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We retrospectively reviewed 104 biopsy specimens of previously untreated skin acute graft-versus-host disease (GVHD) within 100 days after allogeneic stem cell transplantation, and analyzed the relationship between types of infiltrating cells and clinical outcomes. Counting the total number of CD8 ؉ T cells, CD163 ؉ macrophages, and CD1a ؉ dendritic cells in 4 fields under original magnification IntroductionMacrophages are phagocytic cells with various abilities, such as phagocytosis, antigen-presenting, and secretion of cytokines. 1,2 Recently, it was revealed in human sequential biopsy data that recipient macrophages contributed to acute graft-versus-host disease (GVHD) by antigen-presenting and secreting cytokines, causing the activation and proliferation of CD8 ϩ T cells. 3 We focused on macrophage involvement in acute GVHD, especially on the relationship between the macrophage infiltration of skin lesions and refractory GVHD. MethodsBetween January 1997 and October 2007 at the Japanese Red Cross Nagoya First Hospital, we used skin biopsy specimens within 100 days after allogeneic stem cell transplantation (allo-SCT) of skin lesions clinically considered acute GVHD without any GVHD treatment from 104 patients who underwent allo-SCTs. We analyzed the relationship between types of infiltrating cells and clinical outcomes by counting the total number of CD8 ϩ T cells, CD163 ϩ macrophages, and CD1a ϩ dendritic cells in 4 fields of a skin biopsy specimen under original magnification ϫ200. Immunohistochemical analysis using paraffin sections was performed using monoclonal antibodies against CD8, CD163, and CD1a (Novocastra). CD163 is a member of the scavenger receptor cystein-rich superfamily and is an exclusive marker for macrophages, playing a major role in the scavenging components of damaged cells. [4][5][6][7] The endpoints of this study were the outcomes of acute GVHD and overall survival (OS). Acute GVHD was diagnosed and graded according to the consensus criteria. 8 We defined refractory GVHD as that exhibited by patients who had persistent lesions after primary steroid treatments. To establish parameters, we analyzed the numbers of infiltrating , disease risk (low vs high), human leukocyte antigen (HLA) disparity (match vs mismatch), donor source (related vs unrelated), graft source (bone marrow vs peripheral blood), age at allo-SCT (Յ 50 years vs Ͼ 50 years), conditioning regimen (conventional regimens vs reduced intensity regimens), and skin GVHD stage at biopsy (stages 1-2 vs stages 3-4). A significance level of P Ͻ .05 was used for all analyses, which were based on all data available as of August 31, 2008. Protocols were approved by the Japanese Red Cross Nagoya First Hospital's Institutional Review Board, and all patients provided informed consent in accordance with the Declaration of Helsinki. Table 1 summarizes the characteristics of patients and information gathered about GVHD. We divided patients into 4 groups according to the amount of infiltrating cells (FM and FT, 60.6%; MT and FM, 18.2%; MT...

To assess the impact of minimal residual disease (MRD) and tyrosine kinase inhibitor (TKI) administration on allogeneic hematopoietic cell transplantation (allo-HCT) for Ph-positive ALL (Ph+ALL), we retrospectively analyzed data from a registry database for 432 adult Ph+ALL patients in first CR (CR1) who received pre-transplant TKI administration. Negative MRD (MRD(− )) at allo-HCT was achieved in 277 patients. OS in patients transplanted in MRD( − ) was significantly better than that in patients transplanted in MRD(+) (MRD( − ): 67% vs MRD(+): 55% at 4 years; P = 0.001). MRD( − ) at allo-HCT was a significant risk factor for survival along with age at allo-HCT in multivariate analyses. Incidence of relapse in patients transplanted in MRD( − ) was significantly lower than that in patients transplanted in MRD(+) (MRD( − ): 19% vs MRD(+): 29% at 4 years; P = 0.006). In multivariate analyses, MRD(+) at allo-HCT was a significant risk factor for relapse. A post-transplant TKI was administered to 103 patients. In subanalyses regarding the effect of post-transplant TKI administration, post-transplant TKI administration was a significant risk factor for relapse in multivariate analyses (P o0.0001). MRD status at allo-HCT is one of the most important predictive factors for Ph +ALL patients transplanted in CR1.

Key Points• Pretransplant imatinib improved both relapse and nonrelapse mortality in patients with BCR-ABL-positive acute lymphoblastic leukemia.We aimed to evaluate the impact of pretransplant imatinib administration on the outcome of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in adults with Philadelphia chromosome-positive (Ph 1 ) acute lymphoblastic leukemia (ALL). We retrospectively analyzed 738 patients with Ph 1 ALL that underwent allo-HSCT between 1990 and 2010 using data from the Transplant Registry Unified Management Program of the Japan Society of Hematopoietic Cell Transplantation. We compared the allo-HSCT outcomes between 542 patients who received imatinib before allo-HSCT during the initial complete remission period (imatinib cohort) and 196 patients who did not receive imatinib (non-imatinib cohort).The 5-year overall survival after allo-HSCT was significantly higher in the imatinib cohort than in the non-imatinib cohort (59% vs 38%; 95% confidence interval [CI], 31-45%; P < .001). Multivariate analysis indicated that pretransplant imatinib administration had beneficial effects on overall survival (hazard ratio [HR], 0.57; 95% CI, 0.42-0.77; P < .001), relapse (HR, 0.66; 95% CI, 0.43-0.99; P 5 .048), and nonrelapse mortality (HR, 0.55; 95% CI, 0.37-0.83; P 5 .005). In conclusion, our study showed that imatinib administration before allo-HSCT had advantageous effects on the clinical outcomes of allo-HSCT in patients with Ph 1 ALL. (Blood. 2014;123(15):2325-2332

To identify factors to improve the outcomes of related and unrelated allogeneic stem cell transplantations (allo-SCT) for Philadelphia chromosome-negative acute lymphocytic leukemia (Ph ؊ ALL) in the first complete remission (CR1), we retrospectively analyzed 1139 Ph ؊ ALL patients using the registry data, particularly the details of 641 patients transplanted in CR1. Overall survival was significantly superior among patients transplanted in CR1, but no significant difference was observed between related and unrelated allo-SCTs (related vs unrelated: 65% vs 62% at 4 years, respectively; P ‫؍‬ .19). Among patients transplanted in CR1, relapse rates were significantly higher in related allo-SCT compared with unrelated allo-SCT, and multivariate analysis demonstrated that less than 6 months from diagnosis to allo-SCT alone was associated with relapse. On the other hand, nonrelapse mortality (NRM) was significantly higher in unrelated allo-SCT compared with related allo-SCT, and multivariate analysis demonstrated that 10 months or longer from diagnosis to allo-SCT, human leukocyte antigen mismatch, and abnormal karyotype were associated with NRM. In conclusion, our study showed comparable survival rates but different relapse rates, NRM rates, and risk factors between related and unrelated allo-SCTs. After a close consideration of these factors, the outcome of allo-SCT for adult Ph ؊ ALL in CR1 could be improved.

Macrophage infiltration of skin GVHD lesions correlates directly with disease severity, but the mechanisms underlying this relationship remain unclear and GVHD with many macrophages is a therapeutic challenge. Here, we characterize the macrophages involved in GVHD and report that dexamethasone palmitate (DP), a liposteroid, can ameliorate such GVHD by inhibiting macrophage functions. We found that host-derived macrophages could exacerbate GVHD in a mouse model through expression of higher levels of pro-inflammatory TNF-α and IFN-γ, and lower levels of anti-inflammatory IL-10 than resident macrophages in mice without GVHD. DP significantly decreased the viability and migration capacity of primary mouse macrophages compared to conventional dexamethasone in vitro. DP treatment on day 7 and day 14 decreased macrophage number, and attenuated GVHD score and subsequent mortality in a murine model. This is the first study to provide evidence that therapy for GVHD should be changed on the basis of infiltrating cell type.

Hematologic stem cell transplantation (HSCT) is the most potent consolidation therapy for high-risk acute lymphoblastic leukemia (ALL), but their outcomes and complications in adolescent and young adult (AYA) patients remain unclear. We compared outcomes after HSCT for ALL among children (age 1 to 9 years; n = 607), adolescents (age 10 to 19 years; n = 783), and young adults (age 20 to 29 years old, n = 603), based on Japanese nationwide registry data. The 5-year overall survival (OS) rate among AYA patients was worse than that of children, at 64% (95% confidence interval [CI], 60% to 68%). In the AYA, the 5-year treatment-related mortality (TRM) after HSCT was 19% (95% CI, 16% to 22%), significantly higher than that in younger patients. The most common cause of TRM in the AYA was infection. The relapse rate was not different across the 3 age groups. When focusing on older adolescents (age 15 to 19 years), there was no difference in outcomes between those treated in pediatric centers and those treated in adult centers. In conclusion, the AYA had a greater risk of nonrelapse death than younger patients, and infection was the most common cause. Further optimization is required for HSCT in AYAs with ALL.

Allo-SCT using CB led to OS similar to those of RD or URD in any disease status. To avoid missing the appropriate timing, CB is a favorable alternative source for adult Ph(-) ALL patients without a suitable RD or URD.