Xiao-Dong Mo

Controlled, Randomized, Open-Label Trial of Risk-Stratified Corticosteroid Prevention of Acute Graft-Versus-Host Disease After Haploidentical Transplantation

PURPOSE This study evaluated whether a prophylaxis strategy directed by the graft-versus-host disease (GVHD) biomarker might reduce the 100-day incidence of acute GVHD grades II to IV. PATIENTS AND METHODS This controlled, open-label, randomized trial included 228 patients who underwent haploidentical transplantation. On the basis of bone marrow allogeneic graft CD4:CD8 ratios, patients were categorized as low risk (n = 83; group A) or high risk (n = 145). Patients at high risk were randomly assigned to either receive (n = 72; group B) or not receive (n = 73; group C) low-dose corticosteroid prophylaxis. RESULTS The incidence in group B was 21% (95% CI, 11% to 31%) compared with 26% (95% CI, 16%to 36%; P = .43) in group A and 48% (95% CI, 32% to 60%; P < .001) in group C. Low-dose corticosteroid prophylaxis was significantly associated with a relatively low risk of acute GVHD grades II to IV (hazard ratio, 0.66; 95% CI, 0.49 to 0.89; P = .007) and rapid platelet recovery (hazard ratio, 0.30; 95% CI, 0.23 to 0.47; P < .001). The incidence of moderate-to-severe chronic GVHD in group B (21%) was lower than that in both group A (50%; P = .025) and group C (36%; P = .066). The 100-day corticosteroid doses were 205 ± 111 mg in group B, 229 ± 149 mg in group A (P = .256), and 286.54 ± 259.67 mg in group C (P = .016). Compared with group C, group B showed significantly lower incidences of femoral head necrosis (P = .034) and hypertension (P = .015). Infection rates were comparable among these groups. CONCLUSION Our results suggest that risk stratification-directed, low-dose corticosteroid prophylaxis significantly decreased the incidence of acute GVHD grades II to IV, accelerated platelet recovery, and reduced adverse events without increasing infections.

The hematopoietic cell transplantation‐specific comorbidity index (HCT‐CI) is an outcome predictor for partially matched related donor transplantation

To validate the predictive ability of the Hematopoietic Cell Transplantation‐Specific Comorbidity Index (HCT‐CI) on the outcome of hematopoietic stem cell transplantation (HSCT) patients who received transplants from partially matched related donors (PMRD), a total of 526 patients who received PMRD HSCT between January 2006 and December 2009 at the Institute of Hematology, Peking University were enrolled. Patients were grouped according to their HCT‐CI score; 31.0%, 31.4%, and 37.6% of patients had HCT‐CI scores of 0, 1–2, and ≥3, respectively. Patients with HCT‐CI scores of ≥3 had a significantly poorer 2‐year overall survival (OS) than patients with HCT‐CI scores of 0–2 (54.55% vs. 78.05%, P < 0.001). In addition, patients with HCT‐CI scores of ≥3 had a significantly higher 2‐year cumulative incidence of relapse and nonrelapse mortality (NRM) than patients with scores of 0–2 (relapse: 23.23% vs. 11.59%, P < 0.001; NRM: 34.30% vs. 15.93%, P < 0.001). HCT‐CI scores of <3 were associated with better OS, less relapse, and lower NRM in multivariate analysis. Patients who had high comorbidity scores as well as high‐risk disease had the poorest outcomes. Therefore, we found that HCT‐CI is associated with the outcomes of PMRD HSCT and we should closely monitor patients with a high comorbidity burden. Am. J. Hematol. 88:497–502, 2013.

Haploidentical hematopoietic stem cell transplantation in adults with Philadelphia‐negative acute lymphoblastic leukemia: No difference in the high‐ and low‐risk groups

Allogeneic hematopoietic stem cell transplantation (HSCT) is the most effective post‐consolidation therapy and curative option for adult patients with Philadelphia chromosome‐negative (Ph‐negative) acute lymphoblastic leukemia (ALL) in first complete remission (CR1). A human leukocyte antigen (HLA)‐haploidentical related donor (haplo‐RD) is one of the most important alternative sources for those without HLA‐identical sibling donor (ISD). The present study aimed to evaluate the outcomes of haploidentical hematopoietic stem cell transplantation (haplo‐HSCT) in adult Ph‐negative ALL CR1 patients (n = 183). We produced an unmanipulated haplo‐HSCT protocol including granulocyte colony stimulating factor (G‐CSF) for all donors, intensive immune suppression, anti‐thymocyte globulin, and combination of G‐CSF‐primed bone marrow harvest and G‐CSF‐mobilized peripheral blood stem cells harvest as the source of stem cell grafts. The median age for high‐risk versus low‐risk groups were 29 versus 23 years. Three‐year incidences of relapse mortality and nonrelapse mortality for high‐risk versus low‐risk groups were 7.1% versus 11.1% (p = 0.498) and 18.0% versus 16.2% (p = 0.717), respectively. Three‐year probabilities of disease‐free survival and overall survival for high‐risk versus low‐risk groups were 67.6% versus 68.2% (p = 0.896) and 74.9% versus 72.7% (p = 0.981), respectively. Multivariate analysis showed that limited cGVHD and a lower pre‐HSCT comorbidity burden were associated with better outcomes. In summary, comparable outcomes were observed among high‐ and low‐risk Ph‐negative ALL CR1 patients after haplo‐HSCT. Haplo‐RD could be considered for adults with Ph‐negative ALL in CR1 as an important alternative source of donors in cases when no ISD is available.

Patients receiving HLA-haploidentical/partially matched related allo-HSCT can achieve desirable health-related QoL that is comparable to that of patients receiving HLA-identical sibling allo-HSCT.

To investigate the health-related quality of life (HRQoL) of patients receiving allogeneic hematopoietic SCT (allo-HSCT) from HLA-haploidentical/partially matched related donors (HID/PMRD) and to compare this value with that of patients receiving allo-HSCT from HLA-identical sibling donor (ISD), a total of 350 patients receiving allo-HSCT were enrolled in a study (ISD: 173; HID/PMRD: 177). HRQoL post transplantation was evaluated by an SF-36 questionnaire. The effect of various factors on the HRQoL was analyzed through COX regression. Compared with the ISD group, patients in the HID/PMRD group had higher scores in physical functioning, general health, bodily pain, vitality and emotional role functioning, and these patients functioned significantly better on the physical and mental component summaries. Also, long-term survivors exhibit better HRQoL. Measured by multivariate analysis, extensive chronic GVHD was observed to have a strongly negative impact on patients’ HRQoL, while male gender status, lower age when receiving allo-HSCT and returning to work or school were associated with positive impacts on at least one subscale. These results showed that the HRQoL of patients receiving HID/PMRD hematopoietic SCT (HSCT) is comparable to that of patients receiving ISD HSCT, and HLA disparity is not the factor affecting the HRQoL.

Haploidentical allograft is superior to matched sibling donor allograft in eradicating pre-transplantation minimal residual disease of AML patients as determined by multiparameter flow cytometry: a retrospective and prospective analysis.

BackgroundThis study compared the effects of pre-transplantation minimal residual disease (pre-MRD) on outcomes in AML patients who underwent human leukocyte antigen-matched sibling donor transplantation (MSDT) or who received unmanipulated haploidentical allografts.MethodsA retrospective study (n = 339) and a prospective study (n = 340) were performed. MRD was determined using multiparameter flow cytometry.ResultsEither after retrospective or prospective analysis, patients with negative pre-MRD (pre-MRDneg) had a lower incidence of relapse than those with positive pre-MRD (pre-MRDpos) in MSDT settings (P < 0.001 for all), but relapse was comparable in Haplo-SCT settings for patients with pre-MRDneg versus pre-MRDpos (P = 0.866 and 0.161, respectively). In either the retrospective (n = 65) or the prospective study (n = 76), pre-MRDpos subjects receiving Haplo-SCT experienced a lower incidence of relapse than those who underwent MSDT (P < 0.001 and p = 0.017, respectively). Of the patients with pre-MRDpos in either the total (n = 141) or the subgroup excluding cases which received donor lymphocyte infusion (DLI; n = 105), those who underwent MSDT had a higher incidence of relapse than those receiving haplo-SCT (P < 0.01 for all). Multivariate analysis showed that, for pre-MRDpos cases, haplo-SCT was associated with a low incidence of relapse and with better LFS and OS in either retrospective group, prospective group, combination groups, or subgroup not including cases which received DLI.ConclusionsThe results indicated that, for pre-MRD-positive AML patients, haplo-SCT was associated with lower incidence of relapse and better survival, suggesting a stronger anti-leukemia effect.

Chronic GVHD induced GVL effect after unmanipulated haploidentical hematopoietic SCT for AML and myelodysplastic syndrome

The aim of this study was to investigate the impact of occurrence of chronic GVHD (cGVHD) and its severity on transplantation outcomes in a consecutive cohort of AML and myelodysplastic syndrome (MDS) patients who received unmanipulated haploidentical hematopoietic SCT (haplo-HSCT; n=324). The cumulative incidence of relapse was significantly decreased in patients with cGVHD compared with the non-cGVHD group (1 year: 3.2% vs 11.9%, P=0.002; 3 years: 6.0% vs 16.3%, P=0.002), particularly in those with mild cGVHD. The cumulative incidence of non-relapse mortality was comparable between patients with and without cGVHD. The probabilities of disease-free survival (DFS) were significantly better in patients with cGVHD than in those in the non-cGVHD group (1 year: 90.5% vs 78.5%, P=0.002; 3 years: 86.5% vs 71.5%, P<0.001), particularly in those with mild or moderate cGVHD; however, no significant impact of severe cGVHD on DFS was seen. Our findings highlight the close relationship between cGVHD and the immune-mediated GVL effect in patients with AML and MDS receiving unmanipulated haplo-HSCT; however, only mild or moderate cGVHD was associated with a lower risk of relapse translating into improved DFS.

Haploidentical transplantation for pediatric patients with acquired severe aplastic anemia.

Techniques for haploidentical hematopoietic stem cell transplantation (haplo-HSCT) to treat severe aplastic anemia (SAA) have recently improved, but no protocol has been evaluated in a large number of pediatric patients. Fifty-two children with SAA received haplo-HSCT in our center. The treatment protocol used G-CSF-primed bone marrow with G-CSF-mobilized PBSCs without in vitro T-cell depletion. The conditioning regimen included busulfan/cyclophosphamide and antithymocyte globulin. Fifty-one patients achieved primary engraftment; one child died of regimen-related toxicity on the day +1. Secondary graft failure occurred in three patients. The cumulative incidences of aGVHD grade II–IV and grade III–IV were 39.2±0.5 and 13.7±0.2%, respectively. The cumulative incidence of cGVHD was 34.2±0.5%. The 3-year overall and failure-free survival rates were 84.5±5.0 and 82.7±5.2%, respectively, with a median follow-up time of 744.5 days (100–3294) for surviving patients. The Eastern Cooperative Oncology Group score was the only predictor of overall and failure-free survival rates. Clinical outcomes were similar between the upfront and salvage group. This result suggests that both newly diagnosed and refractory pediatric SAA patients benefit from haplo-HSCT, especially when patients are in good general condition. Therefore, haplo-HSCT might be an alternative therapy for pediatric SAA patients without HLA-matched sibling donors.

Salvage chemotherapy followed by granulocyte colony-stimulating factor-primed donor leukocyte infusion with graft-vs.-host disease control for minimal residual disease in acute leukemia/myelodysplastic syndrome after allogeneic hematopoietic stem cell transplantation: prognostic factors and clinical outcomes

This study investigated the prognostic factors and clinical outcomes of preemptive chemotherapy followed by granulocyte colony‐stimulating factor‐primed donor leukocyte infusion (Chemo‐DLI) according to minimal residual disease (MRD) status in patients with acute leukemia and myelodysplastic syndromes who received allogeneic hematopoietic stem cell transplantation (HSCT) (n = 101). Patients received immunosuppressive drugs to prevent graft‐vs.‐host disease (GVHD) after Chemo‐DLI. The 3‐yr cumulative incidences of relapse, non‐relapse mortality, and disease‐free survival (DFS) after HSCT were 39.5%, 9.6%, and 51.7%, respectively. The cumulative incidences of relapse and DFS were significantly poorer in patients who exhibited early‐onset MRD. Forty‐four patients turned MRD negative 1 month after Chemo‐DLI; their cumulative incidences of relapse and DFS were significantly better than those with persistent MRD 1 month after preemptive Chemo‐DLI (relapse: 19.8% vs. 46.8%, P = 0.001; DFS: 69.6% vs. 46.4%, P = 0.004). The cumulative incidences of relapse and DFS after HSCT were significantly better in patients with chronic GVHD (cGVHD) than those without cGVHD (relapse: 19.6% vs. 63.7%, P < 0.001; DFS: 74.4% vs. 23.8%, P < 0.001). Early‐onset MRD, persistent MRD after Chemo‐DLI, and non‐cGVHD after Chemo‐DLI, which were associated with increased relapse and impaired DFS, suggest unsatisfactory response to preemptive Chemo‐DLI.

Higher frequency of regulatory T cells in granulocyte colony-stimulating factor (G-CSF)-primed bone marrow grafts compared with G-CSF-primed peripheral blood grafts

BackgroundRegulatory T cells (Treg) in allografts are important for the prevention of graft-versus-host disease (GVHD) post-transplantation. The aim of this study was to compare the contents of Tregs and effector T cells in granulocyte colony-stimulating factor (G-CSF)-primed bone marrow grafts (G-BM) and peripheral blood grafts (G-PB).MethodG-BM and G-PB were obtained from 20 allogeneic donors. T-cell subgroups, including conventional T cells and different types of Treg cells, as well as the percentage of Ki67 expression on CD4+CD25highFoxp3+ Treg cells, were analyzed using flow cytometry. The levels of interferon-γ (IFN-γ) and interleukin-17 (IL-17) secreted by T cells stimulated with PMA and ionomycin were also determined by flow cytometry.ResultsThe percentage of CD4+CD25highCD127-/dimCD62L+ Treg cells was significantly higher in the G-BM group, with higher proportions of CD45RA+ naïve Treg cells and higher expression of CD69 on Treg cells in G-BM (P < 0.05). The percentage of Ki67 expression in CD4+CD25highFoxp3+ Treg cells in G-BM was significantly higher than that on G-PB. The suppressive functions of Treg cells in inhibiting T-cell activation were comparable between G-BM and G-PB. The proportions of CD4+CD25−CD69+ Treg subsets as well as Th1 cells in G-BM were also significantly higher than those in G-PB (P < 0.001). The proportions of conventional T cells and Th17 effector cells were comparable in G-BM compared with those in G-PB. Thus, the ratio of conventional T cells and CD4+CD25highCD127-/dim regulatory T cells were lower in G-BM than that in G-PB (P = 0.014).ConclusionIn addition to the much higher T-cell counts in G-PB grafts that may contribute to more severe GVHD, the higher frequency of Treg cells and lower ratio of conventional T cells to Treg cells in G-BM compared with G-PB grafts might reduce GVHD post-transplantation in G-BM compared with G-PB transplantation.

Epstein-Barr Virus-Related Post-Transplantation Lymphoproliferative Disorder after Unmanipulated Human Leukocyte Antigen Haploidentical Hematopoietic Stem Cell Transplantation: Incidence, Risk Factors, Treatment, and Clinical Outcomes.

We examined the incidence, risk factors, treatments, and clinical outcomes of post-transplantation lymphoproliferative disorder (PTLD) after unmanipulated haploidentical (haplo) hematopoietic stem cell transplantation (HSCT) in 1184 patients between 2006 and 2012. Age-, transplantation time-, and transplantation duration-matched controls were randomly selected from the same cohort. Forty-five patients experienced PTLD. The median time from HSCT to PTLD occurrence was 61 (range, 33 to 360) days and the 1-year cumulative incidence of total PTLD after haplo-HSCT was 3.0%. In multivariate analysis, a lower absolute count of CD8(+) T lymphocytes at day 30, a lower absolute count of immunoglobulin M at day 30, and cytomegalovirus DNAemia after HSCT were significantly associated with higher risk of PTLD. The 2-year probability of overall survival (OS) after HSCT was 42.8%, which was comparable between the probable PTLD and the proven PTLD patients. Patients who received rituximab-based therapy had significantly better 2-year OS (48.2% versus 13.2%, P = .02). Thus, we were able to identify individuals at a high risk of developing PTLD after unmanipulated haplo-HSCT. Rituximab-based therapy can help to improve the outcomes of PTLD patients.