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Minimal residual disease (MRD) has been used for warning of relapse and guiding the therapy selection for hematological malignancies including acute leukemia. Based on MRD-related content reported at the 64th American Society of Hematology (ASH) Annual Meeting, this article discusses the progress of MRD-directed individualized therapy for hematological malignancies with a primary focus on acute myeloid leukemia.
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Minimal residual disease (MRD) has been used not only for relapse prediction, prognosis re-classification and directing pre-emptive therapy of patients with acute leukemia, but also in the field of therapy for patients with other hematological malignancies or solid tumors. A deep understanding of the intension and extension of MRD is important for exploring novel methods for accurate prediction of relapse and consummating the individualized intervention strategies for malignant tumors.
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Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is one of the main curable therapies for patients with acute lymphoblastic leukemia (ALL). This article discusses the status of allo-HSCT for ALL as well as how to combine targeted therapy with allo-HSCT to improve outcomes of ALL in the era of targeted therapy based on the data obtained from the 63rd American Society of Hematology (ASH) Annual Meeting.
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Chimeric antigen receptor(CAR)-T cell immunotherapy for refractory and relapsed acute lymphoblastic leukemia (R/R ALL) is one of the breakthroughs in the field of hematological malignant disease treatment. However, several challenges remain, such as immune rejection of allogeneic CAR-T cells, leukemia relapse, as well as could we apply CAR-T cell immunotherapy to ALL patients with positive measurable residual disease and those of newly diagnosed cases. The safety and efficiency of CAR-T therapy will be further improved for patients with ALL only by establishing appropriate strategies to address these challenges.
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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 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 investigate the incidences and risk factors of poor hematopoietic reconstitution (PHR) in patients with hematological diseases who underwent haploidentical allograft and were treated with rituximab for desensitization.Methods:Eight-three donor specific anti-HLA antibody (DSA, 2000 ≤MFI<10 000) positive patients who underwent haploidentical allograft were prospectively enrolled. Rituximab (375 mg/m 2) was used for desensitization day-3 of conditioning regimen. Incidence and factors associated with PHR, including primary poor graft function and prolonged thrombocytopenia, were investigated. Results:There were 22 males and 61 females with a median age of 39(range: 1-65) years. Kaplan-Meier analysis showed that the 100 day cumulative incidences of neutrophil and platelet engraftment were 93.0% and 90.7%, respectively. The incidences of PHR were 14.7%. The 3-year relapse rate, non-relapse mortality (NRM) rate, event-free survival (EFS), leukemia-free survival (DFS) and overall survival (OS) were 6.5%, 15.1%, 70.8%, 79.4% and 79.4%, respectively. Patients with DSA MFI<5 000 (group A, n=46) experienced lower PHR (4.4% vs. 27.5%, P=0.003), and higher 3-year EFS (79.5% vs. 59.8%, P=0.020) compared to those with DSA MFI≥5 000 (group B, n=37). Multivariate analysis showed that DSA MFI≥5 000 was correlated with PHR ( HR=6.101, P=0.021). PHR was associated with higher NRM ( HR=4.110, P=0.026), lower DFS ( HR=3.656, P=0.019) and OS ( HR=3.656, P=0.019). Conclusion:Our data suggest that high pre-transplant DSA level is a risk factor for PHR in patients with hematological diseases receiving haploidentical allograft and rituximab for desensitization.
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Minimal residual disease (MRD) is one of the important variables to evaluate the outcomes of patients with leukemia, which is related to the relapse and survival of patients after treatment. This article summarizes the new progress on diagnosis and treatment of leukemia from the perspective of MRD in combination with some representative studies on MRD-based prognostic assessment and guidance on treatment options that were reported at the 62nd American Society of Hematology (ASH) Annual Meeting.
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Objective:To explore the relationship between anti-human leukocyte antigen (HLA) antibodies and transplant outcomes in patients with hematological diseases who underwent matched sibling donor transplantation (MSDT).Methods:A retrospective analysis was conducted in 168 patients with hematological diseases who received MSDT in Peking University People's Hospital from March 2015 to November 2017. All patients received detection of anti-HLA antibodies before transplantation, and the correlation between anti-HLA antibodies and transplant outcomes such as hematopoietic cells implantation, blood product transfusion and prognosis after transplantation were analyzed.Results:Among the 168 patients, 28 (16.7%) were positive for anti-HLA class Ⅰ or class Ⅱ antibodies, and 14 (8.3%) were positive for both anti-HLA class Ⅰ and class Ⅱ antibodies. All patients received neutrophil engraftment, 164 patients (97.9%) received platelet engraftment. Univariate analysis showed that there were no effects of anti-HLA antibodies on neutrophil engraftment and engraftment time, platelet engraftment and engraftment time, the volume of red cell transfusion, the volume of platelet transfusion, overall survival (OS) rate, disease free survival (DFS) rate and transplant-related mortality (TRM) in patients with hematological diseases underwent MSDT (all P > 0.05). Multivariate analysis showed that platelet engraftment was associated with better OS ( HR=0.065, 95% CI 0.017-0.252, P < 0.01), better DFS ( HR=0.083, 95% CI 0.024-0.289, P < 0.01) and lower TRM ( HR=0.094, 95% CI 0.014-0.626, P=0.015). Conclusion:Anti-HLA antibodies have no effect on transplant outcomes of patients with hematological diseases who have received MSDT.
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Human leukocyte antigen (HLA)-matched donors for hematopoietic stem cell transplantation (HSCT) have long been scarce in China. Haploidentical (haplo) donors are available for the vast majority of patients, but toxicity has limited this approach. Three new approaches for haplo-HSCT originated from Italy, China, and USA in 1990 and have been developed to world-renowned system up to now. The Chinese approach have been greatly improved by implementing new individualized conditioning regimens, donor selection based on non-HLA systems, risk-directed strategies for graft-versus-host disease and relapse, and infection management. Haplo-HSCT has exhibited similar efficacy to HLA-matched HSCT and has gradually become the predominant donor source and the first alternative donor choice for allo-HSCT in China. Registry-based analyses and multicenter studies adhering to international standards facilitated the transformation of the unique Chinese experience into an inspiration for the refinement of global practice. This review will focus on how the new era in which "everyone has a donor" will become a reality in China.
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Humans , China , Donor Selection , Graft vs Host Disease , Allergy and Immunology , HLA Antigens , Allergy and Immunology , Hematologic Neoplasms , Allergy and Immunology , General Surgery , Hematopoietic Stem Cell Transplantation , Histocompatibility , Histocompatibility Testing , Randomized Controlled Trials as Topic , Transplantation ConditioningABSTRACT
Hematologic neoplasm relapse remains one of the major causes of death after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Relaspe prediction, prophylaxis and treatment after allo-HSCT are the key issues for improving the therapeutic effects and prognosis. This paper chooses some representative reports from 60th American Society of Hematology (ASH) Annual Meeting to discuss the progress of allo-HSCT.
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Objective@#To evaluate the efficacy of consolidation chemotherapy combined with allogeneic natural killer (NK) cell infusion in the treatment of low or intermediate-risk (LIR) acute myeloid leukemia (AML) .@*Methods@#A cohort of 23 LIR AML patients at hematologic complete remission (CR) received NK cell transfusion combined with consolidation chemotherapy after 3 consolidation courses from January 2014 to June 2019 were reviewed. Control group cases were concurrent patients from Department of Hematology, and their gender, age, diagnosis, risk stratification of prognosis, CR and the number of courses of consolidate chemotherapy before NK cell transfusion were matched with LIR AML patients.@*Results@#A total of 45 times of NK cells were injected into 23 LIR AML patients during 4 to 7 courses of chemotherapy. The median NK cell infusion quantity was 7.5 (6.6-8.6) ×109/L, and the median survival rate of NK cells was 95.4% (93.9%-96.9%) . Among them, the median CD3-CD56+ cell number was 5.0 (1.4-6.4) ×109/L, accounting for 76.8% (30.8%-82.9%) ; The number of CD3+ CD56+ cells was 0.55 (0.24-1.74) ×109/L, accounting for 8.8% (4.9%-20.9%) . Before NK cell infusion, the number of patients with positive MRD in the treatment and control groups were 9/23 (39.1%) and 19/46 (41.3%) (χ2=0.030, P=0.862) respectively. After NK infusion, There was no significant difference in terms of MRD that went from negative to positive between the treatment and the control groups (14.3% vs 22.2%, χ2=0.037, P=0.847) . In the treatment group, 66.7% (6/9) of the MRD were converted from positive to negative, which was significantly higher than that in the control group (10.5%, 2/19) (χ2=6.811, P=0.009) . Morphological recurrence occurred in 1 case of MRD negative in the treatment group and 2 cases of MRD positive in the control group. By the end of follow-up, the median follow-up was 35 (10-59) months, the number of patients with morphological recurrence in the treatment group was 30.4% (7/23) , which was significantly lower than that in the control group (50.2%, 24/46) (χ2=2.929, P=0.087) , although there was no statistically significant difference between the two groups. There was no significant difference on MRD-negative between the treatment and the control groups (43.5% vs 43.5%, χ2=1.045, P=0.307) . The 3-year leukemia-free survival was better in the treatment group [ (65.1±11.1) %] than that in the control group [ (50.0±7.4) %] (P=0.047) . The 3-year overall survival in the treatment and control groups were (78.1±10.2) % and (65.8±8.0) % (P=0.212) , respectively.@*Conclusion@#The consolidation of chemotherapy combined with allogeneic NK cell infusion contributed to the further remission of patients with LMR AML and the reduction of long-term recurrence.
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Since the founding of the People's Republic of China, much progress has been made in the field of stem cell transplantation by Chinese scholars. From the successful treatment of the first case with syngeneic bone marrow transplantation to the international original establishment of T-cell-replete haploidentical blood and marrow transplant system (known as the "Beijing Protocol"). The transformation of hematopoietic stem cell transplantation from "follow-up" to "lead-up" has been realized, and the problem of donor source has been basically solved. This article summarized the development status of stem cell transplantation in treatment of hematological malignancies in China, and the challenges that need to be addressed.
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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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To establish optimal reference values for recovered immune cell subsets, we prospectively investigated post-transplant immune reconstitution (IR) in 144 patients who received allogeneic stem cell transplantation (allo- SCT) and without showing any of the following events: poor graft function, grades II‒IV acute graft-versus-host disease (GVHD), serious chronic GVHD, serious bacterial infection, invasive fungal infection, or relapse or death in the first year after transplantation. IR was rapid in monocytes, intermediate in lymphocytes, CD3 Tcells, CD8 T cells, and CD19 B cells, and very slow in CD4 T cells in the entire patient cohort. Immune recovery was generally faster under HLA-matched sibling donor transplantation than under haploidentical transplantation. Results suggest that patients with an IR comparable to the reference values display superior survival, and the levels of recovery in immune cells need not reach those in healthy donor in the first year after transplantation.We suggest that data from this recipient cohort should be used as reference values for post-transplant immune cell counts in patients receiving HSCT.
Subject(s)
Adolescent , Adult , Child , Child, Preschool , Female , Humans , Male , Middle Aged , Young Adult , China , Disease-Free Survival , Graft vs Host Disease , Allergy and Immunology , Mortality , HLA Antigens , Allergy and Immunology , Hematopoietic Stem Cell Transplantation , Immune Reconstitution , Reference Values , Siblings , T-Lymphocytes , Allergy and Immunology , Tissue Donors , Transplantation, HomologousABSTRACT
In recent years, the indications of allogeneic hematopoietic stem cell transplantation (allo-HSCT) have been expanded due to the improvement of transplant technique. More attentions have been paid to donor specific anti-human leukocyte antigen antibodies because of the widely application of haploidentical SCT. Relapse remains a hot topic in patients with hematological malignancies who underwent allo-HSCT. Here, the progress of allo-HSCT is discussed according to some reports from 59th American Society of Hematology (ASH) Annual Meeting.
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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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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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In recent years, the advances in the comprehension of the biological characteristics of acute myeloid leukemia (AML) promote the diagnosis and risk stratification. The clinical routine detection of minimal residual disease makes prognosis system more plentiful. More strategies for AML including haploidentical transplantation and target therapy were established.
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In the past ten years, much progress has been made in the pathophysiology, risk-stratification, and treatment of multiple myeloma (MM). Emerging paradigms in the therapy of MM including new drugs, chimeric antigen receptor-modified T cells, and allogeneic stem cell transplantation have improved the prognosis of MM patients.