Satoshi Nishiwaki

Allogeneic stem cell transplantation for adult Philadelphia chromosome-negative acute lymphocytic leukemia: comparable survival rates but different risk factors between related and unrelated transplantation in first complete remission

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.

Clinicopathological manifestations and treatment of intestinal transplant-associated microangiopathy

Intestinal transplant-associated microangiopathy (i-TAM) is an important complication after allogeneic hematopoietic SCT. From 1997 to 2006, 87 of 886 patients with diarrhea after transplantation received colonoscopic biopsy. i-TAM, GVHD and CMV colitis were diagnosed histopathologically. The median duration from transplantation to the onset of diarrhea was 32 days (range: 9–130 days) and that from the onset of diarrhea to biopsy was 12 days (range: 0–74 days). The median maximal amount of diarrhea was 2 l/day (range: 130–5600 ml/day). Histopathological diagnosis included i-TAM (n=80), GVHD (n=26), CMV colitis (n=17) and nonspecific findings (n=2) with overlapping. Among 80 patients with i-TAM, abdominal pain was a major symptom, and only 11 patients fulfilled the proposed criteria for systemic TAM. Non-relapse mortality (NRM) among patients without resolution of diarrhea was 72% and i-TAM comprised 57% of NRM. NRM was 25% among patients without intensified immunosuppression, but was 52, 79 and 100% among those with intensified immunosuppression before diarrhea, after diarrhea, and before and after diarrhea, respectively. In conclusion, i-TAM is a major complication presenting massive refractory diarrhea and abdominal pain, which causes NRM. Avoiding intensified immunosuppression that damages vascular endothelium until the resolution of i-TAM may improve transplant outcome.

Impact of macrophage infiltration of skin lesions on survival after allogeneic stem cell transplantation: a clue to refractory graft-versus-host disease

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 x200, the infiltration of more than 200 cells of CD163(+) macrophages (many macrophages [MM]) was the only significant predictor for refractory GHVD (odds ratio, 3.79; 95% confidence interval, 1.22-11.8; P = .02). In 46 patients given steroid treatments, MM was the only significant predictor for refractory acute GVHD (odds ratio, 5.05; 95% confidence interval, 1.19-21.3; P = .03). Overall survival of patients with MM was significantly lower than that of those with an infiltration of less than 200 cells of CD163(+) macrophages. Macrophage infiltration of skin lesions could be a significant predictive factor for refractory GVHD and a poor prognosis.

Mesenchymal Stem Cells Stably Transduced with a Dominant-Negative Inhibitor of CCL2 Greatly Attenuate Bleomycin-Induced Lung Damage

Acute respiratory distress syndrome (ARDS) is a crippling disease with no effective therapy characterized by progressive dyspnea. Mesenchymal stem cells (MSCs) have emerged as a new therapeutic modality for ARDS because MSCs can attenuate inflammation and repair the damaged tissue by differentiating into several cell types. Macrophages participate in the development of ARDS; however, MSCs only weakly modulate macrophage function. The chemokine CCL2 is a potent inducer of macrophage recruitment and activation, and its expression is elevated in patients with ARDS. We established MSCs that are stably transduced by a lentiviral vector expressing 7ND, a dominant-negative inhibitor of CCL2, to enhance the therapeutic function of MSCs. 7ND-MSCs retained the innate properties of MSCs and produced a large amount of 7ND. Many 7ND-MSCs were detected in bleomycin-treated lungs (immunostaining 24 hours after injection), suggesting that MSCs could work as a drug delivery tool. Mice treated with 7ND-MSCs showed significantly milder weight loss, lung injury, collagen content, accumulation of inflammatory cells and inflammatory mediators that were induced by bleomycin, and subsequent survival benefit. No evidence of 7ND-MSC-induced toxicity was observed during or after treatment. Thus, inhibiting the effects of macrophages may greatly enhance the ability of MSCs to effect lung repair in ARDS.

Pretransplant administration of imatinib for allo-HSCT 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(+)) acute lymphoblastic leukemia (ALL). We retrospectively analyzed 738 patients with Ph(+) 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 = .048), and nonrelapse mortality (HR, 0.55; 95% CI, 0.37-0.83; P = .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(+) ALL.

Mast cells promote the growth of Hodgkin's lymphoma cell tumor by modifying the tumor microenvironment that can be perturbed by bortezomib

Hodgkins lymphoma is frequently associated with mast cell infiltration that correlates directly with disease severity, but the mechanisms underlying this relationship remain unclear. Here, we report that mast cells promote the growth of Hodgkins tumor by modifying the tumor microenvironment. A transplantation assay shows that primary murine mast cells accelerate tumor growth by established Hodgkins cell lines, and promote marked neovascularization and fibrosis. Both mast cells and Hodgkins cells were sensitive to bortezomib, but mast cells were more resistant to bortezomib. However, bortezomib inhibited degranulation, PGE2-induced rapid release of CCL2, and continuous release of vascular endothelial growth factor-A from mast cells even at the concentration that did not induce cell death. Bortezomib-treated mast cells lost the ability to induce neovasculization and fibrosis, and did not promote the growth of Hodgkin tumor in vivo. These results provide further evidence supporting causal relationships between inflammation and tumor growth, and demonstrate that bortezomib can target the tumor microenvironment.

Eosinophilia predicts better overall survival after acute graft-versus-host-disease

The prognostic significance of eosinophilia after allogeneic hematopoietic SCT (HSCT) and the relationship between eosinophilia and acute GVHD are not well studied. We retrospectively analyzed 201 adult patients who underwent their first allogeneic HSCT. Seventy-three (36%) patients developed eosinophilia within the first 100 days after HSCT. Eosinophilia was observed more frequently among those patients with acute GVHD than those without it (48 vs 25%, P=0.009). However, it was associated with milder acute GVHD and lower incidence of gut and liver acute GVHD. Among patients with acute GVHD, the 3-year OS for patients with and without eosinophilia was 63.4 and 47.2% (P=0.02), respectively, and 3-year nonrelapse mortality (NRM) was 20.2 and 37.5% (P=0.01), respectively. Multivariate analysis confirmed that eosinophilia was associated with a better OS (P=0.03) and lower NRM (P=0.046) in patients with acute GVHD, whereas it was not associated with a higher relapse rate (P=0.45). In contrast, eosinophilia was not associated with outcomes in those patients without acute GVHD. In conclusion, eosinophilia was associated with milder acute GVHD and better prognosis among patients with acute GVHD. The pathophysiology behind eosinophilia after allogeneic HSCT remains to be investigated.

Reduced-intensity vs myeloablative conditioning allogeneic hematopoietic SCT for patients aged over 45 years with ALL in remission: a study from the Adult ALL Working Group of the Japan Society for Hematopoietic Cell Transplantation (JSHCT)

In this study, outcomes for 575 adult ALL patients aged ⩾45 years who underwent first allo-SCT in CR were analyzed according to the type of conditioning regimen (myeloablative conditioning (MAC) for 369 patients vs reduced-intensity conditioning (RIC) for 206 patients). Patients in the RIC group were older (median age, 58 vs 51 years, P<0.0001). There were no statistically significant differences in 3-year OS, disease-free survival (DFS) and non-relapse mortality (NRM): 51% vs 53%, 47% vs 39% and 38% vs 36%, respectively. Multivariate analysis showed that CR2 and HLA mismatching were associated with poor OS (P=0.002 and P=0.019, respectively). HLA mismatching was associated with lower rate of relapse (P=0.016), but was associated with higher rate of NRM (P=0.001). RIC was associated with good OS and DFS in patients who received HLA-mismatch transplantation and were aged ⩾55 years compared with MAC by multivariate analysis for each event with interaction (hazard ratio (HR) and 95% confidence interval 0.35 and 0.15–0.81, P=0.014 for OS and 0.36 and 0.16–0.81, P=0.013 for DFS). Therefore, patients ⩾55 years of age with HLA-mismatch transplantation should be candidates for RIC rather than MAC.

Reduced-intensity versus conventional myeloablative conditioning for patients with Philadelphia chromosome–negative acute lymphoblastic leukemia in complete remission

To the editor: We read with interest the results of the comparison between reduced-intensity conditioning (RIC) and conventional myeloablative conditioning (MAC) allogeneic stem cell transplantation (allo-SCT) for patients with acute lymphoblastic leukemia (ALL) in complete remission (CR), reported

Dexamethasone palmitate successfully attenuates hemophagocytic syndrome after allogeneic stem cell transplantation: macrophage-targeted steroid therapy

Hemophagocytic syndrome (HPS) induced by uncontrolled macrophage activation and subsequent graft failure is a frequent and prominent complication after allogeneic stem cell transplantation (allo-SCT), a cause of severe morbidity and death, and a therapeutic challenge. Liposome-incorporated dexamethasone, dexamethasone palmitate (DP), shows greater efficacy against macrophages as compared to dexamethasone sodium phosphate (DSP). Based on our findings that DP achieves significantly larger decrease than DSP on the viability of primary human macrophages compared in vitro, we tested the effects of DP in patients with HPS. A decrease in number of macrophages in the bone marrow and prevention of engraftment failure were observed in all patients without any severe complications. In conclusion, these data provide a rationale for testing DP as a first-line treatment for patients with HPS after allo-SCT.