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Donor lymphocyte infusion (DLI) might be used prophylactically to reduce relapse after allogeneic hematopoietic stem cell transplantation for very high-risk leukemia/lymphoma without effective targeted therapy. To compare the safety and efficacy of prophylactic DLI for prevention of relapse after allogeneic peripheral blood stem cell transplantation from haploidentical donors (HID-SCT) and matched-sibling donors (MSD-SCT) in patients with very high-risk acute myeloid leukemia (AML), we performed a retrospective analysis in a cohort of 21 HID-SCT and 13 MSD-SCT recipients, displaying similar baseline characteristics except for donor's gender distribution. Grade 2-4 acute graft-versus-host disease (GVHD) at 100-day post-DLI was higher in HID-SCT group than that in MSD-SCT group (59.5% vs. 30.8%, p = 0.05). The grade 3-4 acute GVHD (17.5% vs. 7.7%), 1-year chronic GVHD (36.6% vs. 33.2%), and severe chronic GVHD (15.3% vs. 27.3%) were not statistically significant different between groups. One-year non-relapse mortality was higher in HID-SCT group than that in MSD-SCT group with marginal significance (27.9% vs. 0.0%, p = 0.061). One-year relapse rate was not statistically significant different between HID-SCT group and MSD-SCT group (21.6% vs. 36.5%, p = 0.543). For HID-SCT recipients, 1-year relapse rate was lower in patients receiving prophylactic DLI than that in a control cohort of eight patients with same very high-risk features but not receiving prophylactic DLI (62.5% vs. 28.3%, p = 0.037). No statistically significant difference was observed in 1-year overall survival (OS, 55.1% vs. 83.9%, p = 0.325) and relapse-free survival (RFS, 50.1% vs. 74.0%, p = 0.419) rates between HID-SCT group and MSD-SCT group. In multivariate analyses, non-remission status prior to transplant, poor-risk gene mutations, and donor's age ≥ 48 years predicted a higher risk of relapse after DLI. Non-remission status prior to transplant predicted inferior OS and RFS. Patient's age ≥ 40 years also predicted an inferior OS. In conclusion, prophylactic DLI was very safe and efficient for reducing relapse in patients with very high-risk AML receiving MSD-SCT. In the recipients of HID-SCT, the application of prophylactic DLI could reduce the risk of relapse, although with a higher incidence of DLI-associated acute GVHD than those of MSD-SCT. [ABSTRACT FROM AUTHOR]

Unmanipulated haploidentical peripheral blood stem cell transplantation (haplo-PBSCT) has been an established treatment to cure high-risk leukemia/lymphoma. Relapse is the main cause of treatment failure for patients with relapsed/refractory disease or with very high-risk gene mutations such as TP53, TET2, and DNMT3a. In this study, we aimed to establish the tolerance and efficacy of prophylactic donor lymphocyte infusion (DLI) with G-CSF-primed peripheral blood progenitors for prevention of relapse in these very high-risk patients after haplo-PBSCT. The prophylactic DLI was given at a median of 77 days after transplantation in 31 of 45 consecutive patients with very high-risk leukemia/lymphoma. The median dose of CD3+ cells for infusion was 1.8 × 107/kg. The 100-day incidences of acute graft-versus-host disease (GVHD) grades 2-4 and 3-4 after DLI were 55.3% and 10.2%. The 2-year incidences of chronic GVHD and severe chronic GVHD were 52.0% and 18.2%. The 2-year incidences of non-relapse mortality and relapse were 33.1% and 32.5%. The 2-year probabilities of overall survival and relapse-free survival were 40.1% and 31.9%. Poor-risk gene mutations (p = 0.029), disease in non-remission status prior to transplantation (p = 0.005), and donors older than 40 years of age (p = 0.043) were associated with relapse after DLI. In multivariate analysis, disease in non-remission status prior to transplantation was an independent risk factor of relapse (hazard ratio = 4.079; p = 0.035). These data showed the feasibility of the prophylactic DLI in the haplo-PBSCT setting and the anti-leukemic efficacy in very high-risk leukemia/lymphoma. [ABSTRACT FROM AUTHOR]

The features of graft-versus-host disease ( GVHD) were compared between patients who underwent myeloablative conditioning and received a peripheral blood stem cell transplant ( PBSCT) from either a haploidentical donor ( HID) or a matched sibling donor ( MSD) during the same period of time. The HID group included more patients with advanced disease. Both groups received the same GVHD prophylaxis with the addition of antithymoglobulin ( ATG) in HID group. Higher cumulative incidences ( CI) of acute GVHD grade 2-4 (35·1% vs. 13·9%, P = 0·003), similar CI of grade 3-4 (14·5% vs. 9·8%, P = 0·595), less 3-year CI of extensive chronic GVHD (17·1% vs. 41·5%, P = 0·017) and less severe chronic GVHD (5·8% vs. 21·2%, P = 0·049) occurred in the HID group compared with the MSD group. There was no difference in the sites of the involved organs between these two groups. Higher 3-year CI of non-relapse mortality (24·0% vs. 10·2%, P = 0·014), relapse (39·0% vs. 22·6%, P = 0·032) and inferior disease-free survival (45·7% vs. 78·9%, P = 0·000) were recorded in the HID cohort compared with the MSD group. More HID patients had Karnofsky scores above 90 than those in MSD group ( P = 0·016). In conclusion, ATG plays a key role in the unmanipulated HID PBSCT protocol, producing better quality of life in survivors. [ABSTRACT FROM AUTHOR]

This retrospective study compared the transplantation outcomes of 98 consecutive patients with acute leukemia. Allogeneic hematopoietic stem cell transplantation was performed using G-CSF-mobilized bone marrow and blood (G-BM&PB) or G-CSF-mobilized peripheral blood (G-PB) from HLA-identical sibling donors. The G-BM&PB and G-PB groups displayed significantly different neutrophil recovery rates (medians of 15 vs. 14 d, respectively; p = 0.009) but similar platelet recovery rates. The cumulative incidences of grades II-IV acute graft-versus-host disease ( aGVHD) in the G-BM&PB and G-PB cohorts were similar (16.2 ± 4.7% vs. 21.8 ± 7.4%, respectively; p = 0.676), but the incidences of grades III-IV aGVHD were significantly different (5.5 ± 3.1% vs. 18.9 ± 7.1%, respectively; p = 0.042). The G-BM&PB and G-PB cohorts displayed similar cumulative incidences of chronic GVHD ( cGVHD, 49.1 ± 5.7% vs. 42.7 ± 6.8%, respectively; p = 0.465), one-yr cumulative incidences of treatment-related mortality (16.5 ± 3.5% vs. 24.4 ± 4.1%, respectively; p = 0.220), and five-yr cumulative incidences of relapse (13.9 ± 4.8% vs. 26.8 ± 7.2%, respectively; p = 0.113). The five-yr probability of leukemia-free survival (LFS) was significantly higher in the G-BM&PB group than in the G-PB group (77.8 ± 5.2% vs. 57.6 ± 8.6%, respectively; p = 0.023). Multivariate analysis identified G-PB as an independent risk factor for grades III-IV aGVHD and LFS. Our results suggest that HLA-identical transplantation with G-BM&PB results in superior clinical outcomes compared with G-PB for patients with acute leukemia. [ABSTRACT FROM AUTHOR]

We retrospectively compared the antileukemic effects of chemotherapy alone and chemotherapy followed by modified donor lymphocyte infusion ( DLI) in 82 patients with relapsed acute leukemia after haploidentical hematopoietic stem cell transplantation ( HSCT) without in vitro T-cell depletion. We also investigated prognostic factors in patients receiving chemotherapy followed by modified DLI. Thirty-two patients received chemotherapy alone, and the remaining 50 patients received chemotherapy followed by modified DLI. In patients receiving chemotherapy followed by modified DLI, complete remission rate was significantly higher (64.0% vs. 12.5%, P = 0.000), the incidence of relapse was significantly lower (50.0% vs. 100.0%, P = 0.000), and disease-free survival was significantly improved (36.0% vs. 0.0%, P = 0.000) compared with patients receiving chemotherapy alone. Multivariate analysis demonstrated that patients with chronic graft-versus-host disease ( GVHD) after intervention ( P = 0.000) and patients receiving chemotherapy followed by modified DLI ( P = 0.037) were associated with a lower relapse rate. Furthermore, in patients receiving chemotherapy followed by modified DLI, multivariate analysis demonstrated that chronic GVHD after modified DLI ( P = 0.039) and duration of minimal residual disease ( MRD) (−) ≥4 months after modified DLI ( P = 0.001) were associated with a lower relapse rate. Our study is the first to suggest that chemotherapy followed by modified DLI is associated with stronger antileukemic effects and better survival in relapsed acute leukemia after haploidentical HSCT without in vitro T-cell depletion. Furthermore, our study suggests that lack of chronic GVHD and duration of MRD (−) <4 months after modified DLI are associated with higher relapse rates in patients receiving chemotherapy followed by modified DLI. [ABSTRACT FROM AUTHOR]

Acute graft-versus-host-disease (aGvHD) is the major cause of non-relapse mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Recently, diagnostic biomarkers for aGvHD have been shown to play important roles in evaluating disease status and mortality risk after allo-HSCT. To identify plasma biomarkers for aGvHD with high sensitivity and specificity, a quantitative proteomic approach using 8-plex isobaric tags for relative and absolute quantitation (8-plex iTRAQ) was employed to screen differentially expressed proteins in peripheral blood before and after the onset of aGvHD. Four target proteins, ceruloplasmin (CP), myeloperoxidase (MPO), complement factor H (CFH), and alpha-1-acid glycoprotein (AGP), were chosen for preliminary validation with enzyme linked immunosorbent assay (ELISA) in 20 paired samples at both the time of diagnosis of aGvHD and the time of complete response. The most promising candidate, ceruloplasmin, was further validated at fixed time points after allo-HSCT and during aGvHD. The plasma ceruloplasmin levels were significantly increased during the period of aGvHD onset and were markedly decreased as aGvHD resolved. The plasma ceruloplasmin levels at different time points post-transplant in the aGvHD (+) group were significantly higher than those in the aGvHD (−) group (p<0.001). The elevation of ceruloplasmin level in patients with active aGvHD was independent of infection status. Patients whose ceruloplasmin levels were elevated above 670 μg/ml at 7, 14 and 21 days after allo-HSCT had a remarkably increased probability of subsequently developing aGvHD. In conclusion, our results suggest that plasma ceruloplasmin is a potential plasma biomarker of aGvHD, and it also has prognostic value for risk-adapted prophylaxis during the consecutive time points monitored in the first month after allo-HSCT. [ABSTRACT FROM AUTHOR]

We performed a study to investigate the profile of donor lymphocyte infusion ( DLI)-associated acute graft-versus-host disease ( GVHD) in haploidentical T-cell-replete hematopoietic stem cell transplantation ( HSCT). A total of 124 patients receiving modified DLI after haploidentical T-cell-replete HSCT were enrolled. The cumulative incidence of DLI-associated acute GVHD was 53.2% for grades II- IV and 28.4% for grades III- IV. The duration of GVHD prophylaxis after DLI was the only risk factor for DLI-associated grades III- IV acute GVHD (p < 0.05). The cumulative incidence of grades III- IV acute GVHD in patients with prophylaxis more than six, four to six, two to four, and <2 wk were 9.3%, 14.4%, 31.6%, and 49.5%, respectively (p = 0.018). Furthermore, DLI-associated grades III- IV acute GVHD was the only risk factor for overall survival (p = 0.038, OR = 2.869) and transplant-related mortality (p = 0.018, OR = 3.296) but not a risk factor for relapse after DLI (p = 0.840). This study confirms for the first time that the duration of GVHD prophylaxis after DLI is the only risk factor for the development of grades III- IV acute GVHD. Donor lymphocyte infusion with prophylaxis more than six wk was associated with a lower incidence of grades III- IV acute GVHD. [ABSTRACT FROM AUTHOR]

Regulatory T cells ( Tregs) maintain transplantation tolerance and suppress graft-versus-host disease ( Gv HD) in humans. We monitored 17 subjects with acute GvHD to determine whether Treg frequency correlates with acute GvHD. We found the percent of CD4+ CD25− CD69+ Tregs decreases when acute GvHD develops and increases after acute GvHD is controlled. We next sequentially studied 50 subjects receiving conventional allotransplants. We show a high frequency and increased numbers of CD4+ CD25− CD69+ Tregs are associated with a reduced risk of acute GvHD. We also show that CD4+ CD25− CD69+ Treg numbers increase substantially early after allografts and that a low percent of CD4+ CD25− CD69+ Tregs is associated with an increased risk of acute Gv HD. Reconstitution of Tregs early post-transplant is associated with less acute GvHD. These data imply that CD4+ CD25− CD69+ Tregs are a novel subset of regulatory T cells that may protect against acute GvHD after allotransplants. [ABSTRACT FROM AUTHOR]

The outcomes of an historic comparison of 117 consecutive, high-risk, acute leukemia patients undergoing hematopoietic stem cell transplantation (HSCT) from HLA-mismatched/haploidentical donors (HID, n = 81) or HLA-identical sibling donors (ISD, n = 36) without the use of in vitro T cell depletion (TCD), between the period of January 2005 and April 2009 were compared. Full engraftment was achieved in 98% of patients in the HID group and 97% in the ISD group. The cumulative incidences of grades II–IV acute graft-versus-host disease (aGVHD) in the HID and ISD cohorts were 49% and 24%, respectively (P = .014) with a relative risk (RR) of 2.99 (1.25-7.21) (P = .014). The incidence of chronic GVHD (cGVHD) did not differ significantly between the 2 cohorts. The 2-year cumulative incidence of relapse was significantly lower in HID (26%) than in ISD patients (49%) (P = .008). The 2-year cumulative incidence of nonrelapse mortality (NRM) was comparable in recipients of HID (34%) and ISD grafts (38%) (P = .85). The 3-year probability of overall survival (OS) was higher in HID patients (42%) than in ISD (20%) (P = .048) patients. Our comparisons suggest that HID transplants can achieve a stronger graft-versus-leukemia (GVL) effect than ISD for high-risk acute leukemia patients. [ABSTRACT FROM AUTHOR]

Zhao X-S, Liu K-Y, Liu D-H, Xu L-P, Chen H, Huang X-J. Potential immunosuppressive function of plasma indoleamine 2,3-dioxygenase in patients with aGVHD after allo-HSCT. Clin Transplant 2011: 25: E304-E311. © 2011 John Wiley & Sons A/S. Given the function of indoleamine 2,3-dioxygenase (IDO) in the induction of immune tolerance as a T-cell inhibitor, we investigated whether plasma IDO levels correlate with the biological activity of acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). Plasma levels of IDO were monitored by ELISA in 147 samples from 65 patients who fulfilled the diagnostic histopathological and/or clinical criteria of aGVHD and 16 episodes of infection after allo-HSCT. Elevated plasma IDO levels were associated with occurrence of infection or mild aGVHD (grade I-II). Most patients with grade III-IV aGVHD had relatively low levels of IDO compared to those with mild aGVHD or infection. Responses of aGVHD to immunosuppressive therapy were associated with a decrease in IDO levels in the majority of patients with mild aGVHD, whereas secondary infection was characterized by persistent or increased IDO levels after treatment. Although plasma IDO levels may indicate the severity and outcome of aGVHD and point to appropriate therapies through its function in immune tolerance, it is not aGVHD specific and may not be a distinguishing biomarker of aGVHD. [ABSTRACT FROM AUTHOR]

Background: Heart failure (HF) occurring after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is rare but severe. We examine the role of pre-HSCT therapeutic exposures, conditioning regimens, pre-HSCT comorbidities, severe transplant-related complications, and post-HSCT cardiovascular risk factors in the development of heart failure after allo-HSCT. Methods: A nested case-control study was designed. Cases with HF and controls matched for age, year of allo-HSCT, and length of follow-up were identified from a cohort of 2455 patients who underwent allo-HSCT between 2000 and 2011 for hematologic malignancies. Results: Forty-two patients suffered from HF; mean age at presentation was 35years (±14years) and mean time to presentation was 5months (±9months) post-HSCT. The number of pre-HSCT cycles of chemotherapy was significantly greater (7 vs. 5 courses, P=0.023). Cases were significantly more likely to have severe acute GVHD (≥grade III), hemorrhagic cystitis (≥grade 2), and multiple severe transplant-related complications compared with controls (42.9% vs. 20.4%, P=0.008). Multivariate analysis revealed that pre-HSCT cycles of chemotherapy of ≥5 courses (OR=3.5, P=0.003) and two or more severe transplant-related complications (OR=3.6, P=0.003) were independently associated with HF. Conclusions: These results identify the individuals who are at higher risk of developing HF after allo-HSCT. We should pay more attention to these patients and more active management would be reasonable. [ABSTRACT FROM AUTHOR]

Abstract: We report the results of low-dose methotrexate (MTX) as first-line therapy mostly in combination with other immunosuppressive agents in patients with chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Between November 2001 and March 2008, 86 patients with cGVHD after allo-HSCT received low-dose MTX therapy until a complete or partial response (CR, PR) was achieved, or until treatment failure or intolerable side effects were found. The median time from HSCT to the start of MTX was 154 (range: 80-993) days. The median number of MTX administrations was 4 (range: 2-18). The overall response rate among all enrolled patients was 83% (71 of 86 patients). The response rate for GVHD involving various organs was 90% (45 of 50) in the skin, 75% (39 of 52) in the liver, 42% (5 of 12) in the mouth, 3 of 7 in the eye, and 2 of 2 in the gut. In addition, MTX treatment allowed for a significant reduction in the prednisone dosage (median 90%) from 20 (2.5-100) mg at the start of MTX administration to 5 (0-30) mg 1 month after MTX was last used. Multivariate analysis showed that the only significant factor related to higher CR rate was sole organ involvement (P = .007). Grade 3 toxicities occurred in only 3 patients presenting cytopenias or oral mucositis. From this analysis, MTX appears to be a well-tolerated, effective, and inexpensive agent when used as a first-line treatment in combination with other immunosuppressive agents for cGVHD, especially for skin or sole organ involvement without concomitant thrombocytopenia. [Copyright &y& Elsevier]

Abstract: 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. [Copyright &y& Elsevier]

Human cytomegalovirus (CMV)-specific cytotoxic T lymphocyte (CTL) immune response must be reconstituted for long-term protection against CMV relapse and disease in hematopoietic stem cell transplantation (HSCT) recipients. We phenotypically quantitated absolute numbers of CMV-pp65 peptide-specific CTLs (CTLCMV) in 50 related donor unmanipulated allografts infused into HLA-matched or -mismatched recipients and examined the incidence of CMV reactivation. High CTLCMV with terminally differentiated effector CD45RO-CD62L- cell (TEMRA) phenotype in the allografts were associated with reduced risk of CMV reactivation, in the presence of sufficient CD45RO+CD62L- cell (TEM) infusion (≥0.208 × 106/kg). Early after transplantation, there was significant expansion of CTLCMV with the central memory CD45RO+CD62L+ cell (TCM) phenotype when CMV was reactivated. The frequencies of CTLCMV TNaive (CD45RO-CD62L+), TCM, and TEM at day 90 posttransplantation and of CTLCMV TEMRA at day 60 posttransplantation were greater in recipients with higher infusions of CTLCMV TEMRA, suggesting protective immunity transferred by infusion of CTLCMV within allografts. Moreover, the majority of the CTLCMV identified in the recipients early after HSCT was of donor origin. Our findings support that measuring levels of CTLCMV and its subsets in the donor grafts and manipulating these cells early after transplantation may help control CMV reactivation, which is closely correlated with immune reconstitution and differentiation of CTLCMV subsets. [Copyright &y& Elsevier]

Abstract: The effect of natural killer (NK) cell alloreactivity on the outcome of haploidentical hematopoietic stem cell transplantation (HSCT), with or without in vitro T cell depletion, remains controversial. Killer immunoglobulin-like receptors (KIRs) recognize human leukocyte antigen C and B epitopes on target cells, thereby regulating NK cell activity. To examine the recovery of CD94:NKG2A and KIR (CD158a, CD158b, and CD158e) expression by NK cells, we used flow cytometry to evaluate samples from 24 patients and their donors before and in the year following unmanipulated HLA-haploidentical/mismatched blood and marrow transplantation. Linear regression analysis demonstrated that NKG2A recovery was inversely correlated with CD158b recovery in the year following transplant. The doses of T cell subgroups CD4+ and CD8+ were inversely associated with CD158a and CD158e expression during the 2 months following transplantation. Moreover, patients with grades II-IV acute graft-versus-host disease (aGVHD) or who received “high” doses of T cells (>1.37 × 108/kg) showed delayed recovery of KIRs during the 2 months following transplantation. Univariate analysis showed that patients with high CD94 expression by day 60 (>90%) or who received donors with high CD94 expression (>80%) were associated with higher transplantation-related mortality (P = .006 or .067, respectively) and poorer leukemia-free survival (P = .012 or .094, respectively). Thus, the occurrence of aGVHD or the receipt of high doses of T cells in the allograft altered KIR reconstitution. Furthermore, high levels of CD94 expression in donors or in recipients by day 60 might be a good predictor for poor prognosis. [Copyright &y& Elsevier]