Feng-Rong Wang

Long-term follow-up of haploidentical hematopoietic stem cell transplantation without in vitro T cell depletion for the treatment of leukemia: nine years of experience at a single center.

Many patients who require allogeneic hematopoietic stem cell transplantation (allo‐HSCT) lack a human leukocyte antigen (HLA)‐matched donor. Recently, a new strategy was developed for HLA‐mismatched/haploidentical transplantation from family donors without in vitro T cell depletion (TCD).

Who is the best donor for a related HLA haplotype-mismatched transplant?

The best donor for a related donor for a human leukocyte antigen (HLA) haplotype-mismatched transplant for hematological neoplasms is controversial. We studied outcomes in 1210 consecutive transplant recipients treated on a uniform protocol. Younger donors and male donors were associated with less nonrelapse mortality (NRM; hazard ratio [HR] = 0.30; 95% confidence interval [CI] = 0.01-0.39; P = .008 and HR = 0.65; 95% CI = 0.49-0.85; P = .002) and better survival (HR = 0.73; 95% CI = 0.54-0.97; P = .033 and HR = 0.73; 95% CI = 0.59-0.91; P = .005). Father donors were associated with less NRM (HR = 0.65; 95% CI = 0.45-0.95; P = .02), acute graft-versus-host disease (GVHD) (HR = 0.69; 95% CI = 0.55-0.86; P = .001), and better survival (HR = 0.66; 95% CI = 0.50-0.87; P = .003) compared with mother donors. Children donors were associated with less acute GVHD than sibling donors (HR = 0.57; 95% CI = 0.31-0.91; P = .01). Older sister donors were inferior to father donors with regard to NRM (HR = 1.87; 95% CI = 1.10-3.20; P = .02) and survival (HR = 1.59; 95% CI = 1.05-2.40; P = .03). Noninherited maternal antigen-mismatched sibling donors were associated with the lowest incidence of acute GVHD compared with parental donors and noninherited paternal antigen-mismatched sibling donors. Specific HLA disparities were not significantly correlated with transplant outcomes. Our data indicate which HLA haplotype-mismatched related donors are associated with the best transplant outcomes in persons with hematological neoplasms.

MRD-directed risk stratification treatment may improve outcomes of t(8;21) AML in the first complete remission: results from the AML05 multicenter trial

We aimed to improve the outcome of t(8;21) acute myeloid leukemia (AML) in the first complete remission (CR1) by applying risk-directed therapy based on minimal residual disease (MRD) determined by RUNX1/RUNX1T1 transcript levels. Risk-directed therapy included recommending allogeneic hematopoietic stem cell transplantation (allo-HSCT) for high-risk patients and chemotherapy/autologous-HSCT (auto-HSCT) for low-risk patients. Among 116 eligible patients, MRD status after the second consolidation rather than induction or first consolidation could discriminate high-risk relapse patients (P = .001). Allo-HSCT could reduce relapse and improve survival compared with chemotherapy for high-risk patients (cumulative incidence of relapse [CIR]: 22.1% vs 78.9%, P < .0001; disease-free survival [DFS]: 61.7% vs 19.6%, P = .001), whereas chemotherapy/auto-HSCT achieved a low relapse rate (5.3%) and high DFS (94.7%) for low-risk patients. Multivariate analysis revealed that MRD status and treatment choice were independent prognostic factors for relapse, DFS, and OS. We concluded that MRD status after the second consolidation may be the best timing for treatment choice. MRD-directed risk stratification treatment may improve the outcome of t(8;21) AML in CR1. This trial was registered at http://www.chictr.org as #ChiCTR-OCH-12002406.

A novel protocol for haploidentical hematopoietic SCT without in vitro T-cell depletion in the treatment of severe acquired aplastic anemia

Mismatched related donors of hematopoietic SCT (HSCT) for severe aplastic anemia (SAA) present challenges mainly associated with graft failure and GVHD. The greater the HLA disparity, the poorer the OS. About 19 consecutive SAA/very SAA (VSAA) patients who received HSCT from haploidentical family donors in our center are reported in this study, 18/19 pairs had 2–3 loci mismatched. All 19 cases failed to respond to previous therapy and were heavily transfused before transplantation. The conditioning regimen before HSCT included BU, CY and thymoglobulin. The recipients received CsA, mycophenolate mofetil (MMF) and short-term MTX for GVHD prophylaxis. The source of stem cell grafts was a combination of G-CSF-primed BM and G-CSF-mobilized peripheral blood stem cells. All patients achieved 100% donor myeloid engraftment; the median time for myeloid engraftment was 12 days (ranging from 10–29 days) and for platelets was 18 days (ranging from 8–180 days) with a cumulative platelet engraftment incidence of 84.21±10.53%. The cumulative incidence was 42.1±11.3% for grade II–IV acute GVHD and 56.2±12.4% for chronic GVHD. The OS was 64.6±12.4% with a median 746-day (90–1970) follow-up for surviving patients. These limited retrospective analysis data suggest that HLA-haploidentical HSCT for SAA patients without an HLA-identical sibling donor might be feasible. Further research to increase OS by decreasing GVHD while maintaining stable engraftment will be needed in the future.

Association of an Impaired Bone Marrow Microenvironment with Secondary Poor Graft Function after Allogeneic Hematopoietic Stem Cell Transplantation

Poor graft function (PGF) is a serious complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Whether abnormalities of the bone marrow (BM) microenvironment are involved in the pathogenesis of PGF is unclear. In the present prospective nested case-control study, 19 patients with secondary PGF, 38 matched patients with good graft function (GGF) after allo-HSCT, and 15 healthy donors (HDs) were enrolled. The cellular elements of the BM microenvironment, including endosteal cells, perivascular cells, and vascular cells, were analyzed by flow cytometry as well as hematoxylin and eosin and immunohistochemical staining in situ. The median time to occurrence of secondary PGF was 90 days post-transplantation (range, 58 to 264 days). The patients with PGF showed markedly hypocellular marrow (10% versus 45% versus 45%; P < .0001) with scattered hematopoietic cells and significantly lower CD34(+) cells (0.07% versus 0.26% versus 0.26%; P < .0001), endosteal cells (4 per high-power field [hpf] versus 16 per hpf versus 20 per hpf; P < .001), perivascular cells (0.008% versus 0.10% versus 0.12%; P < .0001), and endothelial progenitor cells (0.008% versus 0.16% versus 0.18%; P < .0001) compared with GGF allo-HSCT recipients and HDs, respectively. Multivariate analyses revealed that endothelial progenitor cells (odds ratio, 150.72; P = .001) and the underlying disease (odds ratio, 18.52; P = .007) were independent risk factors for secondary PGF. Our results suggest that the impaired BM microenvironment may contribute to the occurrence of secondary PGF post-HSCT.

Influence of two different doses of antithymocyte globulin in patients with standard-risk disease following haploidentical transplantation: a randomized trial

To evaluate the effect of the different doses of antithymocyte globulin (ATG) on the incidence of acute GVHD among patients receiving hematopoietic SCT without ex vivo T-cell-depletion from haploidentical donors, 224 patients with standard-risk hematological malignancy were randomized in this study. One hundred and twelve patients received 6 mg/kg ATG, whereas the remaining patients received 10 mg/kg ATG. This study was registered at http://www.chictr.org as No. ChiCTR-TRC-11001761. The incidence of grade III–IV acute GVHD was higher in the ATG-6 group (16.1%, 95% confidence interval (CI), 9.1–23.1%) than in the ATG-10 group (4.5%, CI, 0.7–8.3%, P=0.005, 95% CI for the difference, −19.4% to −3.8%). EBV reactivation occurred more frequently in the ATG-10 group (25.3%, 17.1–33.5%) than in the ATG-6 group (9.6% (4.0–15.2%), P=0.001). The 1-year disease-free survival rates were 84.3% (77.3–91.3%) and 86.0% (79.2–92.8%) for the ATG-6 group and ATG-10 groups, respectively (P=0.88). In conclusion, although 6 mg/kg ATG applied in haploidentical transplantation decreased the risk of EBV reactivation compared with 10 mg/kg ATG, this treatment exposes patients to a higher risk for severe acute GVHD.

Prevention of relapse using granulocyte CSF-primed PBPCs following HLA-mismatched/haploidentical, T-cell-replete hematopoietic SCT in patients with advanced-stage acute leukemia: a retrospective risk-factor analysis

The role of donor lymphocyte infusion (DLI) in the prophylaxis of relapse has not been defined. We retrospectively analyzed the data from 88 patients with advanced-stage acute leukemia after HLA-mismatched/haploidentical hematopoietic SCT (HSCT) whose treatment did (n=61) or did not (n=27) include granulocyte CSF (GCSF)-primed PBPCs infusion (GPBPCI). The two groups were compared with respect to relapse and OS. Further, a detailed analysis of risk factors was performed. The 2-year cumulative incidence of relapse in patients receiving prophylactic GPBPCI and not receiving prophylactic GPBPCI were 36% and 55% (P=0.017), respectively. Estimated survival at 3 years was 31% for patients receiving prophylactic GPBPCI and 11% for patients not receiving prophylactic GPBPCI (P=0.001). The three-year probability of leukemia-free survival was also higher in patients who received prophylactic GPBPCI (22%) compared with patients who did not (11%) (P=0.003). Multivariate analysis for relapse showed that use of prophylactic GPBPCI after transplantation was an independent prognostic factor (P=0.025). Higher OS was associated with use of prophylactic GPBPCI (P=0.002), AML (P=0.027) and female sex (P=0.023). Our results suggest that use of prophylactic GPBPCI may increase survival of patients with advanced-stage acute leukemia who receive HLA-mismatched/haploidentical HSCT.

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.

Allogeneic hematopoietic SCT in combination with tyrosine kinase inhibitor treatment compared with TKI treatment alone in CML blast crisis.

CML treatment with tyrosine kinase inhibitors (TKIs) has improved many patients’ prognosis, but during the disease’s terminal phase, the blast crisis (CML-BC), has been disappointing. Allo-HSCT is another treatment, but survival rates are still disappointing. Currently, a combination of these two is suggested but with little evidence. This retrospective comparison reports on this combination and TKI alone for treatment of CML-BC. Of the 83 CML-BC patients, 45 received TKIs (imatinib; nilotinb or dasatinib after imatinib resistance; TKIs group) and 38 were treated with allo-HSCT after TKI (TKIs+allo-HSCT group). Treatment success was measured in terms of the hematologic, cytogenic and molecular responses, and subject outcome. Follow-up was 30–126 months or until death. Univariate and multivariate analyses determined EFS and OS predictors. Allo-HSCT significantly improved the 4-year OS (46.7 vs 9.7%, P<0.001) and EFS (47.1 vs 6.7%, P<0.001) compared to TKI treatment alone. Hemoglobin <100 g/L, non-return to chronic phase after TKI therapy and TKI treatment alone are independent adverse predictors of OS and EFS. Allo-HSCT with individualized intervention after TKI therapy is superior to TKI alone for CML-BC.

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.