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Deferasirox is an oral iron‐chelating agent having possible antileukemia and immune modulatory effects. Few reports have evaluated deferasirox in the setting of allogeneic hematopoietic stem cell transplantation (allo‐HSCT). We investigated the impact of deferasirox after allo‐HSCT in acute myeloid leukemia (AML). Of 326 consecutive patients undergoing allo‐HSCT in remission, analysis of 198 patients not receiving deferasirox revealed the negative prognostic effect of hyperferritinemia (≥1000 ng/mL) before and after allo‐HSCT on survival mainly due to increase in relapse. Of 276 patients with hyperferritinemia at 1 month after allo‐HSCT, 128 patients (46%) received deferasirox. Deferasirox induced a faster decline in serum ferritin level with a manageable safety profile, which significantly reduced relapse rather than nonrelapse mortality, resulting in better survival compared to patients not receiving deferasirox. Of note, the deferasirox group had a significantly higher incidence of chronic graft‐vs‐host disease, indicating improved graft‐vs‐leukemia (GVL) effects evidenced by the presence of suppressed regulatory T cells and sustained higher proportion of NK cells in peripheral blood. This study firstly demonstrates the improved survival and restoration of GVL effects of patients with AML by deferasirox, which also clarifies the detrimental effect of hyperferritinemia through after allo‐HSCT.

The incidence of Philadelphia chromosome positivity (Ph+) in adults with acute myeloid leukemia (AML) is very low. Ph+ AML is considered to be high risk for failure to attain remission or for early relapse after standard chemotherapy. Because of the low incidence of the disease, it has been difficult to determine the best treatment, including the effects of tyrosine kinase inhibitors. We retrospectively analyzed 29 patients with Ph+ AML (median age, 45 years; range, 18 to 80) managed at our center between 2002 and 2016. Two patients were not treated at all, 3 received repeated low-dose cytarabine, and 24 were treated with 3 + 7 standard induction chemotherapy. All 27 treated patients also received interim imatinib 400 mg orally until the day of the next chemotherapy cycle began or as conditioning for allogeneic hematopoietic cell transplantation (HCT), which was performed in 17 patients. Of the 29 patients with Ph+ AML, 7 (24.1%) had additional inv(16), 3 of whom had therapy-related AML. In the 7 with inv(16), the median age was younger (31 versus 44 years, P = .083) and the complete remission (CR) rate was relatively higher (85.7% versus 54.5%, P = .214) than in those without inv(16). Among the 27 treated patients, 20 (74.1%) achieved CR after standard chemotherapy with interim imatinib and 2 (7.4%) achieved CR after low-dose cytarabine with interim imatinib. After a median follow-up of 65.5 months (range, 13.4 to 156.6), the 5-year overall survival (OS) among all 27 treated patients was 43.1%. For the 17 patients who underwent HCT the 5-year OS of 17 patients (10 in subgroup without inv(16) and 7 in subgroup with inv(16)) treated with allogeneic HCT was 69.3%. All 7 with inv(16) were still alive at the end of the study. In contrast, all patients not treated with HCT died within a median of 6.25 months (range, .2 to 18.2). Interim imatinib combined with chemotherapy yielded an acceptable remission rate in adult patients with Ph+ AML. Allogeneic HCT as a postremission therapy provided long-term disease control in two-thirds of those who underwent the transplant. We also demonstrated that inv(16) was related to a favorable outcome in Ph+ AML, including therapy-related AML.

OBJECTIVES We intended to identify the predictive abilities of recently published transplant-specific prognostic scoring systems in patients with myelodysplastic syndrome (MDS) receiving haploidentical transplantation. METHODS The outcomes of 73 patients with MDS receiving haploidentical transplantation were analyzed, according to the MTPSS, the TRI, and the CIBMTR scoring systems. RESULTS The median age of patients at transplantation was 50 (range, 19-69) years. The IPSS-R cytogenetic risks of very good/good, intermediate, and poor/very poor were, respectively, observed in 35 (48.0%), 25 (34.2%), and 13 (17.8%) patients, including 4 (5.5%) with a monosomal karyotype. Pretransplant treatment failure and high (≥3) HCT-CI were observed in 30 (41.1%) and 35 (48.0%) patients, respectively. With survivor's median follow-up of 42.3 months, the overall survival rate at 4 years of all patients was 65.5% (95% CI, 52.4-75.9). The MTPSS (100%, 77.3%, 62.5%, and 42.0% at 4 years; P = .02) and the TRI (100%, 79.9%, 76.0%, and 17.1% at 4 years; P

Although vascular endothelial growth factor-C (VEGF-C) is known to be expressed in acute myeloid leukemia (AML) blasts, the relevance of VEGF-C in the clinical setting remains to be fully explored. We examined the effect of VEGF-C on achievement of complete remission (CR) in adult de novo AML and immune cell population profiles according to VEGF-C mRNA expression. In comparison of VEGF-C expression between the no-CR and CR groups, the CR group showed a trend toward higher levels of plasma VEGF-C (P = .088), whereas mRNA expression of VEGF-C was downregulated (P = .008). Next, patients with continuous data for VEGF-C were divided into two groups (low vs. high) by a ROC curve analysis. The low- versus high-level groups for plasma VEGF-C (RR of 0.20, P = .030), mRNA expression of VEGF-C (RR of 18.75, P = .003), and the ratio of plasma level to mRNA expression (RR of 0.05, P = .007) were potential predictors of CR on univariate analysis. After adjusting for potential clinical factors including genetic group, multivariate analyses revealed that high VEGF-C mRNA expression was an independent risk factor for failure of induction chemotherapy. Furthermore, patients with high VEGF-C mRNA expression had a lower frequency of NKT and CD8+ cells and showed a trend for a lower frequency of NK cells. These results suggest that interruption of VEGF-C signaling might be a potential therapeutic target for antileukemic treatment in AML patients.

The recovery of myeloid-derived suppressor cells (MDSCs) and its relevance in clinical acute graft-versus-host disease (GVHD) and post-hematopoietic stem cell transplantation (HSCT) infections remain to be fully characterized. We examined the expansion of circulating monocytic (M-) MDSCs and granulocytic (G-) MDSCs at the time of engraftment in 130 patients undergoing allogeneic HSCT (allo-HSCT). Compared with the G-MDSC group, the high M-MDSC group had a higher infection rate within 100 days, along with worse 1-year cumulative incidence of treatment-related mortality (TRM) and 2-year probability of event-free survival (EFS). The frequency of M-MDSCs was associated with preceding severe mucositis. Transcriptome profiling analysis of 2 isolated MDSC subtype showed significantly greater matrix metalloproteinase-9 (MMP-9) expression in M-MDSCs than in G-MDSCs. M-MDSCs produced abundantly more MMP-9. Importantly, compared with G-MDSCs, M-MDSCs isolated from patients post-HSCT had a greater capacity to suppress T cell responses, and MMP-9 blockade more forcefully inhibited their immunosuppressive effect. MMP-9 levels also were associated with the occurrence of infections and with transplantation outcomes. Based on these findings, we identify M-MDSCs as a major contributor to infections early after allo-HSCT and worse clinical outcomes via MMP-9.

Stem cell transplantation (SCT) from an unrelated donor (URD) is often considered in patients with severe aplastic anemia (SAA) whom immunosuppressive therapy failed and matched sibling donor is not available. To reduce the incidence of graft-versus-host disease (GVHD) in URD SCT, introducting antithymocyte globulin (ATG) into the conditioning regimen has been proposed. Although ATG was shown to play a role in reducing GVHD in a cohort with diverse hematologic diseases, its role in SAA remains uncertain. The aim of this study was to determine the efficacy and toxicity of ATG in URD SCT for adult patients with SAA. We investigated 83 adult patients with SAA who underwent URD SCT between 2003 and 2014. The transplantation strategy consisted of total body irradiation (total 800 cGy) and cyclophosphamide (total 100 mg/kg to 120 mg/kg), followed by tacrolimus and a short-term methotrexate. We divided patients into 2 groups: group 1 (n = 25), which received HLA-matched (8/8) bone marrow (BM) without ATG, and group 2 (n = 58), which received SCT from either an HLA-mismatched donor or peripheral blood (PB). Thereafter, group 2 was subdivided according to ATG use into group 2A (without ATG, n = 26), which served as a historical cohort, and group 2B (with ATG, n = 32). Rabbit ATG (Thymoglobulin; Genzyme-Sanofi, Lyon, France) was used in group 2B at a dose of 2.5 mg/kg. The median age of all patients was 30 years (range, 17 to 59 years). The incidence of GVHD was significantly lower in group 2B than group 2A, as demonstrated by the rate of grade II to IV acute GVHD at day 100 (31.2% versus 61.5%, P = .003) and the rate of chronic GVHD at 3 years (21.9% versus 65.4%, P = .002). The overall survival rates of the 3 groups were similar. However, GVHD-free, failure-free survival (GFFS) was significantly higher in group 2B than group 2A (P = .034). A multivariable model identified use of ATG as an independent factor affecting grades II to IV acute GVHD (hazard ratio [HR], 2.902; 95% confidence interval [CI], 1.417 to 5.942; P = .004), chronic GVHD (HR , 3.005; 95% CI, 1.279 to 7.059; P = .012), and GFFS (HR, 2.363; 95% CI, 1.162 to 4.805; P = .014). Toxicities, including infectious complications, were not different among the 3 groups. In conclusion, low-dose ATG (2.5 mg/kg) can reduce the incidence of acute and chronic GVHD and improve the quality of life in patients with SAA who receive stem cells from either an HLA-mismatched donor or PB; importantly, these benefits are achieved without increased toxicity. Furthermore, ATG can be considered in URD SCT from HLA-matched BM cells.

This retrospective study aimed to compare the clinical features of paramedullary lesions (PLs) and extramedullary lesions (ELs) of plasmacytomas at diagnosis, using positron emission tomography integrated with computed tomography, using glucose labeled with the positron-emitting radionuclide 18F (18F-FDG-PET/CT) in newly diagnosed multiple myeloma (NDMM), and to address their prognostic impact. Sixty-four patients with NDMM presenting ELs (n=22) and/or PLs (n=42) were included. Patients with ELs at initial presentation had unfavorable laboratory parameters of calcium and lactate dehydrogenase, a higher percentage of bone marrow plasma cells, and showed a trend toward advanced international staging system (ISS), compared to patients with PLs. Using X-ray imaging, high bone disease (HBD) was observed in 50% and 71% of patients with ELs and PLs, respectively. After a median follow-up of 29.2 months (range, 3.4-76.5 months) in survivors, patients with ELs had a significantly lower overall survival (OS) (p=0.033) than patients with PLs did, whereas the progression-free survival (PFS) did not differ significantly (p=0.818). However, the PFS after 1st progression was significantly worse in patients with ELs than in those with PLs (p=0.017). In the multivariate analyses, the negative impact of initial ELs on OS (p=0.033) was sustained. Our results demonstrated the different clinical features and outcomes of ELs and PLs in NDMM. Patients with initial ELs showed a shorter PFS after 1st progression, which translated into poor OS, providing insight into the different biological effect of ELs.

Objective Short tandem repeat (STR) loci are most frequently used for chimerism analysis after hematopoietic stem cell transplantation (HSCT). The aim of this study was to evaluate the practical informativeness of STR chimerism by integrating theoretical and analytical points. Methods Theoretical and practical informativess of 16 STR loci were evaluated from 1249 pairs of recipients and donors who were prepared for HSCT. Results Theoretical informativeness was influenced by genetic diversity including allele frequency and heterozygosity, and was higher in the unrelated HSCT group (90.5 ± 5.3%) compared to the related HSCT group (66.2 ± 4.4%). Practical informativeness was lower than theoretical (6.1 ± 1.7%) because several STR loci were excluded due to stutter peaks and less reliable results, especially in type II-2 donor-recipient match pattern with no recipient-specific allele. We simulated an efficient STR combination for reliable chimerism analysis. Eight informative STR loci were required to analyze chimerism with at least one practically informative locus in the related HSCT group (D18S51, FGA, D2S1338, D13S317, D8S1179, D21S11, D16S539 and D7S820) while only three loci were needed in the unrelated group (D2S1338, FGA and D18S51). A minimum set of 2, 4 or 7 STR loci were required to provide at least 1, 3 or 5 practically informative loci in 95% of the unrelated HSCT group while 3, 8 or 12 loci were required in the related HSCT group. Conclusion We deducted the practical informativeness of STR chimerism, identified the major influencing factors on the practical informativeness of each STR locus, and successfully simulated the efficient STR combination for reliable chimerism analysis.

The role of autologous hematopoietic cell transplantation (auto-HCT) for postremission therapy of acute myeloid leukemia is yet to be elucidated. We retrospectively analyzed 240 patients treated with auto-HCT in first remission. All patients were treated with standard induction chemotherapy, and CD34+ stem cells were collected at each cycle of consolidation. Stem cells were infused after total body irradiation (1200 cGy), cytarabine (9 g/m2), and melphalan (100 mg/m2). Estimated 5-year overall survival, disease-free survival (DFS), cumulative incidence of relapse (CIR), and nonrelapse mortality were 58.4%, 55.3%, 38.8%, and 5.9%, respectively. We identified that poor-risk karyotype showed very poor outcome after auto-HCT, and then analyzed 85 patients with good to intermediate-risk molecular cytogenetics with available molecular study results and markers for minimal residual disease (MRD) such as WT1 and core-binding factor (CBF) associated MRD (ie, AML1/ETO and CBFβ/MYH11). Our data identified that old age, pre-HCT markers for MRD, and high post-HCT WT1, high dose of CD34+ stem cell (≥4.5 × 106/kg) infusion, and c-kit or FLT3-ITD mutations were associated with higher relapse rate and poor DFS. Using pre-HCT parameters, except for post-HCT WT1, multivariate analysis revealed that patients with young age (

Although the antimyeloma effect of lenalidomide is associated with activation of the immune system, the exact in vivo immunomodulatory mechanisms of lenalidomide combined with low-dose dexamethasone (Len-dex) in refractory/relapsed multiple myeloma (RRMM) patients remain unclear. In this study, we analyzed the association between immune cell populations and clinical outcomes in patients receiving Len-dex for the treatment of RRMM. Peripheral blood samples from 90 RRMM patients were taken on day 1 of cycles 1 (baseline), 2, 3, and 4 of Len-dex therapy. Peripheral blood CD3(+), CD4(+), and CD8(+) cell frequencies were significantly decreased by 3 cycles of therapy, whereas NK cell frequency was significantly increased after the 3rd cycle. For the myeloid-derived suppressor cell (MDSC) subset, the frequency of granulocytic MDSCs transiently increased after the 1st cycle, whereas there was an increase in monocytic MDSC (M-MDSC) frequency after the 1st and 3rd cycles. Among 81 evaluable patients, failure to achieve a response of VGPR or greater was associated with a decrease in CD8(+) cell frequency and increase in M-MDSC frequency after 3 cycles of Len-dex treatment. A high proportion of natural killer T (NKT)-like cells (CD3(+)/CD56(+)) prior to Len-dex treatment might predict a longer time to progression. In addition, patients with a smaller decrease in the frequency of both CD3(+) cells and CD8(+) cells by 3 cycles exhibited a longer time to the next treatment. These results demonstrated that early changes in immune cell subsets are useful immunologic indicators of the efficacy of Len-dex treatment in RRMM.

Podoplanin+ cells are indispensable in the tumor microenvironment. Increasing evidence suggests that podoplanin may support the growth and metastasis of solid tumors; however, to the best of our knowledge no studies have determined whether or not podoplanin serves a supportive role in acute myeloid leukemia (AML). The effects of co‑culture with podoplanin+ cells on the cellular activities of the leukemic cells, such as apoptosis and cell proliferation, in addition to the expression of podoplanin in leukemic cells, were investigated. Due to the fact that genetic abnormalities are the primary cause of leukemogenesis, the overexpression of the fibromyalgia‑like tyrosine kinase‑3 gene in colony forming units was also examined following cell sorting. Podoplanin+ cells were found to play a protective role against apoptosis in leukemic cells and to promote cell proliferation. Tumor‑associated antigens, including Wilms' tumor gene 1 and survivin, were increased when leukemic cells were co‑cultured with podoplanin+ cells. In combination, the present results also suggest that podoplanin+ cells can function as stromal cells for blast cell retention in the AML tumor microenvironment.

Cytomegalovirus (CMV)-reactivation is associated with graft-vs-leukemia (GVL) effect by stimulating natural-killer or T-cells, which showed leukemia relapse prevention after hematopoietic stem cell transplantation (HSCT). We enrolled patients with acute myeloid leukemia (n = 197) and acute lymphoid leukemia (n = 192) who underwent allogeneic-HSCT in first remission. We measured RQ-PCR weekly to detect CMV-reactivation and preemptively used ganciclovir (GCV) when the titer increased twice consecutively, but GCV was sometimes delayed in patients without significant graft-vs-host disease (GVHD) by reducing immunosuppressive agents. In the entire group, CMV-reactivation showed poor overall survival (OS). To evaluate subsequent effects of CMV-reactivation, we excluded early relapse and deaths within 100 days, during which most of the CMV-reactivation occurred. Untreated CMV-reactivated group (n = 173) showed superior OS (83.8% vs. 61.7% vs. 74.0%, p < 0.001) with lower relapse rate (10.1% vs 22.1% vs. 25.5%, p = 0.004) compared to GCV-treated CMV-reactivated group (n = 122) and CMV-undetected group (n = 42). After excluding chronic GVHD, untreated CMV-reactivated group still showed lower relapse rate (9.4% vs. 24.1% vs. 30.2%, p = 0.006). Multivariate analysis showed adverse-risk karyotype and patients in other than untreated CMV-reactivated group were independent factors for relapse prediction. Our data showed possible GVL effect of CMV-reactivation and minimizing antiviral therapy may benefit for relapse prevention in acute leukemia.

Previously, we found that dual therapy by the CXCR4 inhibitor Plerixafor and cytosine arabinoside (Ara-C) effectively eradicated leukemia cells and concurrently activated immune cells in acute myeloid leukemia (AML). To reveal the significance of programmed death-ligand1 (PD-L1) in AML and as a strategic approach, we investigated the anti-leukemic effect of a triple combinational therapy by utilizing Plerixafor and anti-PD-L1 in combination with chemotherapy in an AML mouse model. We examined leukemic myeloid blast cells in multiple organs after the successive treatment with Ara-C, Plerixafor, and anti-PD-L1. The results showed that noticeable benefits of triple combinational therapy for eradication of myeloid blast cells in vivo with prolonged survival rates. The frequencies of regulatory T cells (Tregs), monocytic-myeloid-derived suppressor cells (M-MDSCs), and granulocytic-myeloid-derived suppressor cells (G-MDSCs), in the peripheral blood of leukemic mice were consistently decreased, even when mice were sacrificed alive at D + 26 after completion of the triple combinational therapy, compared to the other subgroups. These findings imply that the modulation by the triple combinational therapy may lead to more efficient leukemic myeloid blast cell ablation through the suppression of Tregs or M-MDSCs and G-MDSCs in AML. Although Plerixafor and PD-L1 antagonist do not have a direct anti-leukemic role, our results provide some clues and guidelines to develop clinically therapeutic strategies for chemotherapy-resistant patients by the modulation of leukemic microenvironments.

The bone marrow microenvironment (BMM) provides a protective niche that supports the growth and survival of leukemic stem cells. It is known that a regulation of homing to BM and retention of hematopoietic stem cells (HSCs) occur by SDF-1/CXCR4 axis in BMM. Previously, we found that altering the BMM by the CXCR4 antagonist led to enhanced cytotoxic activity of immune cells, which leads to increased susceptibility of leukemic cells to chemotherapeutic agents such as cytosine arabinoside (Ara-C) in leukemic BMM. However, no reports have yet shown an architectural change of BMM such as the sinusoidal vessel and megakaryocyte by plerixafor treatment. Thus, we performed immunohistochemistry and observed that the capillary density of sinusoidal vessels was highly increased by CXCR4 antagonist with Ara-C in leukemia, showing the reconstruction of BMM with megakaryocytes in sinusoidal vessels by dual treatment. The number of megakaryocytes was also increased in the Plerixafor treated group, compared to that of leukemic or wild groups. Ultimately, we addressed the normalization of megakaryocyte and BMM in leukemia by showing the reconstitution of the sinusoidal vasculature by Plerixafor. This study proposed that chemotherapy with CXCR4 antagonist represents an advanced therapeutic strategy of targeting the leukemic niche.

Core-binding factor acute myeloid leukemia (CBF-AML) data in Asian countries has been rarely reported. We analyzed 392 patients with CBF-AML [281 with t(8;21), 111 with inv.(16)/t(16;16)] among data from 3041 patients with AML from the Korean AML Registry. Interestingly, del(9q) was less frequently detected in Korean than in German patients with t(8;21) (7.5% vs. 17%), and del(7q) was more frequently detected in Korean patients with inv(16). Overall survival (OS) was similar between patients in the first complete remission (CR) who received allogeneic (alloSCT) and autologous stem cell transplantation (ASCT) for CBF-AML. OS of t(8;21) patients was poor when undergoing alloSCT in second/third CR, while OS of inv(16) patients in second/third CR was similar to that in first CR. Patients with > 3-log reduction of RUNX1/RUNX1T1 qPCR had improved 3-year event-free survival (EFS) than those without (73.2% vs. 50.3%). Patients with t(8;21) AML with D816 mutation of the c-Kit gene showed inferior EFS and OS. These poor outcomes might be overcome by alloSCT. Multivariate analysis for OS in patients with t(8;21) revealed older age, > 1 course of induction chemotherapy to achieve CR, loss of sex chromosome, del(7q), and second/third CR or not in CR before SCT as independent prognostic variables. Especially, del(7q) is the most powerful prediction factor of poor outcomes, especially in patients with t(8;21) (hazard ratio, 27.23; P

The aim of this study was to explore if measurement of pretransplant circulating CD161-expressing cells, in addition to clinical risk factors, could predict mucositis and infections in patients with multiple myeloma (MM) undergoing autologous stem cell transplantation (ASCT). To determine if CD161-expressing cells are likely to predict early complications, namely, mucositis (≥grade 3), infections, and cytomegalovirus (CMV) reactivation, we prospectively examined CD161-expressing cells (CD3+CD4+CD161+and CD3+CD8+CD161+) in peripheral blood samples from 108 patients with MM undergoing ASCT. After adjusting for factors identified by univariate analysis that predicted mucositis (≥grade 3), infection before engraftment, and CMV reactivation, multivariate analyses revealed that the low proportion of CD3+CD4+CD161+cells in peripheral blood was an independent predictor of mucositis (≥grade 3) (P=0.020), infections before engraftment (P=0.014), and CMV reactivation (P=0.010). In addition, we found that female sex and decreased glomerular filtration rate were independent factors for predicting mucositis. Female sex and severe pulmonary comorbidity were independent factors for predicting infection before engraftment. We found that the proportion of circulating CD3+CD4+CD161+cells is useful for predicting the occurrence of early complications, including mucositis and infections, after ASCT in patients with MM.