Erythrocytosis after hematopoietic stem cell transplantation: report of 3 cases and literature review / 中华内科杂志

This is a report of three cases of three male patients. One of the patients had myelodysplastic syndrome, and two had aplastic anemia; their ages were 28, 32, and 21 years old, respectively. Two patients underwent sibling allogeneic hematopoietic stem cell transplantation, and one underwent haploidentical hematopoietic stem cell transplantation. All the patients showed elevated hemoglobin and hematocrit at 6, 16, and 9 months after transplantation, with normal white blood cells and platelets and no splenomegaly. All causes of secondary polycythemia were ruled out. Bone marrow morphology showed no erythroid hyperplasia. The PCR result for BCR-ABL (P210, P230, P190, and variants) was negative, and there were no mutations at the amino acid site 617 of JAK2, exon 12 of JAK2, exon 9 of CALR, and amino acid site 515 of MPL. All three patients had hypertension. One patient was treated with amlodipine, and the other two patients were treated with angiotensin receptor blockers. The durations of erythrocytosis for these three patients were 6 years and 3 months, 4 years and 7 months, and 5 years and 3 months, respectively through December 2022. There was no tendency for spontaneous remission. Erythrocytosis after hematopoietic stem cell transplantation is a rare complication. Previous reports in the literature suggest that the mechanism of post-transplant erythrocytosis in recipients of allogeneic hematopoietic stem cell transplantation may be different from that of recipients of other transplants.

Clinical characteristics of patients with human adenovirus infection undergoing allogeneic hematopoietic stem cell transplantation / 中华内科杂志

Objective:To investigate the clinical characteristics and prognosis of human adenovirus (HAdV) infection in patients with allogeneic hematopoietic stem cell transplantation (allo-HSCT).Methods:This is a retrospective case series study. Patients who received allo-HSCT and had symptoms of HAdV infection were tested in the Hematology Department at Perking University People′s Hospital from August 2015 to October 2019. Real-time quantitative PCR was used to detect HAdV DNA from 2 728 patients with potential infection. HAdV DNA-positive patients were defined as having HAdV infection. The clinical features of these patients were analyzed, and a case-pair method was used to select patients without HAdV infection as the control group in a 1∶3 ratio. The clinical results of the two groups were compared using Kaplan-Meier and Log-rank testing.Results:A total of 7 119 samples were tested for HAdV, of which 99 samples from 36 patients were positive. Of these patients, 22 developed HAdV viremia, and 24 patients had concurrent infection with another virus. Nineteen patients had fever (53%), 25 had gastrointestinal symptoms (69%), 11 had respiratory symptoms (31%), nine had reduced liver function (25%), and six had nervous system symptoms (17%). Twenty-three patients developed acute graft-versus-host disease of grade 2 or higher. Of all the patients with HAdV infection, nine were treated with cidofovir, seven of whom became HAdV negative and two had invalid treatment. The median follow-up time was 496 (216, 940) d post-HSCT. The overall survival at 5 years post HSCT was 48.4%±9.2% vs. 91.3%±3.5% ( χ2=65.03, P<0.001) in patients with and without HADV, respectively. The non-relapse mortality at 5 years post-HSCT was 40.8%±8.8% vs. 4.0%±2.0% ( χ2=34.17, P<0.001) in patients with and without HADV, respectively. Conclusions:After allo-HSCT, HAdV-infected patients are dominated by gastrointestinal and respiratory symptoms and have an increased risk of combined acute graft-versus-host disease of >2 degrees. Patients with HAdV infection have poor overall survival and high non-relapse mortality.

Clinical analysis of the efficacies of ganciclovir plus foscarnet and a single antiviral drug for the treatment of cytomegalovirus infection after haploidentical stem cell transplantation / 中华内科杂志

Objective:To evaluate and compare the efficacies of ganciclovir plus foscarnet and a single agent for the treatment of cytomegalovirus (CMV) infection after haploidentical hematopoietic stem cell transplantation.Methods:This study was a non-randomized clinical controlled trial. The data of patients who underwent haploidentical transplantation and developed CMV infection between January 1, 2021, and June 30, 2021, were retrospectively analyzed. Follow-up was conducted through telephone, inpatient consultations, and the review of outpatient medical records. The observed indicators included the incidence of CMV infection (including CMV disease), rate of recurrence of CMV infection, overall survival (OS), and disease-free survival (DFS).Results:A total of 242 patients were diagnosed with post-transplantation CMV infection; 116 patients tested positive for CMV DNA for more than 14 days ( P=0.011). Of the 242 patients with CMV infection, 65 were treated with ganciclovir plus foscarnet, and 156 patients were treated with a single antiviral drug; the median durations of CMV seroconversion were 21 (3-60) and 14 (3-32) days for the combination and single-drug groups, respectively. There were no significant differences between their incidence of CMV infections and 1-year OS and DFS. Of the patients with refractory CMV infections, 53 (45.7%) were treated with ganciclovir plus foscarnet, and 63 (54.3%) were treated with a single antiviral agent. The median durations of CMV seroconversion for the combination and single-drug groups were 21 (15-60) days and 20 (15-45) days, respectively ( P=0.472). Two patients in each group progressed to CMV disease ( P=0.860). During follow-up, 12 patients (22.6%) in the combination group and 8 patients (12.7%) in the single-drug group experienced recurrent episode(s) of CMV infection ( P=0.158). The 1-year OS of the combination and single-drug groups were 92.0% and 87.1%, respectively ( P=0.543); the 1-year DFS were 90.3% and 85.7%, respectively ( P=0.665). Univariate analysis revealed no associations between the antiviral agents used and OS and DFS (OS: HR=0.644, P=0.547; DFS: HR=0.757, P=0.666). Conclusions:There were no significant differences in the duration of CMV infection, incidence of CMV disease, rate of recurrence of CMV infection, and survival of the patients treated with the combination of antiviral drugs and a single antiviral drug.

Application value of metagenomic next-generation sequencing for infectious pathogens in patients receiving allogeneic hematopoietic stem cell transplantation / 中华内科杂志

Objective:To investigate the application value of Metagenomic Next-Generation sequencing (mNGS) in infectious patients after allogeneic hematopoietic stem cell transplantation(allo-HSCT).Methods:Patients suspected with local or systemic infections were retrospectively included after allo-HSCT in our department from April 2019 to November 2020. Pathogenic microorganisms were tested by mNGS in samples from peripheral blood, cerebrospinal fluid, alveolar lavage Liquid, abscess, etc. Other diagnostic methods such as bacterial/fungal culture, viral PCR detection were simultaneously explored comparing with mNGS results.Results:A total of 112 samples in 83 patients were detected by mNGS, and 34 pathogenic microorganisms were determined. Among these positive samples, 11 strains of bacteria (17 times) with the most common Escherichia coli (4/17) were reported. There were 7 strains of fungi (10 times) detected with primary Candida albicans (7/29). Although arvovirus 30.2% (39/129) were predominantly detected, its diagnostic relevance with infections was not definite. Other pathogenic viruses including cytomegalovirus (CMV) 25.6% (33/129) and Epstein Barr virus (EBV) 14.0% (18/129)were of significance. Comparing with golden diagnostic criteria, the sensitivity of mNGS was 86.5%, and specificity was 45.0%. Regarding single pathogen infection, the consistency of mNGS and conventional methods was 82.9% (29/35), while it was 16/17 in combination infections.Conclusion:mNGS could be a potential method to determine pathogens in patients suspected with infections after allo-HSCT.

Positive MRD suggests a poor prognosis for ALL patients with or above CR2 before allogeneic transplantation / 中华检验医学杂志

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.

Prognostic significance of DEK-NUP214 fusion gene in patients with acute myeloid leukemia after allogeneic hematopoietic stem cell transplantation / 中华内科杂志

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.

Comparison of EB virus infection between short term and long term use of mycophenolate mofetil for prophylaxis of graft versus host disease after haploidentical hematopoietic stem cell transplantation / 中华内科杂志

Objective:To investigate the role of short-term use of mycophenolate mofetil (MMF) in EB viral infection and acute graft-versus host disease (GVHD) in patients receiving haploidentical hematopoietic stem cell transplantation (haplo-HSCT) .Method:Adult patients (≥14 years) who were diagnosed with hematological malignancies received haplo-HSCT in Peking University Institute of Hematology from May 2016 to December 2017 were retrospectively reviewed. The median age was 30 (14-60) years old. A total of 498 patients including 277 males and 221 females were enrolled. Donors' median age was 38 (8-66) years old. All patients were classified into long-term use of MMF ( n=199), which was defined as 500 mg every 12 hours from day 9 pre-transplant to 250 mg every 12 hours from day 30 after transplant then withdrawal on day 45 to 60 after transplant, and short-term use of MMF ( n=299), which was defined as 500 mg every 12 hour from day 9 pre-transplant then withdrawal till neutrophil engraftment. Kaplan-Meier model was used to analyze the cumulative incidence of EBV infection, and the Cox proportional regression model for multivariate analysis. Result:Characteristics including sex, age, disease types, mismatched HLA loci, donor-recipient relationship, donor-recipient blood type, donor age, and donor sex were comparable between two groups (all P＞0.05). According to once, the incidence of EBV viremia, defined as EBV＞10 3 copies/ml at least once, in short-term group and long-term group was 19.4% (58/299) and 27.6% (55/199) respectively ( P=0.046).Donor age and the duration of MMF prophylaxis (short-term group as reference) were associated with EBV viremia according to multivariate analysis [ HR=1.022(95% CI 1.006-1.038),1.600(95% CI 1.059-2.418); P=0.006 and 0.026, respectively]. The incidence of grade Ⅱ-Ⅳ and Ⅲ/Ⅳ acute GVHD in long-term and short-term group was 32.2% (64/199) versus 20.7% (62/299)( P=0.005) and 10.1% (20/199) versus 8.0% (24/299) ( P=0.427), respectively. Donor sex (female as reference) and duration of MMF prophylaxis (short-term group as reference) were associated with grade Ⅱ-Ⅳ acute GVHD [ HR=1.908(95% CI 1.079-3.373),1.752(95% CI 1.161-2.643); P=0.026 and 0.008, respectively].There were no statistical differences in the incidence of CMV viremia, refractory CMV viremia and hemorrhagic cystitis (all P＞0.05) between the two groups. Conclusion:Short-term use of MMF can reduce EBV viremia without increasing the development of acute GVHD in haplo-HSCT patients.

Negative effects of donor specific anti-HLA antibody on poor hematopoietic recovery in patients with hematological diseases receiving haploidentical stem cell transplantation and rituximab for desensitization / 中华内科杂志

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.

The effect of donor cytomegalovirus serological status on the outcome of allogeneic stem cell transplantation / 中华内科杂志

Objective:Donor cytomegalovirus (CMV) serological negative status may have an adverse effect on the outcome of allogeneic hematopoietic stem cell transplantation (allo-HSCT), while there is inadequate data for Chinese people. This study is to explore the impact of donor CMV serological status on the outcome of CMV seropositive patients receiving allo-HSCT.Methods:Our study retrospectively analyzed 16 CMV seropositive patients with hematological malignancies receiving allogeneic grafts from CMV seronegative donors (antibody IgG negative) at Peking University People′s Hospital from March 2013 to March 2020, which was defined as D -/R + group. The other 64 CMV seropositive patients receiving grafts from CMV seropositive donors at the same period of time were selected as matched controls through a propensity score with 1∶4 depending on age, disease state and donor-recipient relationship (D +/R + group). Results:Patients in D -/R + group developed CMV DNAemia later than patients in the D +/R + group (+37 days vs. +31 days after allo-HSCT, P=0.011), but the duration of CMV DNAemia in D -/R + group was longer than that of D +/R + group (99 days vs. 34 days, P=0.012). The rate of CMV reactivation 4 times or more in D -/R + group was 4/16, significantly higher than that of D +/R + group (4.7%, 3/64, P=0.01). The incidences of refractory CMV DNAemia (14/16 vs. 56.3%, P=0.021) and CMV disease (4/16 vs. 4.7%, P=0.01) in D -/R + group were both higher than those in D +/R + group. In addition, the application of CMV-CTL as the second-line antiviral treatment in D -/R + group was more than that in D +/R + group. Univariate analysis and multivariate analysis suggested that CMV serological negativity is an independent risk factor for refractory CMV DNAemia and the duration of CMV infection. The cumulative incidence of aGVHDⅡ-Ⅳ, cGVHD, 3-year probability of NRM, overall survival, and the cumulative incidence of relapse were all comparable in two groups. Conclusions:Although there is no significant effect on OS and NRM, the incidence of refractory CMV DNAemia, the frequency of virus reactivation, and the development of CMV disease in D -/R + group are higher than those in controls. Therefore, CMV seropositive donors are preferred for CMV seropositive patients.

Second unmanipulated allogeneic transplantation could be used as a salvage option for patients with relapsed acute leukemia post-chemotherapy plus modified donor lymphocyte infusion / 医学前沿

Relapse is the main problem after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The outcome of a second allo-HSCT (HSCT2) for relapse post-HSCT has shown promising results in some previous studies. However, little is known about the efficacy of HSCT2 in patients with relapsed/refractory acute leukemia (AL) post-chemotherapy plus modified donor lymphocyte infusion (post-Chemo + m-DLI) after the first allo-HSCT (HSCT1). Therefore, we retrospectively analyzed the efficacy of HSCT2 in 28 patients with relapsed/refractory AL post-Chemo + m-DLI in our center. With a median follow-up of 918 (457-1732) days, 26 patients (92.9%) achieved complete remission, and 2 patients exhibited persistent disease. The probabilities of overall survival (OS) and disease-free survival (DFS) 1 year after HSCT2 were 25.0% and 21.4%, respectively. The cumulative incidences of nonrelapse mortality on day 100 and at 1 year post-HSCT2 were 7.1% ± 4.9% and 25.0% ± 8.4%. The cumulative incidences of relapse were 50.0% ± 9.8% and 53.5% ± 9.9% at 1 and 2 years post-HSCT2, respectively. Risk stratification prior to HSCT1 and percentage of blasts before HSCT2 were independent risk factors for OS post-HSCT2, and relapse within 6 months post-HSCT1 was an independent risk factor for DFS and relapse post-HSCT2. Our findings suggest that HSCT2 could be a salvage option for patients with relapsed AL post-Chemo + m-DLI.

Correlation between anti-human leukocyte antigen antibodies and the outcomes of matched sibling donor transplantation in patients with hematological diseases / 白血病·淋巴瘤

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.

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) (χ2=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) (χ2=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) (χ2=7.153, P=0.004) . The mononuclear cells≥8.33×108/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) % (χ2=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) % (χ2=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 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.

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 (CR1) 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 CR1 could achieve better long-term survival by receiving allo-HSCT within 6 months after diagnosis.

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%) (χ2=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%) (χ2=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%) (χ2=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%) (χ2=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%) (χ2=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%) (χ2=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.

Minimal residual disease-directed immunotherapy for high-risk myelodysplastic syndrome after allogeneic hematopoietic stem cell transplantation / 医学前沿

The efficacy of minimal residual disease (MRD)-directed immunotherapy, including interferon-α (IFN- α) treatment and chemotherapy plus granulocyte colony-stimulating factor-primed donor leukocyte infusion (chemo-DLI), was investigated in patients with high-risk myelodysplastic syndrome (MDS) who were MRD-positive after allogeneic hematopoietic stem cell transplantation (allo-HSCT). High-risk MDS patients who received non-T-cell-depleted allo-HSCT at the Peking University Institute of Hematology and were MRD-positive after allo-HSCT were studied (n = 47). The MRD-positive status was considered if leukemia-associated aberrant immune phenotypes or Wilms' tumor gene 1 expression is present in a single bone marrow sample. The cumulative incidence of the relapse and non-relapse mortality 2 years after immunotherapy were 14.5% and 21.4% (P = 0.377) and 9.1% and 0.0% (P = 0.985) for patients in the IFN-α and chemo-DLI groups, respectively. The probability of disease-free and overall survival 2 years after immunotherapy were 76.4% and 78.6% (P = 0.891) and 84.3% and 84.6% (P = 0.972) for patients in the IFN-α and chemo-DLI groups, respectively. Persistent MRD after immunotherapy was associated with poor survival. Thus, the MRD-directed immunotherapy was effective for patients with high-risk MDS who were MRD-positive after allo-HSCT, and the efficacy was comparable between chemo-DLI and IFN-α treatment.

Positive stool culture could predict the clinical outcomes of haploidentical hematopoietic stem cell transplantation / 医学前沿

We aimed to identify the effect of positive stool cultures (PSCs) on the clinical outcomes of patients undergoing haploidentical hematopoietic stem cell transplantation (haplo-HSCT) (n = 332). PSCs were observed in 61 patients (PSC group, 18.4%). Enterobacteriaceae in stool specimens was associated with a higher risk of bloodstream infection, and Candida in stool specimens was related to a higher risk of platelet engraftment failure. The cumulative incidence of infection-related mortality 1 year after haplo-HSCT in the PSC group was higher than that of the patients who showed persistently negative stool cultures (NSC group; 19.2% vs. 8.9%, P = 0.017). The probabilities of overall survival (71.4% vs. 83.8%, P = 0.031) and disease-free survival (69.6% vs. 81.0%, P = 0.048) 1 year after haplo-HSCT for the PSC group were significantly lower than those for the NSC group, particularly for patients who had Candida in their stool specimens. In multivariate analysis, Candida in stool specimens significantly increased the risk of mortality and was associated with poorer survival. Our results showed that PSC influenced the clinical outcomes after haplo-HSCT, particularly those who had Candida in their stool specimens.

Interferon-α salvage treatment is effective for patients with acute leukemia/myelodysplastic syndrome with unsatisfactory response to minimal residual disease-directed donor lymphocyte infusion after allogeneic hematopoietic stem cell transplantation / 医学前沿

The efficacy of salvage interferon-α (IFN-α) treatment was investigated in patients with unsatisfactory response to minimal residual disease (MRD)-directed donor lymphocyte infusion (DLI) (n = 24). Patients who did not become MRD-negative at 1 month after DLI were those with unsatisfactory response and were eligible to receive salvage IFN-α treatment within 3 months of DLI. Recombinant human IFN-α-2b injections were subcutaneously administered 2-3 times a week for 6 months. Nine (37.5%), 6 (25.0%), and 3 (12.5%) patients became MRD-negative at 1, 2, and > 2 months after the salvage IFN-α treatment, respectively. Two-year cumulative incidences of relapse and non-relapse mortality were 35.9% and 8.3%, respectively. Two-year probabilities of event-free survival, disease-free survival, and overall survival were 51.6%, 54.3%, and 68.0%, respectively. Outcomes of patients subjected to salvage IFN-α treatment after DLI were significantly better than those with persistent MRD without IFN-α treatment. Moreover, clinical outcomes were comparable between the salvage DLI and IFN-α treatment groups. Thus, salvage IFN-α treatment may help improve the outcome of patients with unsatisfactory responses to MRD-directed DLI and could be a potential salvage treatment for these patients after allogeneic hematopoietic stem cell transplantation.

Effects of hematological complete remission status before transplantation on outcomes of patients with B-cell acute lymphoblastic leukemia receiving haploidential stem cell transplantation / 临床检验杂志

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.

Outcomes of alternative donor allogeneic hematopoietic stem cell transplantation for Fanconi anemia:a five cases report / 中华内科杂志

Five patients with Fanconi anemia who received hematopoietic cell transplantation were retrospectively analyzed. The conditioning regimens included fludarabine, cyclophosphamide and anti-thymocyte globulin. Two patients received both bone marrow and peripheral blood stem cells as the source of stem cell grafts from haploidentical matched related donors, while the others received peripheral blood stem cells from unrelated donors.All patients tolerated well and reached hematopoietic reconstitution. One patient died of intracranial infection.During follow-up,4 patients survived independent of transfusion with full donor chimerism.