this study. Of them, 95 (54%) patients received allo-HSCT in CR1. Multivariate analyses showed that MRD negativity after the first cycle of consolidation (HR=0.52, 95%CI 0.30-0.89, P=0.017) and achieving CR within 4 weeks (HR=0.43, 95%CI 0.24-0.79, P=0.006) were the factors significantly-associated with longer DFS, and allo-HSCT was associated with both longer DFS (HR=0.13, 95%CI 0.08-0.22, P<0.001) and OS (HR=0.24, 95%CI 0.15-0.41, P<0.001) . Landmark analysis was performed on 121 patients, of 85 patients achieving MRD negativity after the first cycle of consolidation, multivariate analyses showed that MRD negativity after the third cycle of consolidation was significantly-associated with longer DFS (HR=0.18, 95%CI 0.05-0.64, P=0.008) and OS (HR=0.14, 95%CI 0.04-0.50, P=0.003) . For the patients achieving MRD negativity after both the first and the third cycles of consolidation, the 3-year DFS rate in the allo-HSCT cohort had a higher trend compared with that in the chemotherapy cohort (75.2% vs 51.3%, P=0.082) , however, the 3-year OS rates in the 2 cohorts were similar (72.7% vs 68.7%, P=0.992) . In those with MRD positivity after the first and/or the third cycle of consolidation, 3-year DFS (64.8% vs 33.3%, P=0.006) and OS (77.0% vs 33.3%, P=0.028) rates in the allo-HSCT cohort were significantly higher than those in the chemotherapy cohort, and similar to those in the cohort achieving MRD negativity after both the first and the third cycles of consolidation and receiving allo-HSCT.@*Conclusions@#MRD negativity after the first cycle of consolidation was a predictor for better outcome in adults with Ph- ALL in high-risk. The survival advantage of the allo-HSCT cohort was not pronounced compared with that in the chemotherapy cohort even in those with high-risk features but achieving MDR negativity after both the first and third cycles of consolidation. However, allo-HSCT could be a good option for the patients with MRD positivity after the first and/or the third cycle of consolidation.
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Objective@#To investigate the association of hematological complete remssion (HCR) status on the outcomes of the patients with B-cell acute lymphoblastic leukemia (B-ALL) who were undergoing haploidentical stem cell transplantation (Haplo-SCT). @*Methods@#Retrospective analysis was performed on 317 patients with B-ALL who received Haplo-SCT with HCR before transplantation in the Institute of Hematology, Peking University from September 2012 to June 2016. A Cox proportional hazards model was used to analyze the effects of HCR status before transplantation on the outcomes of Haplo-SCT. @*Results@#The 3-year cumulative incidences of non-relapse mortality (NRM) and cumulative incidence of relapse (CIR) were 15% and 15%, respectively. The 3-year probabilities of leukemia-free survival (LFS) and overall survival (OS) were 71% and 74%, respectively. There was no statistical difference for 3-year NRM, CIR and LFS among the HCR patients with recovery of absolute neutrophil count (ANC) and platelet (CR) group, without recovery of ANC and with or without recovery of platelet (CRi) group and those in HCR with recovery of ANC but without recovery of platelet (CRp) group (P value ＞0.05 for all). The probability of OS in cases of CR group was significantly higher than that of CRi group (76% vs 59%，P=0.049). Multivariate analysis showed that factors associated with CIR included pre-transplantation minimal residual disease (P=0.006) and chronic GVHD (P=0.020). Platelet engraftment was associated with NRM, LFS, and OS (P＜0.001 for all). Grades Ⅲ-Ⅳ GVHD was associated with NRM (P＜0.001) and OS (P=0.035). Chronic GVHD was correlated with LFS (P＜0.001). @*Conclusion@#Our results indicate that no effect of HCR status before transplant on the outcomes was observed in patients with B-ALL who underwent Haplo-SCT.
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Objective@#To assess the prognostic significance of immunophenotype complete remission (ICR) and hematological complete remission (HCR) before human-leukocyte antigen (HLA)-matched sibling donor transplantation (MSDT) in acute myeloid leukemia (AML) patients.@*Methods@#A cohort of 182 AML (non-APL) patients undergoing MSDT in HCR was retrospectively studied [including complete remission with ANC and PLT recovery (CR), CR with incomplete PLT recovery (CRp), CR with inconplete ANC and PLT recovery (CRi)]; ICR was determined as undetective minimal resudial disease (MRD) by multi-parameter flow cytometer.@*Results@#①Of the 182 patients, 97 were male, 85 female, and the median age was 41(4-62) years. ②The CR and CRi+CRp rates were 80.8% (147/182) and 19.2%(35/182), respectively; The 4-year cumulative incidence of relapse[CIR, (11.0±4.3)% vs (16.0±7.1)%, χ2=0.274, P=0.600], non-relapse mortality[NRM, (14.0±4.3)% vs (9.0±6.3)%, χ2=0.913, P=0.339], leukemia-free survival[LFS, (75.0±5.1)% vs (75.0±8.3)%, χ2=0.256, P=0.613], and overall survial [OS, (77.0±5.2)% vs (80.0±8.1)%, χ2=0.140, P=0.708] were comparable between the CRp+CRi and CR groups. ③Compared with the non-ICR group (n=35), the ICR group (n=147) showed lower 4-year CIR [(11.3±3.4) % vs (55.2±8.8) %, χ2=32.687, P<0.001], better 4-year LFS [(76.2±4.7)% vs (32.8±8.7)%, χ2=26.234, P<0.001] and OS[(79.0±4.7)% vs (39.0±9.1)%, χ2=25.253, P<0.001], and comparable NRM[(12.5±4.1)% vs (12.0±7.1)%, χ2=1.002, P=0.656]. ④Mulitvariate analysis confirmed the independent prognostic value of ICR in lower CIR [HR=11.026(95%CI 4.685-25.949), P<0.001], higher LFS [HR=5.785 (95% CI 2.974-11.254), P<0.001] and OS[HR=5.578 (95% CI 2.575-27.565), P<0.001].@*Conclusion@#The results indicated that ICR instead of HCR pre-transplantation had a significant prognostic value in AML patients undergoing MSDT.
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Objective@#To explore and compare 4-color and 8-color fluorescence antibody panels for detecting minimal residual disease of multiple myeloma patients after therapy.@*Methods@#One 8-color antibody panel was built including CD38 and CD138 for the identification of plasma cells (PCs) , membrane antigen CD45, CD19, CD56 and CD117, cytoplasmic Kappa (cκ) and Lambda (cλ) light chain antigen. Six tubes of 4-color panels were built, among them, membrane antigen CD45/CD19, CD56/CD117, CD19/CD56 and light chains were analyzed combined by CD38/CD138 for PCs gate in the tubes M1-3 and tube C-κ/λ, respectively; CD19 or CD45 and cκ/cλ light chains were detected in the tube MC1-CD38 for CD38/SSC identified PCs gate and tube MC2-CD138 for CD138/SSC identified PCs gate separately. Twenty normal volunteer bone marrows and seventy-three specimens from multiple myeloma patients after complete remission were measured and analyzed.@*Results@#MRD positive samples were discriminated in 82.19% of the specimen evaluated through either abnormal plasma cells (aPCs) or clonal plasma cells (cPCs) by 8-color antibody panel. Among of them, consistency was 89.04%. The median percentage of cPCs was 0.105%. The lowest sensitivity of experiment was 0.004%. Percentage of PCs identified by CD38/ SSC gate was higher than that by CD38/CD138 (P<0.001) and CD138/SSC gate (P=0.001) apparently. The lowest MRD positive rate was found in tube C (65.75%) , which lower than 8-color panel obviously (P=0.024) . The percentages of aPCs measured by tube M2-56/117 were significantly lower than other tubes (P=0.014) . MRD positive rate determined by cPCs was higher than that by aPCs both in the tube MC1-CD38 and tube MC2-CD138, whose concordance rate were 68.49% and 79.45%, respectively. Compared with 8-color panel, tube MC2-CD138 the best choice among six tubes of 4-color panels, which has the best sensitivity, accuracy and negative predicted value, higher positive predicted value and specificity. Tube M1-45/19 was the second choice.@*Conclusions@#CD38/CD138 are the best markers for gating PCs. Membrane antigen and cκ/cλ detected simultaneously is a better method for MM MRD detection and 8-color antibody panel is an ideal approach. Two tubes of 4-color antibody combination, M1-45/19 and MC2-CD138 are recommended in the 4-color panels.
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<p><b>BACKGROUND</b>Significant efforts have been made to identify factors that differentiate patients treated with novel therapies, such as bortezomib in multiple myeloma (MM). The exact expression pattern and prognostic value of the cancer/testis antigen preferentially expressed antigen of melanoma (PRAME) in MM are unknown and were explored in this study.</p><p><b>METHODS</b>The transcript level of PRAME was detected in bone marrow specimens from 100 newly diagnosed MM patients using real-time quantitative polymerase chain reaction, and the prognostic value of PRAME was determined through retrospective survival analysis. PRAME expression higher than the upper limit of normal bone marrow was defined as PRAME overexpression or PRAME (+).</p><p><b>RESULTS</b>Sixty-two patients (62.0%) overexpressed PRAME. PRAME overexpression showed no prognostic significance to either overall survival (n = 100) or progression-free survival (PFS, n = 96, all P > 0.05) of patients. The patients were also categorized according to regimens with or without bortezomib. PRAME overexpression tended to be associated with a lower two-year PFS rate in patients treated with non-bortezomib-containing regimens (53.5% vs. 76.9%, P = 0.071). By contrast, it was not associated with the two-year PFS rate in patients with bortezomib-containing regimens (77.5% vs. 63.9%, P > 0.05). When the patients were categorized into PRAME (+) and PRAME (-) groups, treatment with bortezomibcontaining regimens predicted a higher two-year PFS rate in PRAME (+) patients (77.5% vs. 53.5%, P = 0.027) but showed no significant effect on two-year PFS rate in PRAME (-) patients (63.9% vs. 76.9%, P > 0.05).</p><p><b>CONCLUSION</b>PRAME overexpression might be an adverse prognostic factor of PFS in MM patients treated with non-bortezomib-containing regimens. Bortezomib improves PFS in patients overexpressing PRAME.</p>
Subject(s)
Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Young Adult , Antigens, Neoplasm , Metabolism , Boronic Acids , Therapeutic Uses , Bortezomib , Disease-Free Survival , Multiple Myeloma , Drug Therapy , Metabolism , Mortality , Pyrazines , Therapeutic Uses , Real-Time Polymerase Chain ReactionABSTRACT
A 19-year-old female presented with a dark erythematous maculopapule measuring 2 cm in diameter on the left lower limb for more than one year.Physical examination revealed an enlarged cherry-like lymph node in the right inguinal region.Histopathology of the lesion revealed that the normal structure of skin disappeared absolutely,and there was a diffuse infiltrate of medium-sized lymphoid tumor cells with unclear nucleoli.Immunohistochemically,the tumor cells strongly expressed CD4,CD56 and CD123,and partially expressed terminal deoxynucleotidyl transferase (TdT).Flow cytometric analysis of bone marrow aspirates showed that abnormal cells amounted to 59.9％,and were positive for CD123st (strong),human leucocyte antigen-DRst (strong),CD56,CD304 (blood dendritic cell antigen-4),CD7,CD11b,CD33,CD36 and chemokine (C-X-C motif) receptor 4,CD13 (dim),CD4 (partial) and CD117 (partial).Transmission electron microscopy of bone marrow cells revealed that there were massive uniformly sized lymphoid cells with thick processes on cell surfaces,a high nucleus/cytoplasm ratio,centrally located round nuclei occasionally with deep gyrus-like notches,clumped marginated heterochromatin and multiple nucleoli.Moreover,a small amount of cytoplasm was observed in the lymphoid cells with the presence of mitochondria and endoplasmic reticulum arranged in concentric circles,which were characteristic of plasma cells.The features of both dendritic cells and plasma cells were found in the tumor cells through transmission electron microscopy.Based on the above findings,a diagnosis of blastic plasmacytoid dendritic cell neoplasm (BPDCN) was made.