Therapeutic progress in relapsed/refractory multiple myeloma.

Improvement in the therapeutics for multiple myeloma (MM) has been continuously developed owing to the application of novel drugs and technologies in the last 20 years. The standard first-line therapy for MM consists of a three-drug induction regimen based on immunomodulatory drugs and proteasome inhibitors combined with autologous stem cell transplantation. However, MM remains incurable; therefore, therapies for relapsed/refractory MM (RRMM) are emerging and evolving rapidly. This study aimed to summarize and review the results of RRMM trials over the past 5 years to provide a holistic overview and insights for practitioners in related fields and to provide additional ideas for clinical trialists. This study shows that daratumumab and isatuximab continue to significantly advance as treatment options. Additionally, novel antibody drugs, such as elotuzumab and selinexor, as well as bispecific antibodies, teclistamab and talquetamab, are currently undergoing clinical research with promising outcomes. However, chimeric antigen receptor-T cell therapy targeting B-cell maturation antigen remains the optimal approach for MM treatment.

Outcomes of haploidentical peripheral blood stem cell transplantation following myeloablative conditioning using two types of rabbit ATG: a propensity score-matched analysis.

During hematopoietic stem cell transplantation (HSCT), ATG depletes T cells in-vivo to improve engraftment and prevent graft-versus-host disease (GVHD). Here, we compared the clinical efficacy of two different types of ATGs: thymoglobulin and anti-human T-lymphocyte immunoglobulin (Grafalon). A total of 469 patients who received haploidentical transplantation were enrolled in this retrospective study. We applied a propensity score (PS)-matched analysis and 209 patients were assigned to each group. Clinical outcomes were compared between two groups and primary outcome was overall survival (OS). There was no significant difference in OS between two groups. Within the first 180 days after HSCT, Grafalon was associated with lower incidences of Epstein-Barr virus (EBV) viremia (31.6 vs. 54.5%, P < 0.0001) and cytomegalovirus viremia (CMV) viremia (54.5 vs. 67.9%, P = 0.005) compared to thymoglobulin. Patients receiving Grafalon had a higher rate of moderate/severe chronic GVHD (26.3 vs. 18.2%, P = 0.046). However, the incidences of engraftment failure, grade II-IV acute GVHD, relapse, non-relapse mortality (NRM), and GVHD-free relapse-free survival (GRFS) did not differ greatly between groups. In the subgroup analysis, Grafalon improved the OS of lymphoid malignancies with young ages (< 40 years old) (HR, 0.55; P = 0.04) or with a high/very high disease risk index (HR, 0.36; P = 0.04). In the myeloid cohort, Grafalon reduced NRM in the patients who received non-female for male transplantation grafts (HR, 0.17; P = 0.02). Our results suggest the two types of ATG may differentially influence transplant outcomes and it may optimize ATG selection according to the condition of patients.

Risk factors and prognosis of early death in secondary hemophagocytic lymphohistiocytosis.

The aim of our study was to summarize the clinical characteristics of early death patients with newly diagnosed secondary hemophagocytic lymphohistiocytosis (sHLH), analyze the risk factors of early death, and analyze the survival of patients. The clinical characteristics of 324 newly diagnosed sHLH patients admitted to the First Affiliated Hospital of Zhejiang University Medical College and Zhejiang Provincial Cancer Hospital from January 2014 to February 2021 were analyzed retrospectively. Analyze the independent risk factors of early death, compare the secondary diseases and treatment methods of patients with early death group and non early death group, and analyze the survival of all patients with sHLH. Among the 324 newly diagnosed patients with sHLH, 134 died early, with an early mortality rate of 41.4%. Comparing the clinical characteristics of patients with early death group and patients with non early death group, logistic regression model was used to conduct multifactor analysis. Age > 60 years, Plt ≤ 20.0 × 109/L, APTT > 36.0 s and LDH > 1000.0 U/L were independent risk factors for early death of newly diagnosed sHLH patients (P < 0.05). Comparing the secondary diseases and treatment methods between early death group and non early death group, the proportion of sHLH patients secondary to lymphoma was higher in early death group than that in non early death group (P < 0.05). The proportion of sHLH patients secondary to connective tissue disease and infection was lower in early death group than that in non early death group (P < 0.05), and the proportion of sHLH patients used hormone combined chemotherapy was lower in early death group than that in non early death group (P < 0.05). The median follow-up time of all patients was 12.0 (1-65) months. The 5-year OS rates of patients with age > 60 years and age ≤ 60 years were 25.8% and 49.6% respectively (P < 0.001); The 5-year OS rates of patients with Plt > 20.0 × 109/L and Plt ≤ 20.0 × 109/L were 52.5% and 25.5% respectively (P < 0.001); The 5-year OS rates of patients with APTT > 36.0 s and APTT ≤ 36.0 s were 34.5% and 57.4% respectively (P < 0.001); The 5-year OS rates of patients with LDH > 1000.0 U/L and LDH ≤ 1000.0 U/L were 23.3% and 56.3% respectively (P < 0.001). Age > 60 years, Plt ≤ 20.0 × 109/L, APTT > 36.0 s and LDH > 1000.0 U/L are independent risk factors for early death of sHLH patients. The early mortality of lymphoma associated HLH (LA-HLH) patients is high, and early use of hormone combined chemotherapy can reduce the early mortality.

Effect of donor characteristics on T cell-replete haploidentical stem cell transplantation over the last 10 years at a single institution.

One of the most complex issues with haploidentical stem cell transplantation (haplo-SCT) is donor selection, given that multiple haploidentical donors are often available for a given recipient. To develop evidence-based guidance for donor selection in the setting of anti-thymocyte globulin-based haplo-SCT, we performed a prospective cohort study of 512 patients with haematological malignancies who had haplo-SCT to determine which donor variables were most important in favouring transplant outcomes. Increasing donor age was associated with poorer overall survival (OS) [hazard ratio (HR) 1·08, P = 0·044]. Female donors to male recipients was significantly associated with higher non-relapse mortality (NRM; HR 2·05, P = 0·006). Furthermore, increasing donor age had a higher risk of Grades 3-4 acute graft-versus-host disease (aGVHD; HR 1·17, P = 0·005), female donors to male recipients was associated with a higher risk of Grades 2-4 aGVHD (HR 1·50, P = 0·022). Sibling donors had superior OS, disease-free survival, and NRM than parental donors in patients aged <35 years. However, sibling donors had higher NRM than offspring donors in patients aged ≥35 years. A younger donor, usually a young sibling in younger recipients (aged <35 years) or a young offspring in older patients (aged ≥35 years) and avoiding female donors to male recipients should be preferred when multiple haploidentical donors are available.

Effectiveness of prophylactic antiviral therapy in reducing HBV reactivation for HBsAg-positive recipients following allogeneic hematopoietic stem cell transplantation: a multi-institutional experience from an HBV endemic area.

Hepatitis B virus reactivation (HBVr) is not uncommon in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. Hepatitis B surface antigen (HBsAg)-positive patients receiving allo-HSCT have a very high risk of HBVr. However, the validity of prophylactic antiviral treatment in HBsAg-positive allo-HSCT recipients has not been well studied. We aimed to add experience in dealing with HBsAg-positive patients following allo-HSCT. We conducted a cohort study that included 11 years of data of HBsAg-positive allo-HSCT patients in multiple centers. The cumulative incidence of HBVr with antiviral prophylaxis at 60 months following transplantation was 8.9%. Both lamivudine (LAM) and entecavir (ETV) effectively reduced the incidence of HBVr. Patients with absent-mild cGVHD had a lower HBVr rate than that of patients with moderate-severe cGVHD (HR = 0.201, P = 0.020). The incidence of HBsAg seroclearance at 60 months following transplantation was 34.3%. Recipients accepting from anti-HBs-negative donors were associated with a lower HBsAg seroclearance rate than that of those accepting from anti-HBs-positive donors (HR=0.255, P < 0.001). The peripheral blood stem cell (PBSC) donor source had a higher HBsAg seroclearance rates than that of the PBSC plus bone marrow stem cell source (HR = 4.700, P = 0.047). The prophylactic antiviral treatment effectively reduced HBVr in HBsAg-positive recipients receiving allo-HSCT. HBsAg-positive recipients accept anti-HBs-positive PBSC donor sources may facilitate the acquisition of HBsAg seroclearance after transplantation.

Preemptive low-dose interleukin-2 or DLI for late-onset minimal residual disease in acute leukemia or myelodysplastic syndrome after allogeneic hematopoietic stem cell transplantation.

Minimal residual disease (MRD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) heralds high risk of relapse. Whether preemptive recombinant interleukin-2 (pre-IL2) is effective for patients with late-onset MRD (LMRD) remains unknown. We retrospectively compared the efficacy and safety of pre-IL2 (n = 30) and pre-DLI (n = 25) for LMRD in patients receiving allo-HSCT for acute leukemia or myelodysplastic syndrome. The 1-year overall survival (OS) and disease-free survival (DFS) rates were 86.7% and 78.4% (P = 0.267), 83.3% and 75.6% (P = 0.329), the cumulative incidence of grades III-IV acute graft-versus-host disease (aGVHD) at 100 days post-preemptive intervention was 3.3% and 12.0% (P = 0.226) in the pre-IL2 group and pre-DLI group, respectively. The 1-year cumulative incidence of moderate/severe chronic GVHD (cGVHD), relapse (CIR), and non-relapse mortality (NRM) were 7.7% and 27.9% (P = 0.018), 13.6% and 20.0% (P = 0.561) and 3.3% and 5.5% (P = 0.321) in the two groups, respectively. No remarkable differences in CIR, OS, and DFS between the two intervention groups were found in multivariate analysis. The GVHD-free and relapse-free survival (GRFS) were better in the pre-IL2 group than in the pre-DLI group (HR = 0.31, 95% confidence interval (CI), 0.12-0.76; P = 0.011). In conclusion, preemptive low-dose IL2 and preemptive DLI yield comparable outcomes for patients with LMRD receiving allo-HSCT, in terms of aGVHD, NRM, relapse, OS, and DFS. However, preemptive low-dose IL2 has a lower incidence of moderate/severe cGVHD and a higher CRFS. Preemptive low-dose IL2 may be an alternative method for patients who develop LMRD after allo-HSCT, particularly for patients who cannot receive preemptive DLI.

Improved survival for young acute leukemia patients following a new donor hierarchy for allogeneic hematopoietic stem cell transplantation: A phase III randomized controlled study.

The aim of our study was to evaluate the most optimal donor for young acute leukemia (AL) patients with multiple donors available for allogeneic hematopoietic stem cell transplantation (allo-HSCT), including HLA-matched sibling donors (MSDs), HLA-matched unrelated donors (URDs), haploidentical parental donors (HPDs), and haploidentical sibling donors (HSDs). From March 2008 to December 2016, 430 AL patients ≤ 35 years of age were included in the discovery, retrospective study. Patients who received transplantation from a MSD or a HSD had better 5-year OS rates compared with patients who received transplantation from a URD or a HPD. A superior graft-versus-leukemia effect was observed for high-risk patients undergoing HSD-HSCT with a lower relapse rate (p = 0.014) and a higher disease-free survival (DFS) rate (p = 0.029) compared with those undergoing MSD-HSCT. Outcomes of high-risk patients receiving an URD or HPD were equivalent. For intermediate/standard-risk patients, either a MSD or HSD may be the front-line donor selection with comparable outcomes. HLA-matched unrelated donors were preferred over HPDs with reduced non-relapse mortality and higher overall survival (OS) and DFS rates. We further conducted an independent prospective randomized study to evaluate the survival advantage with the new donor hierarchy. Two hundred and fifty patients were randomly assigned to follow our new donor hierarchy or the traditional donor hierarchy at a 2:1 ratio. The new donor hierarchy contributed to significantly superior 2-year OS and DFS rates (OS: 76.2% vs. 67.8%, p = 0.046; DFS: 71.8% vs. 64.5%, p = 0.039).

PTPN21-CDSlong isoform inhibits the response of acute lymphoblastic leukemia cells to NK-mediated lysis via the KIR/HLA-I axis.

Protein tyrosine phosphatase non-receptor type 21 (PTPN21) is a member of the non-receptor tyrosine phosphatase family. We have found that PTPN21 is mutated in relapsed Philadelphia chromosome-negative acute lymphoblastic leukemia (ALL) after allogeneic hematopoietic stem cell transplantation. PTPN21 consists of three types of isoforms according to the length of the protein encoded. However, the roles of different isoforms in leukemic cells have not been elucidated. In the study, PTPN21 isoform constitution in five ALL cell lines were identified by transcriptome polymerase chain reaction combined with Sanger sequencing, and the relationship between PTPN21 isoforms and sensitivity to natural killer (NK) cells mediated killing in ALL cell lines were further assessed by knock-out of different isoforms of PTPN21 using CRISPR-Cas9 technique. Subsequently, we explored the functional mechanisms through RNA sequencing and confirmatory testing. The results showed that there was no significant change when all PTPN21 isoforms were knocked out in ALL cells, but the sensitivity of NALM6 cells with PTPN21-CDSlong knock-out (NALM6-PTPN21lk ) to NK-mediated killing was significantly increased. Whole transcriptome sequencing and further validation testing showed that human leukocyte antigen class I (HLA-I) molecules were significantly decreased, accompanied by a significantly downregulated expression of antigen presenting-related chaperones in NALM6-PTPN21lk cells. Our results uncovered a previously unknown mechanism that PTPN21-CDSlong and CDSshort isoforms may play opposite roles in NK-mediated killing in ALL cells, and showed that the endogenous PTPN21-CDSlong isoform inhibited ALL cells to NK cell-mediated lysis by regulating the KIR-HLA-I axis.

A Novel Strategy for the Prevention of Hepatitis B Virus-Related Hepatitis Following Allogeneic Hematopoietic Stem Cell Transplantation from Hepatitis B Surface Antigen-Positive Donors.

Hematopoietic stem cell transplantation (HSCT) is increasingly being applied globally. Cases in which healthy HSCT donors are chronically infected with hepatitis B virus (HBV) are relatively common in areas where HBV is endemic. Recipients of stem cells from such hepatitis B surface antigen (HBsAg)-positive donors are at risk of viral infection, and thus may develop HBV-related hepatitis. Given the lack of standardized approach to minimizing the risk of such infections from HBsAg+ donors during HSCT, we conducted this study with the aim of developing an efficient strategy to address this challenge. A strategy comprising antiviral treatment for detectable HBV-DNA in HBsAg+ donors, hepatitis B immune globulin (HBIG) administration in HBsAg- recipients with passive immunity, and prophylactic antiviral treatment for HBsAg+ recipients was developed. The strategy was validated using a case-control study of 40 recipients who received stem cells from HBsAg+ donors (group A) and 40 pair-matched controls who received stem cells from HBsAg- donors (group B). The cumulative incidence of HBV-related hepatitis was relatively similar in the 2 groups (group A: 8.5%; 95% confidence interval [CI], -.9% to 17.9%; group B: 7.9%; 95% CI, -.9% to 16.7%; P = .939). In HBsAg- recipients who received passive immunity from HBIG treatment, a significant negative linear correlation was observed between HBsAb titer in vivo and time in the first year after allo-HSCT (R2 = .23; P < .001). This method was cost-effective, with a median cost of all HBV management of USD 332.1 (range, 172.7 to 1985.3), compared with USD 1464.9 (range 409.9 to 1985.3) for conventional strategies (P < .001). The novel strategy presented in here is robust in preventing HBV-related hepatitis after allo-HSCT with stem cells from HBsAg+ donors. This is important for the effective application of allo-HSCT in HBV-endemic areas without precluding the use of HBsAg+ donors.

Calcineurin Inhibitors Replacement by Ruxolitinib as Graft-versus-Host Disease Prophylaxis for Patients after Allogeneic Stem Cell Transplantation.

Graft-versus-host disease (GVHD) is a common complication of allogeneic stem cell transplantation (allo-SCT) that carries a high mortality. Although calcineurin inhibitors (CNIs) have been widely used in GVHD prophylaxis, the incidence of acute GVHD (aGVHD) remains at roughly 30% to 50%. Moreover, some allo-SCT recipients cannot tolerate CNI. Thus, improved GVHD prevention methods are needed. Our study aimed to determine the prophylactic value of ruxolitinib for GVHD in CNI-intolerant patients after allo-SCT. Between September 2017 and March 2019, 10 patients with hematopoietic malignancies after allo-SCT who were intolerant to CNI at our center were enrolled in this study. The regimens were based on a myeloablative busulfan and cyclophosphamide regimen. Antithymocyte globulin was administered to patients with an HLA-haploidentical related donor (HRD) at a dosage of 6 mg/kg. All received ruxolitinib to replace CNI as GVHD prophylaxis. Ruxolitinib was initiated at 5 to 10 mg twice daily until 2 to 3 months post-transplantation and then tapered gradually, and in the absence of GVHD, discontinued by day +180. Eight patients had acute leukemia, 1 patient had myeloproliferative neoplasm, and 1 patient had natural killer T cell (NK/T) lymphoma. The donor type was a matched sibling donor in 3 patients and an HLA-haploidentical related donor (HRD) in 7 patients. All patients received CNI plus short-course of methotrexate as GVHD prophylaxis, but showed intolerance to CNI within 45 days post-transplantation. After ruxolitinib replacement, only 1 patient (10%) developed grade II skin aGVHD within 100 days, and only 1 patient developed severe aGVHD after 100 days. Two patients developed moderate/severe chronic GVHD (cGVHD) after tapering or stopping ruxolitinib, resulting in a 1-year cumulative incidence of moderate/severe cGVHD of 21.4%. Cytomegalovirus (CMV) reactivation occurred in 4 patients (40%), and Epstein-Barr virus (EBV) reactivation occurred in 3 patients (30%). None of the patients developed CMV disease or EBV post-transplantation lymphoproliferative disorder. After a median follow-up of 11 months (range, 2 to 15.5 months), 2 patients (20%) relapsed and 7 (70%) were alive, of whom 6 (60%) were negative for minimal residual disease and 4 were off immunosuppressant therapy. The prophylactic application of ruxolitinib for CNI-intolerant patients after allo-SCT appears to be safe and effective in preventing GVHD, but this awaits further study in larger cohorts.

Determining Whether Prophylactic Antiviral Treatment Is Necessary in HBsAg-Negative/HBcAb-Positive Patients Receiving Allogeneic Hematopoietic Stem Cell Transplantation.

The incidence of hepatitis B virus (HBV) infection is high in the Asian population. Increasing attention is being given to the risk of HBV reactivation in hepatitis B core antibody-positive [HBcAb(+)] patients during immunosuppressive therapy. Knowledge of HBV reactivation in hematopoietic stem cell transplantation (HSCT) is limited. Moreover, the effect of hepatitis B surface antibody (HBsAb) on HBV reactivation in HBcAb(+) patients during HSCT remains uncertain. We sought to investigate the role of HBsAb and the need for prophylactic antiviral treatment in hepatitis B surface antigen-negative [HBsAg(-)]/HBcAb(+) patients during HSCT. We classified 665 HBsAg(-) HSCT recipients into 4 groups: HBcAb(-)HBsAb(-) (n = 189), HBcAb(-)HBsAb(+) (n = 176), HBcAb(+)HBsAb(-) (n = 49), and HBcAb(+)HBsAb(+) (n = 251). HBV reactivation was identified in 16 patients after HSCT. The median time to HBV reactivation was 645 days (range, 455 to 1957 days) after transplantation. The cumulative HBV reactivation rate was significantly higher in the HBcAb(+)HBsAb(-) group compared with the HBcAb(+)HBsAb(+), HBcAb(-)HBsAb(-), and HBcAb(-)HBsAb(+) groups, respectively (P< .001). Notably, the risk of HBV reactivation was significantly higher in the HBcAb(+)HBsAb(-) group compared with the HBcAb(+)HBsAb(+) group (P= .007; hazard ratio, 4.750; 95% confidence interval, 1.531 to 14.737). Our results point to a protective role of HBsAb in HBV-resolved patients undergoing HSCT and indicate that prophylactic anti-HBV treatment might not be mandatory for HBsAg(-), HBcAb(+)HBsAb(+) patients following HSCT. The surveillance protocol of intense follow-up early (HBV DNA and HBsAg monthly) might not be necessary.

Incidence, risk factors and outcome of extramedullary relapse after allogeneic hematopoietic stem cell transplantation in patients with adult acute lymphoblastic leukemia.

Extramedullary relapse (EMR) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) continues to remain a clinical challenge. The data on EMR in acute lymphoblastic leukemia (ALL) are currently limited. Herein, a retrospective analysis of 268 adult ALL patients who underwent allo-HSCT in our center between March 2008 and December 2017 was performed to analyze post-HSCT EMR. Ninety patients (33.58%) experienced relapse; 51(19.03%) experienced bone marrow relapse (BMR), whereas 39 (14.55%) experienced EMR. The 5-year cumulative EMR incidence (CEMRI) revealed that matched sibling donor (MSD)-HSCTs were more likely to develop EMR than unrelated donor (URD)- and haploidentical-related donor (HRD)-HSCTs (CEMRI: 24.02%, 7.69%, and 14.69% for MSD, URD, and HRD, respectively). Notably, MSD-HSCTs (URD vs MSD hazard ratio (HR) = 0.26, p = 0.015; HRD vs MSD HR = 0.46, p = 0.032), history of extramedullary disease (EMD) (HR = 2.45, p = 0.041), and T cell ALL (HR = 2.80, p = 0.012) were independent risk factors for EMR in the multivariate analysis. The median overall survival (OS) for all patients was 15.23 months. However, the OS of EMR patients was significantly longer (19.50 months) than that of BMR patients (12.90 months) (p = 0.003). Multivariate analyses revealed that the leading risk factors for post-relapse deaths were shorter intervals between HSCT and relapse (> 12 months vs ≤ 12 months, HR = 0.30, p < 0.001) and BMR (HR = 0.41, p = 0.002). In conclusion, EMR patients have better survival than BMR patients. ALL patients with allo-HSCT from MSDs, a history of EMD, and the T cell type were significantly associated with EMR.

Eltrombopag treatment promotes platelet recovery and reduces platelet transfusion for patients with post-transplantation thrombocytopenia.

Post-transplantation thrombocytopenia (PT) is a common and severe complication which usually leads to poor prognosis. Eltrombopag (EPAG), a novel oral thrombopoietin (TPO) receptor agonist, has shown promising effects in thrombocytopenia due to immune thrombocytopenic purpura (ITP) and refractory severe aplastic anemia (rSAA), while the effectiveness of EPAG for PT patients still needs to be evaluated. A total of 32 PT patients receiving EPAG were retrospectively analyzed between September 2017 and July 2019, including 15 patients with poor graft function (PGF) and 17 patients with secondary failure of platelet recovery (SFPR). To date, 21 (65.6%) patients achieved overall recovery (OR) and 14 (43.8%) patients achieved complete recovery (CR). Among responders, 18 (85.7%) patients discontinued or tapered the drug and 16 (76.2%) patients successfully maintained their best response. During the EPAG treatment, responders received much lower median platelet transfusion units than non-responders (11 vs. 95, P < 0.001). After a median follow-up time of 364 days (range, 24-842), the overall survival in these patients was 78.1% (100% for responders and 36.4% for non-responders, P < 0.001). In the univariate and multivariate analysis, PGF was identified as the independent risk factor for OR (P = 0.041, HR = 5.333). Megakaryocyte (Megk) amounts (P = 0.025, HR = 14.638) and splenomegaly (P = 0.042, HR = 11.278) were identified as independent risk factors for CR. Besides, PGF patients tended to take a longer time to achieve PR and CR than SFPR patients. In conclusion, our data suggest that EPAG can promote platelet recovery and reduce platelet transfusion in PT patients.

Ruxolitinib combined with etanercept induce a rapid response to corticosteroid-refractory severe acute graft vs host disease after allogeneic stem cell transplantation: Results of a multi-center prospective study.

About half of patients with severe acute graft vs host disease (aGVHD) show resistance to treatment with first-line steroids. We enrolled 64 patients with grades III-IV SR-aGVHD after allogeneic hematopoietic stem cell transplantation (allo-SCT), to assess the efficacy and safety of the combination therapy of ruxolitinib and etanercept. The overall response rate was 87.5% (95% CI, 79.7%-95.3%) at day 28 of the combination treatment, from which 73.4% reached complete response (CR). A marked reduction ≥75% in daily corticosteroid dosing was documented in 75.4% of patients at day 28. Delayed time from aGVHD to ruxolitinib (OR = 4.88, 95% CI, 0.98-23.56), stages 3-4 liver aGVHD (OR = 8.57, 95% CI, 0.96-46.59) and gut Enterobacteriaceae colonization (OR = 12.39, 95% CI, 1.71-59.77) were related to incomplete response. Grades 3/4 anemia, leukopenia, or thrombocytopenia and CMV-reactivation were found in 29.7%, 26.6%, 39.1%, and 50.0% of patients, respectively. So, 25 (39.1%) experienced complications of severe infection ≥3 grade, in which pulmonary infections were most frequent (15/64, 23.4%). The 2-year overall survival (OS) after the combination therapy was 61.2%. The 2-year incidence of non-relapse mortality and relapse of the underlying malignancy was 26.7% and 15.7%, respectively. Combined treatment with ruxolitinib and etanercept was very effective and relatively safe for severe aGVHD patients, while the various infection complications deserve more attention. This study was registered at the Chinese Clinical Trial Registry (ChiCTR1900024408).

Obesity is correlated with poor outcome after allogeneic hematopoietic stem cell transplantation in patients with acute leukemia.

OBJECTIVE: The relationship between body mass index and overall survival has been controversial in patients who suffered from hematological malignancies and underwent hematopoietic stem cell transplantation. METHODS: We collected the data of 686 acute leukemia patients who received only one allogeneic hematopoietic stem cell transplantation in our center from 2008 to 2017. Patients were divided into four groups (underweight, normal weight, overweight and obesity) according to their body mass index pre-hematopoietic stem cell transplantation. RESULTS: 56.4% of patients had normal body mass indices, 17.3% were underweight, 20.4% were overweight and 5.8% were with obesity. Concerning long-term follow-up, the probability of overall survival was significantly lower in overweight (P = 0.010) and patients with obesity (P = 0.065) as compared with normal weight patients, and no statistically significant difference between underweight and normal weight individuals (P = 0.810). The results demonstrated that higher body mass index was associated with poorer overall survival (hazard ratio: 1.79; 95% confidence interval: 1.33-2.40, P < 0.001) and shorter leukemia-free survival (hazard ratio: 1.78; 95% confidence interval: 1.35-2.34, P < 0.001). Additionally, patients exhibiting a higher body mass index were more likely to face the problem of relapse (30.6 vs 20.9%, P < 0.001). Furthermore, non-relapse mortality of patients with obesity was statistically higher than normal weight patients (22.5 vs 9.6%, P = 0.027). Besides, individuals with a higher abdominal girth had shorter survival (hazard ratio: 1.73; 95% confidence interval: 1.29-2.31, P < 0.001) and higher relapse rate (hazard ratio: 1.78; 95% confidence interval: 1.29-2.45, P = 0.001) as compared with those with a lower abdominal girth. CONCLUSION: Our results indicate that obesity at pre-hematopoietic stem cell transplantation stage, whether characterized by higher body mass index or abdominal girth, is correlated with poorer outcome.

Incidence, Risk Factors, and Outcomes of Primary Poor Graft Function after Allogeneic Hematopoietic Stem Cell Transplantation.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative therapy for both malignant and nonmalignant hematologic disorders. However, primary poor graft function (PGF) is a serious early complication of allo-HSCT that leads to a poor outcome. Little is known about the characteristics, incidence, and risk factors of primary PGF occurring after allo-HSCT. Here we performed a 1:4 ratio nested case-control study in 830 patients who underwent allo-HSCT between April 2013 and November 2018 at our center. Twenty-four patients (14 males and 10 females; average age, 35.79 years; range, 17 to 53 years) developed primary PGF. On univariate and multivariate analyses, a CD34+ cell dose <5 × 106/kg (P = .003), a serum ferritin (SF) level >2000 ng/mL (P = .008), and splenomegaly (P = .039) were identified as 3 independent risk factors for primary PGF. After a median follow-up of 7.5 months (range, 1 to 48 months), only 5 patients (20.8%) survived. The survival rate of patients with primary PGF was significantly lower than that of patients with good graft function (GGF) (1-year overall survival, 25.0% versus 90.6%; P < .001). Cox regression analysis suggested that PGF and high SF level were strongly associated with rapid death in these patients. In conclusion, allo-HSCT recipients with a low CD34+ cell dose in their graft and exhibiting a high SF level and splenomegaly should be monitored for the development of primary PGF after allo-HSCT, and effective therapies need to be explored.

Decitabine plus CLAG chemotherapy as a bridge to haploidentical transplantation in the setting of acute myeloid leukemia relapse after HLA-matched sibling transplantation: a case report.

BACKGROUND: Patients with relapsed/refractory acute myeloid leukemia after hematopoietic stem cell transplantation (HSCT) have a poor prognosis, with a 2-year survival rate of 14%. The optimal treatment for these patients remains unclear. To treat these patients, we designed a new salvage regimen consisting of decitabine, cladribine, cytarabine, and granulocyte-stimulating factor (D-CLAG). CASE PRESENTATION: Here, we describe a case of acute monocytic leukemia with a complex karyotype in a 38-year-old female patient who relapsed after her first HSCT, which was performed using a matched sibling donor. The patient did not respond to standard induction chemotherapy and subsequently achieved complete remission with the D-CLAG regimen. No severe hematological or extramedullary toxicity was observed. Subsequently, the patient received a second D-CLAG regimen as a bridge therapy and directly underwent haploidentical related HSCT. Following HSCT, the marrow showed complete hematologic and cytogenetic remission. Currently, 1 year after transplantation, the patient's general condition remains good. CONCLUSIONS: This case suggests that the D-CLAG regimen can be an option for reinduction in relapsed refractory AML patients as a bridge to transplantation. Nevertheless, further research will be required in the future as this report describes only a single case.

Correction to: Decitabine plus CLAG chemotherapy as a bridge to haploidentical transplantation in the setting of acute myeloid leukemia relapse after HLA-matched sibling transplantation: a case report.

Following publication of the original article [1], the authors reported that the incorrect Fig. 2A was published in the article. The recovery times required to achieve a normal neutrophil count was omitted. The corrected Fig. 2 is given below.

mTOR inhibitor rapamycin induce polymorphonuclear myeloid-derived suppressor cells mobilization and function in protecting against acute graft-versus-host disease after bone marrow transplantation.

The mammalian target of rapamycin (mTOR) inhibitor rapamycin (RAPA) has been shown to be an effective immunosuppressor in the management of acute graft-versus-host disease (aGVHD) after bone marrow transplantation. Myeloid-derived suppressor cells (MDSCs) also have a protective effect in aGVHD regulation. However, the relationship between RAPA and MDSCs in aGVHD models is unclear. Meanwhile, the effect of RAPA on different subgroups of MDSCs is also less well described. In this study, we demonstrate that in vivo administration of RAPA results in the expansion and functional enhancement of polymorphonuclear MDSCs (PMN-MDSCs) in a murine model of aGVHD. RAPA treatment can enhance the suppressive function of PMN-MDSCs via up-regulation of arginase1 (Arg1) and induced nitric oxide synthase (iNOS) at later time points. Moreover, RAPA can also induce a strong immunosuppressive function in PMN-MDSCs from murine bone marrow in vitro, but has a contrary effect on monocytic MDSCs (M-MDSCs). We found that RAPA-treated PMN-MDSCs can restrain the differentiation of Th1/Th2 cells and promote induction of regulatory T cells in in vitro studies.

Reduction of Foxp3+ T cell subsets involved in incidence of chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation.

Foxp3+ T cells (CD4+ Tregs and CD8+ Treg) have been demonstrated to play roles in the maintenance of tolerance after allogeneic hematopoietic stem cell transplantation (Allo-HSCT). We have found that Foxp3+ γδTCR+ Treg cells (γδTregs) exerted regulatory functions. In the current study, patients were recruited and divided as non-cGVHD, limited cGVHD and extensive cGVHD groups. Healthy volunteers were recruited as healthy group. Treg cells were evaluated by flow cytometry. Serum cytokine levels of IL-2, tumour necrosis factor-α, interferon-γ and transforming growth factor-ß1 (TGF-ß1) were evaluated by ELISA. The results showed that percentages of CD4+ Tregs, CD8+ Tregs and γδTregs were all significantly increased in non-cGVHD group compared with those in healthy group, limited cGVHD group and extensive cGVHD group. Moreover, compared with extensive cGVHD group, percentages of these three types of Tregs were significantly increased in limited cGVHD group. The levels of TGF-ß1 increased dramatically in non-cGVHD group compared with other groups. Spearman's correlation analysis revealed that the increased levels of TGF-ß1 and IL-2 were positively associated with increased Treg subsets, indicating that TGF-ß1 and IL-2 participated in the expansion process of Foxp3+ Tregs in vivo. Our findings support that increasing the number of Tregs following allo-HSCT would be a preferential strategy for controlling cGVHD. Copyright © 2015 John Wiley & Sons, Ltd.