Clinical significance of Epstein-Barr Virus detection in the cerebrospinal fluid of patients who underwent hematopoietic stem cell transplantation / 中华血液学杂志

Objective: To analyze the detection rate, clinical significance, and prognosis of Epstein-Barr virus (EBV) in the cerebrospinal fluid (CSF) of patients following allogeneic hematopoietic stem cell transplantation. Methods: A retrospective analysis was performed on 1100 patients who underwent the CSF virus test after allogeneic hematopoietic stem cell transplantation in Peking University People's Hospital between January 2017 and June 2022. Among them, 19 patients were screened positive for EBV in their CSF, and their clinical characteristics, treatment, and prognosis were analyzed. Results: Among 19 patients with EBV-positive cerebrospinal fluid, 12 were male and 7 were female, with 5 patients aged <18 years and 12 aged ≥18 years, with a median age of 27 (5-58) years old. There were 7 cases of acute myeloid leukemia, 8 of acute lymphocytic leukemia, 2 of aplastic anemia, 1 of Hodgkin's lymphoma, and 1 of hemophagocytic syndrome. All 19 patients underwent haploid hematopoietic stem cell transplantation, including 1 secondary transplant. Nineteen patients had neurological symptoms (headache, dizziness, convulsions, or seizures), of which 13 had fever. Ten cases showed no abnormalities in cranial imaging examination. Among the 19 patients, 6 were diagnosed with EB virus-related central nervous system diseases, with a median diagnosis time of 50 (22-363) days after transplantation. In 9 (47.3%) patients, EBV was detected in their peripheral blood, and they were treated with intravenous infusion of rituximab (including two patients who underwent lumbar puncture and intrathecal injection of rituximab). After treatment, EBV was not detected in seven patients. Among the 19 patients, 2 died from EBV infection and 2 from other causes. Conclusion: In patients who exhibited central nervous system symptoms after allogeneic hematopoietic stem cell transplantation, EBV should be screened as a potential pathogen. EBV detected in the CSF may indicate an infection; however, it does not confirm the diagnosis.

Clinical analysis of the usefulness of letermovir for prevention of cytomegalovirus infection after haploidentical hematopoietic stem cell transplantation / 中华内科杂志

Objective: To analyze the efficacy and safety of letermovir in primary prophylaxis of cytomegalovirus (CMV) reactivation in patients receiving haploidentical hematopoietic stem cell transplantation. Methods: This retrospective, cohort study was conducted using data of patients who underwent haploidentical transplantation at Peking University Institute of Hematology and received letermovir for primary prophylaxis between May 1, 2022 and August 30, 2022. The inclusion criteria of the letermovir group were as follows: letermovir initiation within 30 days after transplantation and continuation for≥90 days after transplantation. Patients who underwent haploidentical transplantation within the same time period but did not receive letermovir prophylaxis were selected in a 1∶4 ratio as controls. The main outcomes were the incidence of CMV infection and CMV disease after transplantation as well as the possible effects of letermovir on acute graft versus host disease (aGVHD), non-relapse mortality (NRM), and bone marrow suppression. Categorical variables were analyzed by chi-square test, and continuous variables were analyzed by Mann-Whitney U test. The Kaplan-Meier method was used for evaluating incidence differences. Results: Seventeen patients were included in the letermovir prophylaxis group. The median patient age in the letermovir group was significantly greater than that in the control group (43 yr vs. 15 yr; Z=-4.28, P<0.001). The two groups showed no significant difference in sex distribution and primary diseases, etc. (all P>0.05). The proportion of CMV-seronegative donors was significantly higher in the letermovir prophylaxis group in comparison with the control group (8/17 vs. 0/68, χ2=35.32, P<0.001). Three out of the 17 patients in the letermovir group experienced CMV reactivation, which was significantly lower than the incidence of CMV reactivation in the control group (3/17 vs. 40/68, χ2=9.23, P=0.002), and no CMV disease development observed in the letermovir group. Letermovir showed no significant effects on platelet engraftment (P=0.105), aGVHD (P=0.348), and 100-day NRM (P=0.474). Conclusions: Preliminary data suggest that letermovir may effectively reduce the incidence of CMV infection after haploidentical transplantation without influencing aGVHD, NRM, and bone marrow suppression. Prospective randomized controlled studies are required to further verify these findings.

Efficacy and safety of secondary allogeneic hematopoietic stem cell transplantation in 70 patients with recurrent hematologic malignancies after transplantation / 中华血液学杂志

Objectives: To investigate the role of donor change in the second hematopoietic stem cell transplantation (HSCT2) for hematological relapse of malignant hematology after the first transplantation (HSCT1) . Methods: We retrospectively analyzed patients with relapsed hematological malignancies who received HSCT2 at our single center between Mar 1998 and Dec 2020. A total of 70 patients were enrolled[49 males and 21 females; median age, 31.5 (3-61) yr]. Results: Forty-nine male and 21 female patients were enrolled in the trial. At the time of HSCT2, the median age was 31.5 (3-61) years old. Thirty-one patients were diagnosed with acute myeloid leukemia, 23 patients with ALL, and 16 patients with MDS or other malignant hematology disease. Thirty patients had HSCT2 with donor change, and 40 patients underwent HSCT2 without donor change. The median relapse time after HSCT1 was 245.5 (26-2 905) days. After HSCT2, 70 patients had neutrophil engraftment, and 62 (88.6%) had platelet engraftment. The cumulative incidence of platelet engraftment was (93.1±4.7) % in patients with donor change and (86.0±5.7) % in patients without donor change (P=0.636). The cumulative incidence of CMV infection in patients with and without donor change was (64.0±10.3) % and (37.0±7.8) % (P=0.053), respectively. The cumulative incidence of grade Ⅱ-Ⅳ acute graft versus host disease was (19.4±7.9) % vs (31.3±7.5) %, respectively (P=0.227). The cumulative incidence of TRM 100-day post HSCT2 was (9.2±5.1) % vs (6.7±4.6) % (P=0.648), and the cumulative incidence of chronic graft versus host disease at 1-yr post-HSCT2 was (36.7±11.4) % versus (65.6±9.1) % (P=0.031). With a median follow-up of 767 (271-4 936) days, 38 patients had complete remission (CR), and three patients had persistent disease. The CR rate was 92.7%. The cumulative incidences of overall survival (OS) and disease-free survival (DFS) 2 yr after HSCT2 were 25.8% and 23.7%, respectively. The cumulative incidence of relapse, OS, and DFS was (52.6±11.6) % vs (62.4±11.3) % (P=0.423), (28.3±8.6) % vs (23.8±7.5) % (P=0.643), and (28.3±8.6) % vs (22.3±7.7) % (P=0.787), respectively, in patients with changed donor compared with patients with the original donor. Relapses within 6 months post-HSCT1 and with persistent disease before HSCT2 were risk factors for OS, DFS, and CIR. Disease status before HSCT2 and early relapse (within 6 months post-HSCT1) was an independent risk factor for OS, DFS, and CIR post-HSCT2. Conclusion: Our findings indicate that changing donors did not affect the clinical outcome of HSCT2.

Incidence and clinical characteristics of engraftment syndrome after syngeneic hematopoietic stem cell transplantation in patients with hematological diseases / 中华血液学杂志

Objective: To explore the incidence and clinical characteristics of engraftment syndrome (ES) after syngeneic hematopoietic stem cell transplantation (syn-HSCT) in patients with hematological diseases. Methods: The clinical data of 21 patients who received syn-HSCT at People's Hospital of Peking University from January 1994 to May 2018 were retrospectively analyzed. Results: Seven (33.3% ) of 21 patients developed ES. The onset of ES symptoms occurred at a median of 8 (range: 5-13) days after HSCT, and the diagnosis of ES occurred at a median of 10 (range: 7-14) days after HSCT. Steroids were administered immediately after the diagnosis of ES, the median time of symptom continuance was 2 (range: 1-5) days, and all patients showed complete resolution of ES symptoms. In the multivariate analysis, patients with acute myeloid leukemia and faster neutrophil reconstitution were the risk factors for ES (HR=15.298, 95% CI 1.486-157.501, P=0.022, and HR=17.459, 95% CI 1.776-171.687, P=0.014) . Meanwhile, there was no significant difference in the overall survival and disease-free survival between patients with ES and those without ES. Conclusion: A high incidence of ES was observed in syn-HSCT recipients. Moreover, the prognosis of ES was excellent.

A retrospective comparative study of haplotype hematopoietic stem cell transplantation and human leukocyte antigen-matched sibling donor hematopoietic stem cell transplantation in the treatment of acute B-lymphocyte leukemia / 中华血液学杂志

Objective: To investigate whether haplotype hematopoietic stem cell transplantation (haplo-HSCT) is effective in the treatment of pre transplant minimal residual disease (Pre-MRD) positive acute B lymphoblastic leukemia (B-ALL) compared with HLA- matched sibling donor transplantation (MSDT) . Methods: A total of 998 patients with B-ALL in complete remission pre-HSCT who either received haplo-HSCT (n=788) or underwent MSDT (n=210) were retrospectively analyzed. The pre-transplantation leukemia burden was evaluated according to Pre-MRD determinedusing multiparameter flow cytometry (MFC) . Results: Of these patients, 997 (99.9% ) achieved sustained, full donor chimerism. The 100-day cumulative incidences of neutrophil engraftment, platelet engraftment, and grades Ⅱ-Ⅳ acute graft-versus-host disease (GVHD) were 99.9% (997/998) , 95.3% (951/998) , and 26.6% (95% CI 23.8% -29.4% ) , respectively. The 3-year cumulative incidence of total chronic GVHD was 49.1% (95% CI 45.7% -52.4% ) . The 3-year cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) of the 998 cases were 17.3% (95% CI 15.0% -19.7% ) and 13.8% (95% CI 11.6% -16.0% ) , respectively. The 3-year probabilities of leukemia-free survival (LFS) and overall survival (OS) were 69.1% (95% CI 66.1% -72.1% ) and 73.0% (95% CI 70.2% -75.8% ) , respectively. In the total patient group, cases with positive Pre-MRD (n=282) experienced significantly higher CIR than that of subjects with negative Pre-MRD [n=716, 31.6% (95% CI 25.8% -37.5% ) vs 14.3% (95% CI 11.4% -17.2% ) , P<0.001]. For patients in the positive Pre-MRD subgroup, cases treated with haplo-HSCT (n=219) had a lower 3-year CIR than that of cases who underwent MSDT [n=63, 27.2% (95% CI 21.0% -33.4% ) vs 47.0% (95% CI 33.8% -60.2% ) , P=0.002]. The total 998 cases were classified as five subgroups, including cases with negative Pre-MRD group (n=716) , cases with Pre-MRD<0.01% group (n=46) , cases with Pre-MRD 0.01% -<0.1% group (n=117) , cases with Pre-MRD 0.1% -<1% group (n=87) , and cases with Pre-MRD≥1% group (n=32) . For subjects in the Pre-MRD<0.01% group, haplo-HSCT (n=40) had a lower CIR than that of MSDT [n=6, 10.0% (95% CI 0.4% -19.6% ) vs 32.3% (95% CI 0% -69.9% ) , P=0.017]. For patients in the Pre-MRD 0.01% -<0.1% group, haplo-HSCT (n=81) also had a lower 3-year CIR than that of MSDT [n=36, 20.4% (95% CI 10.4% -30.4% ) vs 47.0% (95% CI 29.2% -64.8% ) , P=0.004]. In the other three subgroups, the 3-year CIR was comparable between patients who underwent haplo-HSCT and those received MSDT. A subgroup analysis of patients with Pre-MRD<0.1% (n=163) was performed, the results showed that cases received haplo-HSCT (n=121) experienced lower 3-year CIR [16.0% (95% CI 9.4% -22.7% ) vs 40.5% (95% CI 25.2% -55.8% ) , P<0.001], better 3-year LFS [78.2% (95% CI 70.6% -85.8% ) vs 47.6% (95% CI 32.2% -63.0% ) , P<0.001] and OS [80.5% (95% CI 73.1% -87.9% ) vs 54.6% (95% CI 39.2% -70.0% ) , P<0.001] than those of MSDT (n=42) , but comparable in 3-year NRM [5.8% (95% CI 1.6% -10.0% ) vs 11.9% (95% CI 2.0% -21.8% ) , P=0.188]. Multivariate analysis showed that haplo-HSCT was associated with lower CIR (HR=0.248, 95% CI 0.131-0.472, P<0.001) , and superior LFS (HR=0.275, 95% CI 0.157-0.483, P<0.001) and OS (HR=0.286, 95% CI 0.159-0.513, P<0.001) . Conclusion: Haplo HSCT has a survival advantage over MSDT in the treatment of B-ALL patients with pre MRD<0.1% .

A risk score system for stratifying the risk of relapse in B cell acute lymphocytic leukemia patients after allogenic stem cell transplantation / 中华医学杂志(英文版)

BACKGROUND@#For patients with B cell acute lymphocytic leukemia (B-ALL) who underwent allogeneic stem cell transplantation (allo-SCT), many variables have been demonstrated to be associated with leukemia relapse. In this study, we attempted to establish a risk score system to predict transplant outcomes more precisely in patients with B-ALL after allo-SCT.@*METHODS@#A total of 477 patients with B-ALL who underwent allo-SCT at Peking University People's Hospital from December 2010 to December 2015 were enrolled in this retrospective study. We aimed to evaluate the factors associated with transplant outcomes after allo-SCT, and establish a risk score to identify patients with different probabilities of relapse. The univariate and multivariate analyses were performed with the Cox proportional hazards model with time-dependent variables.@*RESULTS@#All patients achieved neutrophil engraftment, and 95.4% of patients achieved platelet engraftment. The 5-year cumulative incidence of relapse (CIR), overall survival (OS), leukemia-free survival (LFS), and non-relapse mortality were 20.7%, 70.4%, 65.6%, and 13.9%, respectively. Multivariate analysis showed that patients with positive post-transplantation minimal residual disease (MRD), transplanted beyond the first complete remission (≥CR2), and without chronic graft-versus-host disease (cGVHD) had higher CIR (P  < 0.001, P = 0.004, and P  < 0.001, respectively) and worse LFS (P  < 0.001, P = 0.017, and P  < 0.001, respectively), and OS (P  < 0.001, P = 0.009, and P  < 0.001, respectively) than patients without MRD after transplantation, transplanted in CR1, and with cGVHD. A risk score for predicting relapse was formulated with the three above variables. The 5-year relapse rates were 6.3%, 16.6%, 55.9%, and 81.8% for patients with scores of 0, 1, 2, and 3 (P  < 0.001), respectively, while the 5-year LFS and OS values decreased with increasing risk score.@*CONCLUSION@#This new risk score system might stratify patients with different risks of relapse, which could guide treatment.

Risk factors analysis for steroid-resistant acute graft versus host disease after haploidentical hematopoietic stem cell transplantation / 中华血液学杂志

Objective: To analyze the risk factors of steroid resistant acute graft- versus-host disease (aGVHD) after haploidentical hematopoietic stem cell transplantation (haplo-HSCT) . Methods: The clinical data of adult patients with acute myeloid leukemia (AML) /Myelodysplastic syndrome (MDS) who developed aGVHD after haplo-HSCT in Peking University Institute of Hematology from January 1st, 2010 to December 31st, 2012 were retrospectively reviewed. Results: A total of 85 patients were enrolled in the study, including 55 males and 30 females, with a median age of 30 (19-67) years. After steroid therapy, there were 53 (62.4%) , 6 (7.1%) and 26 (30.6%) patients achieved complete remission (CR) , partial remission (PR) and non-remission (NR) , respectively. The CR rates of the grade Ⅰ/Ⅱ and Ⅲ/Ⅳ aGVHD by steroid therapy were 66.2% (51/77) vs 25.0% (2/8) (χ(2)=3.639, P=0.048) , respectively. The CR rates of the patients with aGVHD involving 1 target organ and 2 target organs were 77.4% (48/62) vs 21.7% (5/23) (χ(2)=22.157, P<0.001) . The CR rates of patients with standard risk (SR) and high risk (HR) Minnesota risk score was 67.5% (52/77) vs 12.5% (1/8) (χ(2)=7.153, P=0.004) . The mononuclear cells≥8.33×10(8)/kg and the HR Minnesota risk score were independent risk factors for steroid-resistant aGVHD in multivariate analysis. Between Minnesota risk score SR (77 cases) and HR (8 cases) groups, the OS rates at 22 months after transplantation were (90.3±3.8) %vs (75.0±15.3) % (χ(2)=2.831, P=0.092) . After steroid treatment for aGVHD, the OS rates at 22 months in the CR group (53 cases) and non-CR group (32 cases) were (95.2±3.4) %vs (78.6±7.9) % (χ(2)=5.287, P=0.021) respectively. Conclusion: The Minnesota risk score and mononuclear cells count are effective tool for predicting steroid-resistant aGVHD after haplo-HSCT.

Minimal residual disease in adults with Philadelphia chromosome negative acute lymphoblastic leukemia in high-risk / 中华血液学杂志

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 CR(1). 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.

Observation on the efficacy of consolidation chemotherapy combined with allogeneic natural killer cell infusion in the treatment of low and moderate risk acute myeloid leukemia / 中华血液学杂志

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) ×10(9)/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) ×10(9)/L, accounting for 76.8% (30.8%-82.9%) ; The number of CD3(+) CD56(+) cells was 0.55 (0.24-1.74) ×10(9)/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%) (χ(2)=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%, χ(2)=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) (χ(2)=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) (χ(2)=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%, χ(2)=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.

Effects of chemotherapy combined with donor lymphocyte infusion on chronic graft-versus-host disease and prognosis in minimal residual disease positive patients after allogeneic hematopoietic stem cell transplantation / 中华血液学杂志

Objective: To explore clinical features and severity of chronic graft- versus- host disease (cGVHD) after chemotherapy plus donor lymphocyte infusion (Chemo-DLI) in a consecutive cohort of acute leukemia patients who were minimal residual disease (MRD) positive after allogeneic hematopoietic stem cell transplantation (allo-HSCT) . Methods: The global scoring system proposed by National Institutes of Health (NIH) Consensus Conference was used to identify the characteristics and severity of cGVHD in patients who MRD positive after Chemo-DLI. Results: 54 (59.3%) patients were diagnosed with cGVHD after Chemo-DLI, with the median time of onset of 70 (13-504) days. There were 6 cases (6.6%) of mild cGVHD, 21 cases (23.1%) of moderate cGVHD and 27 cases (29.7%) of severe cGVHD.The 5-year cumulative incidence of relapse after Chemo-DLI was 61.9% (95%CI 45.3%-78.5%) , 15.1% (95%CI 1.1%-29.1%) , and 26.6% (95%CI 9.2%-44.0%) (χ(2)=18.901, P<0.001) in non-cGVHD, mild to moderate cGVHD, and severe cGVHD groups, respectively. The 5-year cumulative incidence of relapse after Chemo-DLI was 61.9% (95%CI 45.3%-78.5%) , 19.9% (95%CI 8.1%-31.7%) , and 28.6% (95%CI 0.0%-65.0%) (χ(2)=18.307, P<0.001) in non-cGVHD, classical cGVHD, and overlap syndrome groups, respectively. cGVHD was not associated with non-relapse morality after Chemo-DLI. Probabilities of 5-year leukemia-free survival (LFS) after Chemo-DLI were 24.0% (95%CI 9.1%-38.9%) , 77.2% (95%CI 60.8%-93.6%) , and 64.9% (95%CI 45.7%-84.1%) (χ(2)=24.447, P<0.001) in non-cGVHD, mild to moderate cGVHD, and severe cGVHD groups, respectively. Probabilities of 5-year LFS after Chemo-DLI were 24.0% (95%CI 9.1%-38.9%) , 75.5% (95%CI 62.7%-88.3%) , and 42.9% (95%CI 1.8%-84.0%) (χ(2)=25.665, P<0.001) in non-cGVHD, classical cGVHD, and overlap syndrome groups, respectively. Probabilities of 5-year overall survival (OS) after Chemo-DLI were 50.0% (95%CI 31.1%-68.9%) , 87.9% (95%CI 74.7%-100.0%) , and 71.0% (95%CI 52.0%-90.0%) (χ(2)=9.517, P=0.009) in non-cGVHD, mild to moderate cGVHD, and severe cGVHD groups, respectively. Probabilities of 5-year OS after Chemo-DLI were 50.0% (95%CI 31.1%-68.9%) , 83.9% (95%CI 72.8%-95.0%) , and 51.4% (95%CI 6.2%-96.6%) (χ(2)=10.673, P=0.005) in non-cGVHD, classical cGVHD, and overlap syndrome groups, respectively. In multivariate analysis, patients receiving allo-HSCT in first complete remission stage and classical cGVHD after Chemo-DLI were associated with lower relapse risk and better survival. Conclusions: These findings highlight the close relation between cGVHD and the graft-versus-leukemia effect in patients who were MRD positive and received Chemo-DLI after allo-HSCT. However, overlap syndrome could not improve the clinical outcomes of these patients.

Effects of pre-transplant course on prognosis of allogeneic hematopoietic stem cell transplantation in patients with acute myeloid leukemia / 中华血液学杂志

Objective: To evaluate the impact of pre-transplant course on transplant outcomes in patients with acute myeloid leukemia (AML) . Methods: A retrospective analysis was conducted in 107 patients with AML who received allogeneic hematopoietic stem cells transplantation (allo-HSCT) in the first complete remission stage (CR(1)) from January 2012 to June 2014. Results: ①46 cases received allo-HSCT within 6 months upon diagnosis, including 25 males and 21 females, with a median age of 26 (12-60) y. 61 cases received allo-HSCT after 6 months upon diagnosis, including 34 males and 27 females, with a median age of 31 (14-58) years. There is no statistical significance in patients' age, gender, NCCN risk stratification, courses for induction, minimal residual disease (MRD) status, transplantation type and infection rates prior to transplantation. Total courses of chemotherapy before allo-HSCT were 4 (3-5) and 5 (4-10) for the two groups, respectively. ②Incidences of Grade Ⅱ-Ⅳ aGVHD were 26.09% (12/46) for the <6-month group and 24.59% (15/61) for the ≥6 months group (P=0.860) . Incidences of Grade Ⅲ/Ⅳ aGVHD were 2.17% (1/46) for the <6-month group and 14.75% (9/61) for the ≥6 months group (P=0.027) . ③ Probabilities of 2-year overall survival (OS) were (90.3±4.6) % for the <6 months group and (75.7±5.7) % for the ≥6 months group (P=0.042) . Probabilities of 2-year disease-free survival (DFS) were (90.7±4.4) % for the <6 months group and (76.3±5.5) % for the ≥6 months group (P=0.038) . ④ During the median follow-up of 863 (26-2 026) days, cumulative incidences of non-relapse mortality were (4.4±3.1) % for the <6 months group and (18.2±5.0) % for the ≥6 months group (P=0.047) . ⑤ Univariate analysis showed that age, NCCN risk stratification, MRD status before transplantation and rates of infection was not related to transplantation outcomes. Chemotherapy courses before allo-HSCT (≤4 or >4) was related to OS and DFS (P=0.044, P=0.039) , but not to NRM (P=0.079) . Conclusion: AML patients who obtained CR(1) could achieve better long-term survival by receiving allo-HSCT within 6 months after diagnosis.

Age-related clinical characteristics and prognosis in non-senile adults with acute myeloid leukemia / 中华血液学杂志

Objective: To explore age-related clinical characteristics, early responses and outcomes in non-senile adults with de novo acute myeloid leukemia (AML). Methods: Data of consecutive cases of 18-65 years adults with de novo AML (non-acute promyelocytic leukemia) were reviewed retrospectively. Clinical characteristics at diagnosis, early responses and outcomes across different age groups of patients were analyzed. Results: 1 097 patients were enrolled. 591 (53.9%) were male. Median age was 42 years. Increasing age was significantly associated with decreasing WBC count (P=0.003), increasing PLT count (P=0.034), lower blast proportions in bone marrow (P=0.021). The incidence of NPM1(+)/FLT3-ITD(-) increased with age (P<0.001). Multivariate analyses showed that increasing age was associated with low probabilities of achieving morphologic leukemia free state (MLFS) (P=0.053) and complete remission (CR) (P=0.004) and poor overall survival (OS) (P=0.070) in the whole patients population. However, increasing age was not associated with low MLFS rate and poor OS, except low CR rate (P=0.075) in those receiving standard induction regimen instead of low-intensity regimen. Conclusions: There were significant differences on clinical characteristics, cytogenetics and molecular genetics across different age groups in non-senile adults with de novo AML. In the patients receiving standard induction regimen, age was not associated with MLFS rate and OS.

Clinical analysis of hemorrhagic cystitis in children and adolescents with hematological diseases post haplo-hematopoietic stem cell transplantation / 中华血液学杂志

Objective: To investigate the incidence and clinical features to probe the risk factors of hemorrhagic cystitis (HC) in children and adolescents with hematological diseases post haplo-hematopoietic stem cell transplantation (haplo-HSCT) . Methods: Medical records of 62 children and 27 adolescents with hematological diseases treated with haplo-HSCT between 2015 and 2016 were analyzed. Results: Of 89 cases (56 boys and 33 girls) , 44 patients were diagnosed with ALL, 33 AML, 3 AHL and 9 MDS. HC occurred in 32 of the 89 patients with an incidence of 36%, including 6 with grade Ⅰ, 16 with grade Ⅱ, 8 with grade Ⅲ, 2 with grade Ⅳ HC, respectively. The median time of HC onset was 25 days (range 2-55 days) after haplo-HSCT with the median duration as 19 days (range 3-95 days) , all of them were cured. The incidence of HC was lower in the group of children than that in the group of adolescents (27.4% vs 55.6%, χ(2)=6.466, P<0.05) , and the incidence of HC was higher in the group of patients who were ≥5 years old than that in the group of patients who were <5 years old (0 vs 34%, χ(2)=4.043, P<0.05) . Conclusion: HC is one of common complications in children and adolescents with hematological diseases post haplo-HSCT, older age was associated with increased mortality.

The comparison of predicting clinical outcomes between immunolophenotype and hematological complete remission before human leukocyte antigen-matched sibling donor transplantation in acute myeloid leukemia / 中华血液学杂志

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)%, χ(2)=0.274, P=0.600], non-relapse mortality[NRM, (14.0±4.3)% vs (9.0±6.3)%, χ(2)=0.913, P=0.339], leukemia-free survival[LFS, (75.0±5.1)% vs (75.0±8.3)%, χ(2)=0.256, P=0.613], and overall survial [OS, (77.0±5.2)% vs (80.0±8.1)%, χ(2)=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) %, χ(2)=32.687, P<0.001], better 4-year LFS [(76.2±4.7)% vs (32.8±8.7)%, χ(2)=26.234, P<0.001] and OS[(79.0±4.7)% vs (39.0±9.1)%, χ(2)=25.253, P<0.001], and comparable NRM[(12.5±4.1)% vs (12.0±7.1)%, χ(2)=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.

Association of Persistent Minimal Residual Disease with Poor Outcomes of Patients with Acute Myeloid Leukemia Undergoing Allogeneic Hematopoietic Stem Cell Transplantation / 中华医学杂志(英文版)

Background@#Several studies have shown that detection of minimal residual disease (MRD) in acute myeloid leukemia (AML) is an independent prognostic factor. This study aimed to evaluate the significance of dynamic MRD pretransplantation on outcome of AML patients receiving allogeneic hematopoietic stem cell transplantation (allo-HSCT).@*Methods@#We retrospectively analyzed 145 consecutive AML patients undergoing allo-HSCT in complete remission status between June 2013 and June 2016. MRD was determined with multiparameter flow cytometry after the first and second courses of chemotherapy and pre-HSCT.@*Results@#In matched sibling donor transplantation (MSDT) settings, patients with positive MRD had higher cumulative incidence of relapse (CIR) than those without MRD after the first (32.3 ± 9.7% vs. 7.7 ± 3.1%, χ = 3.661, P = 0.055) or second course of chemotherapy (57.1 ± 3.6% vs. 12.5 ± 2.7%, χ = 8.759, P = 0.003) or pre-HSCT (50.0 ± 9.7% vs. 23.0 ± 3.2%, χ = 5.547, P = 0.019). In haploidentical SCT (haplo-SCT) settings, the MRD status at those timepoints had no significant impact on clinical outcomes. However, patients with persistent positive MRD from chemotherapy to pre-HSCT had higher CIR than those without persistent positive MRD both in MSDT and haplo-SCT settings. Patients with persistent positive MRD underwent MSDT had the highest relapse incidence, followed by those with persistent positive MRD underwent haplo-SCT, those without persistent MRD underwent haplo-SCT, and those without persistent MRD underwent MSDT (66.7 ± 9.2% vs. 38.5 ± 6.0% vs. 18.8 ± 8.7% vs. 12.0 ± 1.0%, χ = 20.763, P < 0.001). Multivariate analysis showed that persistent positive MRD before transplantation was associated with higher CIR (hazard ratio [HR] = 1.69, 95% confidence interval [CI]: 1.200-2.382, P = 0.003), worse leukemia-free survival (HR = 1.812, 95% CI: 1.168-2.812, P = 0.008), and overall survival (HR = 2.354, 95% CI: 1.528-3.627, P < 0.001).@*Conclusion@#Our results suggest that persistent positive MRD before transplantation, rather than positive MRD at single timepoint, could predict poor outcome both in MSDT and haplo-SCT settings.

Preparation of placenta factor and its immunoregulatory effects on lymphocytes in vitro / 中国实验血液学杂志

The study was aimed to establish a new method of preparation of human placenta factor (PF) and to determine its physic-chemical properties, as well as effects on lymphocytes in vitro. PF was prepared by ultrafiltration. The contents and molecular weight of all constitutions were determined by Bradford method and SDS-PAGE, respectively. Cyclosporin A (CsA) was served as positive control, normal saline (NS) was used as negative control. PHA-stimulated lymphocyte proliferation and mixed lymphocyte reaction (MLR) were detected with MTT assay. The expression of CD69 on T cells was analyzed by flow cytometry. Cytotoxicity of natural killer (NK) cells against K562 tumor cells was examined with LDH release assay. The results indicated that PF was determined to be a group of low molecular weight polypeptides, consisting of two major components whose molecular weight were 9.187 and 4.794 kD respectively. The contents of PF were 5.7 - 6.9 mg/g fresh placenta. PF had similar suppressive effects on PHA-stimulated lymphocyte proliferation and MLR in vitro as compared with CsA (P > 0.05). Both PF and CsA could downregulate the expression of CD69 on T cells which had been stimulated by PMA plus ionomycin (PF vs CsA, P > 0.05). The cytotoxicity of NK cells against K562 cells in PF group was slightly higher or equivalent as compared with that in NS group (P > 0.05), but the cytotoxicity in CsA group was much lower than that in NS group (P < 0.05). It is concluded that a new method of preparation of PF has been established. This study first demonstrates that PF has strong immunosuppressive effects on T cell in vitro, and suppresses T cell proliferation and activation induced by mitogen and alloantigen. This study indicats that PF has no any inhibitory effects, but even enhances the cytotoxicity of NK cells against K562 tumor cells. These results suggest that PF may have suppressive effects on graft-versus-host disease (GVHD) without diminishing graft-versus-tumor (GVT) effects. Therefore, PF may probably be an ideal and promising agent against GVHD.