Xiang-Yu Zhao

IL-17-producing T cells contribute to acute graft-versus-host disease in patients undergoing unmanipulated blood and marrow transplantation.

The aim of this study was to investigate the effects of IL‐17‐producing T cells, including Th17 and Tc17 cells, on acute graft‐versus‐host disease (aGVHD) in patients who had undergone granulocyte colony‐stimulating factor (G‐CSF)‐mobilised peripheral blood progenitor cell (PBPC) and G‐CSF‐primed bone marrow (G‐BM) transplantation. Allografts from forty‐one patients were analysed for IL‐17‐producing T cells with respect to aGVHD. Furthermore, ten patients with aGVHD onset were monitored for the presence of Th17 cells in the peripheral blood by flow cytometry. Patients who received a higher dose of Th17 cells in the G‐BM (>8.5×104/kg, p=0.005) or a higher dose of Tc17 cells in PBPC (>16.8×104/kg, p=0.001) exhibited a higher incidence of aGVHD. An increased Th17 population (up to 4.99% CD4+ T lymphocytes) was observed in patients with aGVHD onset. In contrast, the percentage of Th17 population decreased drastically in aGVHD patients following treatment to achieve partial and complete remission (p=0.013 and p=0.008, respectively). All percentages of Th17 and Tc17 cells were significantly reduced after in vivo G‐CSF application. Our results suggested that IL‐17‐producing T cells contributed to aGVHD. The application of G‐CSF in vivo aided in reducing the occurrence of aGVHD through a decrease in IL‐17 secretion by T cells.

Administration of imatinib after allogeneic hematopoietic stem cell transplantation may improve disease-free survival for patients with Philadelphia chromosome-positive acute lymphobla stic leukemia

BackgroundMaintenance therapy with imatinib during the post-transplant period has been used for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL); however, its efficacy has not been demonstrated. A study was designed to investigate the safety of imatinib and its efficacy in preventing hematological relapse and improving disease-free survival (DFS) when administered after allogeneic hematopoietic stem cell transplantation (allo-HCT).MethodsPatients with Ph + ALL that received allo-HCT were enrolled in the study. Real-time quantitative reverse-transcription polymerase chain reaction (qRT-PCR) was used to detect BCR-ABL transcript levels. Imatinib therapy was initiated if patient neutrophil counts were > 1.0 × 109/L and platelet counts were > 50.0 × 109/L, or if they displayed either elevated BCR-ABL transcript levels in two consecutive tests, or a BCR-ABL transcript level ≥ 10-2 after initial engraftment. Patients receiving imatinib after relapse were assigned to the non-imatinib group. The imatinib treatment was scheduled for 3–12 months, until BCR-ABL transcript levels were negative at least for three consecutive tests or complete molecular remission was sustained for at least 3 months.ResultsA total of 82 patients were enrolled. Sixty-two patients initiated imatinib therapy post-HCT. Imatinib therapy was initiated at a median time of 70 days post-HCT. Grade 3–4 adverse events (AEs) occurred in 17.7% of patients. Ten patients (16.1%) terminated imatinib therapy owing to AEs. Among the patients in imatinib and non-imatinib groups, the estimated 5-year relapse rate was 10.2% and 33.1% (p = 0.016), and the 5-year probability of DFS was 81.5% and 33.5% (p = 0.000) with the median follow-up of 31 months (range, 2.5-76 months) and 24.5 months (range, 4–72 months), respectively. Multivariate analysis identified imatinib maintenance therapy post-HCT as an independent prognostic factor for DFS (p = 0.000, hazard ratio [HR] =4.8) and OS (p = 0.000, HR = 6.2).ConclusionsThese results indicate that relapse rate can be reduced and DFS may be improved in Ph + ALL patients with imatinib maintenance therapy after HCT. BCR-ABL monitoring by qRT-PCR can guide maintenance therapy with imatinib including initiation time and treatment duration after allo-HCT.

Platelet Engraftment in Patients with Hematologic Malignancies following Unmanipulated Haploidentical Blood and Marrow Transplantation: Effects of CD34+ Cell Dose and Disease Status

Unmanipulated haploidentical blood and marrow transplantation has been developed as an alternative transplantation strategy for patients without an HLA-matched related or unrelated donor. In this transplantation setting, factors associated with hematopoietic recovery have not been defined completely. The aim of this study was to investigate the effects of donor and recipient characteristics on neutrophil and platelet engraftment after unmanipulated HSCT. The study group comprised 348 patients who underwent unmanipulated haploidentical blood and marrow transplantation to treat hematologic malignancy at a single institution between 2002 and 2007. Factors correlating with neutrophil and platelet engraftment posttransplantation were analyzed retrospectively. All patients achieved an absolute neutrophil count ANC of 500/microL in a median of 13 days (range, 9 to 49 days). Of the 348 patients, 331 (95.11%) achieved an untransfused platelet count of > 20,000/microL in a median of 16 days (range, 7 to 356 days). Multivariate analysis showed that the amount of CD34(+) cells infused (CD34(+) cells >or= 2.19 x 10(6)/kg recipient weight vs < 2.19 x10(6)/kg recipient weight; hazard ratio [HR] = 1.695; 95% confidence interval [CI] = 1.361 to 2.112; P < .0001), and disease stage (advanced vs early; HR = 0.724; 95% CI = 0.577 to 0.907; P = .005) were independently associated with increased risk of platelet engraftment. Our results suggest that low numbers of CD34(+) cells in allografts and advanced-stage disease may be critical factors associated with delayed platelet engraftment after unmanipulated haploidentical transplantation.

Effects of the NK Cell Recovery on Outcomes of Unmanipulated Haploidentical Blood and Marrow Transplantation for Patients with Hematologic Malignancies

The goal of this study was to investigate the association of natural killer (NK) cell recovery with clinical outcomes after unmanipulated haploidentical blood and marrow transplantation. We sequentially monitored the reconstitution kinetics of circulating NK cells, CD56(bright) and CD56(dim), in 43 patients by flow cytometry, and the functionality recovery of cytokine or cytotoxicity of NK cells by flow cytometry or lactate dehydrogenase release assay after transplantation. Reconstitution of NK cells was rapid but accompanied by skewing of cell subsets mainly in CD56(bright), which recovered earlier. Linear regression analysis demonstrated that dose of CD34(+) cells in the allografts was inversely correlated with the ratio of T/NK cells (beta = -0.506, P = .003) and CD56(dim)/CD56(bright) cell (beta = -.403, P = .018) by day 14 after hematopoietic stem cell transplantation (HSCT), and the dose of CD3(+) T cells in the allografts was also inversely correlated with the ratio CD56(dim)/CD56(bright) cells by day 14 after HSCT (beta = -0.474, P = .005). Moreover, the dose of CD56(dim) NK cells in the allograft was positively associated with the day 14 CD56(brigh) NK cells (beta = 0.494, P = .032) and inversely correlated with the day 14 ratio of CD56(dim)/CD56(bright) cells (beta = -0.617, P = .005). Compared with nonacute graft-versus-host disease (GVHD) patients, patients with acute GVHD (aGVHD) had a higher level of NK subsets during week 2 posttransplantation. Cox regression analysis revealed that the patients with more CD56(bright) NK cells in the recovery stage had a higher survival rate (hazard risk [HR], 0.406; P = .017) and the patients with a higher ratio of T/NK (>1.0) had a higher chance of getting aGVHD (HR, 3.436; P = .059) and chronic GVHD (HR, 3.925; P = .028). Our results suggest that the recovery of NK cells is and can be used as an indicator to predicate the clinical outcomes after unmanipulated haploidentical transplantation.

Prognosis after unmanipulated HLA-haploidentical blood and marrow transplantation is correlated to the numbers of KIR ligands in recipients

Objectives:  The goal of this study was to explore the role of NK cell alloreaction in predicting prognosis under unmanipulated HLA‐haploidentical blood and marrow transplantation and examine whether the presence of any individual donor‐activating KIR gene had an influence on the clinical outcome.

The effect of HLA disparity on clinical outcome after HLA‐haploidentical blood and marrow transplantation

Huo M‐R, Xu L‐P, Li D, Liu D‐H, Liu K‐Y, Chen H, Han W, Chen Y‐H, Wang Y, Wang J‐Z, Zhang X‐H, Zhao X‐Y, Huang X‐J. The effect of HLA disparity on clinical outcome after HLA‐haploidentical blood and marrow transplantation. 
Clin Transplant 2011 DOI: 10.1111/j.1399‐0012.2011.01499.x. 
© 2011 John Wiley & Sons A/S.

Conflicting Impact of Alloreactive NK Cells on Transplantation Outcomes after Haploidentical Transplantation: Do the Reconstitution Kinetics of Natural Killer Cells Create These Differences?

Partially HLA-mismatched related, or HLA-haploidentical, donor stem cell transplantation (SCT) is a feasible therapeutic option for advanced hematologic malignancy patients who lack an HLA-matched related or unrelated donor. Natural killer (NK) cells, a major cell type of the innate immune system, express surface receptors that regulate potent effector functions, such as cytolytic activity and the release of cytokines, and play a central role in the inflammatory response and immunoregulation. Conflicting results have been reported regarding the impact of NK cell alloreactivity on the outcome of haploidentical SCT in leukemic patients. This review summarizes the heterogeneous clinical results and explains the underlying mechanisms with respect to the reconstitution kinetics of NK cells and the interactions between NK cells and T cells.

Monocytic and promyelocytic myeloid-derived suppressor cells may contribute to G-CSF-induced immune tolerance in haplo-identical allogeneic hematopoietic stem cell transplantation

We investigated the effects of granulocyte colony‐stimulating factor (G‐CSF) on monocytic (M), promyelocytic (P), and granulocytic (G) myeloid‐derived suppressor cells (MDSCs) both in bone marrow and peripheral blood of 20 healthy donors and the association of MDSCs subgroups with acute and chronic graft‐versus‐host disease (aGvHD/cGvHD) in 62 patients who underwent haplo‐identical allogeneic hematopoietic stem cell transplantation (allo‐HSCT). Patients who received a higher absolute counts of M‐MDSCs or P‐MDSCs exhibited lower incidence of grade II–IV aGvHD (P = 0.001; P = 0.031) and extensive cGvHD (P = 0.011; P = 0.021). In the multivariate analysis, absolute counts of MDSCs in allografts emerged as independent factors that reduced the occurrence of grade II–IV aGvHD (M‐MDSCs: HR = 0.087, 95% CI = 0.020–0.381, P = 0.001; P‐MDSCs: HR = 0.357, 95% CI = 0.139–0.922, P = 0.033) and extensive cGvHD (M‐MDSCs: HR = 0.196, 95% CI = 0.043–0.894, P = 0.035; P‐MDSCs: HR = 0.257, 95% CI = 0.070–0.942, P = 0.04). Delayed M‐MDSC reconstitution was associated with aGvHD onset. The 3‐year cumulative incidence of transplant related mortality and relapse, 3‐year probability of disease‐free survival, and overall survival did not differ significantly between these subgroups. Our results suggested that G‐CSF‐induced immune tolerance may be mediated by M/P‐MDSCs in allo‐HSCT. Am. J. Hematol. 90:E9–E16, 2015.

Recipient expression of ligands for donor inhibitory KIRs enhances NK‐cell function to control leukemic relapse after haploidentical transplantation

Natural killer (NK) cells that express self‐HLA‐specific receptors (where HLA is human leukocyte antigen) are “licensed” and more readily activated than unlicensed cells; therefore, NK‐cell licensing could influence the antileukemia effects of NK cells following haploidentical stem cell transplantation (haplo‐SCT). In this study, we compared the functionality of reconstituting NK cells, based on CD107α expression and interferon‐γsecretion, in a cohort of 29 patients that expressed (n = 8) or lacked (n = 21) class I human leukocyte antigens for donor inhibitory killer cell immunoglobulin‐like receptors (KIRs) following T‐cell‐replete haplo‐SCT. We also addressed whether recipient expression of class I ligands for donor inhibitory KIRs could predict relapse occurrence in another cohort of 188 patients. A longitudinal analysis indicated that patients presenting class I for all donor inhibitory KIRs showed more capable functional NK effector cells when tested against class I negative K562 cells and primary leukemic cells within 3 months of transplantation. The lowest 7‐year relapse incidence was observed when donor KIRs were ligated by recipient class I (n = 60) compared with donor–host partnerships where donor KIR+ cells were ligated by donor, but not recipient class I (n = 86, p = 0.026) or KIRs that were ligated by neither donor nor recipient class I (n = 42, p = 0.043). This study suggests that haplo‐SCT recipients presenting class I for donor inhibitory KIRs promote NK‐cell licensing, leading to decreased relapse rates.

Influence of lymphocyte recovery on outcome of haploidentical transplantation for hematologic malignancies.

Unmanipulated human leukocyte antigen (HLA)-mismatched/haploidentical blood and marrow transplantation is an established treatment for patients without HLA-matched related or unrelated donors. However, the prognostic significance of early lymphocyte recovery in this transplant setting is not defined. In this study, we investigated the association of day 30 absolute lymphocyte count (ALC-30) with outcome after unmanipulated HLA-mismatched/haploidentical transplantation. We prospectively analyzed the relationship between ALC-30 and transplant outcomes in 206 patients with hematologic malignancies receiving T-cell-replete transplantation from HLA-mismatched/haploidentical related donors. Multivariate analysis showed that ALC-30 above the cutoff value of 300 cells/&mgr;L was associated with improved overall survival (hazard ratio [HR], 0.258; 95% confidence interval [CI], 0.141-0.472; p < 0.0001); improved cancer-free survival (HR, 0.289; 95% CI, 0.166-0.501; p < 0.0001); reduced relapse (HR, 0.370; 95% CI, 0.161-0.853; p = 0.020); and decreased transplant-related mortality (HR, 0.211; 95% CI, 0.097-0.457; p < 0.0001). Our results suggest that the recovery of ALC-30 might have an influence on transplant outcomes following unmanipulated HLA-mismatched/haploidentical transplantation. Abbreviations: ALC = absolute lymphocyte count, ALC-30 = absolute lymphocyte count on day 30 posttransplant, ALC-60 = absolute lymphocyte count on day 60 posttransplant, ALC-90 = absolute lymphocyte count on day 90 posttransplant, CI = confidence interval, G-CSF = granulocyte colony-stimulating factor, GVHD = graft-versus-host disease, HLA = human leukocyte antigen, HR = hazard ratio, HSCT = hematopoietic stem cell transplantation, IV = intravenous, NK = natural killer.