Koji Iwato

Tacrolimus instead of cyclosporine used for prophylaxis against graft-versus-host disease improves outcome after hematopoietic stem cell transplantation from unrelated donors, but not from HLA-identical sibling donors: a nationwide survey conducted in Japan.

Summary:Despite recent advances, graft-versus-host disease (GVHD) remains the main cause of treatment failure for patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Tacrolimus (FK506) has been increasingly used in place of cyclosporine (CSP), and several studies have shown that FK506 reduces the incidence of acute GVHD more effectively than does CSP. However, no survival benefits have been demonstrated, and no established consensus exists on the choice of these immunosuppressive agents. To compare a CSP-based and an FK506-based regimen, we performed a large-scale retrospective study by using the data of 1935 patients who underwent HSCT from HLA-identical sibling donors (SIB-HSCT) and 777 patients who underwent HSCT from unrelated donors (UD-HSCT). For patients undergoing UD-HSCT, FK506 significantly reduced the risk of acute GVHD and treatment-related mortality (TRM) without an increase in relapse, thus improving overall survival (OS) (hazard ratio (HR): 2.20, 95% confidence interval (CI): 1.60–3.04, P<0.0001 for grade II–IV acute GVHD; HR: 1.81, 95% CI: 1.32–2.48, P=0.0003 for TRM; HR: 1.62, 95% CI: 1.23–2.14, P=0.0007 for OS). This superiority of FK506 was not observed in SIB-HSCT cases. These findings indicate that the use of FK506 instead of CSP for GVHD prophylaxis is beneficial for patients undergoing UD-HSCT.

Related transplantation with HLA-1 Ag mismatch in the GVH direction and HLA-8/8 allele-matched unrelated transplantation: a nationwide retrospective study

To clarify which is preferable, a related donor with an HLA-1 Ag mismatch at the HLA-A, HLA-B, or HLA-DR loci in the graft-versus-host (GVH) direction (RD/1AG-MM-GVH) or an HLA 8/8-allele (HLA-A, HLA-B, HLA-C, and HLA-DRB1)-matched unrelated donor (8/8-MUD), we evaluated 779 patients with acute leukemia, chronic myelogenous leukemia, or myelodysplastic syndrome who received a T cell-replete graft from an RD/1AG-MM-GVH or 8/8-MUD. The use of an RD/1AG-MM-GVH donor was significantly associated with a higher overall mortality rate than the use of an 8/8-MUD in a multivariate analysis (hazard ratio, 1.49; P < .001), and this impact was statistically significant only in patients with standard-risk diseases (P = .001). Among patients with standard-risk diseases who received transplantation from an RD/1AG-MM-GVH donor, the presence of an HLA-B Ag mismatch was significantly associated with a lower overall survival rate than an HLA-DR Ag mismatch because of an increased risk of treatment-related mortality. The HLA-C Ag mismatch or multiple allelic mismatches were frequently observed in the HLA-B Ag-mismatched group, and were possibly associated with the poor outcome. In conclusion, an 8/8-MUD should be prioritized over an RD/1AG-MM-GVH donor during donor selection. In particular, an HLA-B Ag mismatch in the GVH direction has an adverse effect on overall survival and treatment-related mortality in patients with standard-risk diseases.

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.

Increased expression of the c-myc gene may be related to the aggressive transformation of human myeloma cells

Summary. Alteration and abnormal expression of the c‐myc oncogene were investigated in human multiple myeloma. Human myeloma cells were highly purified (more than 95%) from bone marrow aspirates in 14 cases of advanced multiple myelomas and one case of plasma cell leukaemia. Southern blotting revealed that a rearranged configuration of c‐myc gene was found in only one case of them, but this was a novel truncation of the gene in its coding exon II: a rearranged 3·4 kb band was detected by digestion with Xba I using c‐myc exon II probe, but no rearranged band was found using exon III probe. In this case, the truncated c‐myc allele was not transcribed: normal sized (2·4 kb) c‐myc mRNA was markedly expressed, but no aberrant mRNA was detected. On the other hand, by Northern blotting, the nine cases, including the case with the rearranged c‐myc gene, showed increased expression of normal sized (2·4 kb) c‐myc mRNA. Elevated c‐myc mRNA expressions were well related to the in vitro proliferation (3H‐TdR uptake), but not to IL‐6 response. Interestingly, extremely high expressions of c‐myc mRNA were detected in two cases of aggressive myelomas, including the case with the rearranged c‐myc gene, and in one of plasma cell leukaemia. These two cases of aggressive myelomas were the ones who showed the markedly high 3H‐TdR uptakes, and had the common clinical features with the formation of an extramedullary mass and very short survival. These results suggest that the activation of c‐myc gene could induce high proliferative activities and the subsequent aggressive transformation of myeloma cells.

Effect of graft-versus-host disease on the outcome of bone marrow transplantation from an HLA-identical sibling donor using GVHD prophylaxis with cyclosporin A and methotrexate.

The effect of graft-versus-host disease (GVHD) on relapse incidence and survival has been analyzed in several studies, but previous studies included heterogeneous patients. Therefore, we analyzed the data of 2114 patients who received unmanipulated bone marrow graft from an HLA-identical sibling donor with a GVHD prophylaxis using cyclosporin A and methotrexate. Among the 1843 patients who survived without relapse at 60 days after transplantation, 435 (24%) developed grade II–IV acute GVHD. Among the 1566 patients who survived without relapse at 150 days after transplantation, 705 (47%) developed chronic GVHD. The incidence of relapse was significantly lower in patients who developed acute or chronic GVHD, but disease-free survival (DFS) was significantly inferior in patients who developed acute GVHD. A benefit of ‘mild’ GVHD was only seen in high-risk patients who developed grade I acute GVHD. The strongest association between GVHD and a decreased incidence of relapse was observed in patients with standard-risk acute myelogenous leukemia/myelodysplastic syndrome. In conclusion, the therapeutic window between decreased relapse and increased transplant-related mortality due to the development of GVHD appeared to be very narrow.

A decision analysis of allogeneic hematopoietic stem cell transplantation in adult patients with Philadelphia chromosome-negative acute lymphoblastic leukemia in first remission who have an HLA-matched sibling donor

Clinical studies using genetic randomization cannot accurately answer whether adult patients with Philadelphia chromosome-negative acute lymphoblastic leukemia (ALL) who have a human leukocyte antigen (HLA)-matched sibling should undergo allogeneic hematopoietic stem cell transplantation (HSCT) or chemotherapy in first remission, as, in these studies, patients without a sibling donor undergo alternative donor transplantation or chemotherapy alone after a relapse. Therefore, we performed a decision analysis to identify the optimal strategy in this setting. Transition probabilities and utilities were estimated from prospective studies of the Japan Adult Leukemia Study Group, the database of the Japan Society for Hematopoietic Cell Transplantation and the literature. The primary outcome measure was the 10-year survival probability with or without quality of life (QOL) adjustments. Subgroup analyses were performed according to risk stratification on the basis of white blood cell count and cytogenetics, and according to age stratification. In analyses without QOL adjustments, allogeneic HSCT in first remission was superior in the whole population (48.3 vs 32.6%) and in all subgroups. With QOL adjustments, a similar tendency was conserved (44.9 vs 31.7% in the whole population). To improve the probability of long-term survival, allogeneic HSCT in first remission is recommended for patients who have an HLA-matched sibling.

A phase II, open-label, sequential-cohort, dose-escalation study of romiplostim in Japanese patients with chronic immune thrombocytopenic purpura.

This phase II, multicenter, open-label, sequential-cohort, dose-escalation study was designed to evaluate the safety and efficacy of romiplostim, a novel peptibody that increases platelet production, in Japanese patients with chronic immune thrombocytopenic purpura (ITP). Sequential cohorts of four patients each received romiplostim (1, 3, or 6 μg/kg) subcutaneously on days 1 and 8 of the dose-escalation phase. Patients who achieved platelet responses (doubling of baseline platelet counts to ≥50 × 109/L) continued romiplostim weekly during the treatment-continuation phase. Romiplostim produced dose-dependent increases in mean and peak platelet counts. Five patients received romiplostim during the treatment-continuation phase, with platelet counts ≥50 × 109/L maintained in approximately half of the weekly assessments. Romiplostim was well tolerated. No severe, serious, or life-threatening adverse events were reported. No binding antibodies to romiplostim or thrombopoietin were detected. Romiplostim is safe and well tolerated in Japanese patients with chronic ITP and is effective in producing platelet count increases, consistent with the results from studies in non-Japanese patients. On the basis of these findings, a starting dose of 3 μg/kg was recommended for phase III evaluation of romiplostim in Japanese patients with chronic ITP.

Expressions of DNA topoisomerase I and II gene and the genes possibly related to drug resistance in human myeloma cells

Summary In order to clarify the mechanism of drug resistance in human myeloma cells, we investigated the expressions of DNA topoisomerase I and topoisomerase II gene and the genes possibly related to drug resistance; multi‐drug resistant gene 1 (MDR‐1), glutathione S‐transferase class π gene (GST‐π), by Northern blotting. Myeloma cells in eight of 15 cases prior to chemotherapy expressed topoisomerase I mRNA considerably, while the expression of topoisomerase II mRNA was detected weakly in only one of 16 myeloma patients. There was not any correlation between expression of topoisomerase I mRNA and clinical drug resistance. Significant expression of MDR‐1 mRNA and P‐glycoprotein was not detected in 25 cases of multiple myeloma prior to chemotherapy and even after several courses of VAD (vincristine, adriamycin and dexamethasone) therapy by Northern blotting and immunostaining using monoclonal anti‐P‐glycoprotein antibody (MRK‐16), respectively. On the other hand, 16 of 21 myeloma cases showed significant expression of GST‐π protein and GST‐π mRNA with the various strengths, but there was no apparent correlation between GST‐π mRNA expression and clinical response. Therefore these data suggest that expression of the genes we tested may not determine the level of drug resistance in multiple myeloma, but lower or no significant expression of topoisomerase II mRNA in most myeloma cells indicates the possibility that topoisomerase II inhibitors such as VP‐16 and topoisomerase II‐mediated cytotoxic drugs such as adriamycin, are not so effective for the treatment of multiple myeloma.

Impact of cytogenetics on outcome of stem cell transplantation for acute myeloid leukemia in first remission: A large-scale retrospective analysis of data from the Japan Society for Hematopoietic Cell Transplantation

On the basis of transplantation data from the Japan Society for Hematopoietic Cell Transplantation, we retrospectively analyzed the impact of cytogenetics at diagnosis on the outcome of transplantation in 628 patients with acute myeloid leukemia who underwent autologous (n = 200), allogeneic related (n = 363), or allogenic unrelated (n = 65) stem cell transplantation (SCT) at first complete remission. For autologous SCT, patients at good cytogenetic risk had a significantly lower relapse rate (P = .017) and a significantly higher event-free survival (EFS) (P = .013) compared with those at intermediate risk. For allogeneic SCT, patients at good cytogenetic risk had a significantly lower relapse rate (P = .019) and insignificantly higher EFS (P = .093) than those at poor risk. For unrelated SCT, there was no significant difference in relapse rate or EFS between patients at good risk and those at intermediate risk. Comparison of the 3 transplantation modalities revealed that autologous SCT patients had a significantly higher incidence of relapse compared with related or unrelated SCT patients in the intermediate-risk group but not in the good-risk group. However, there were no significant differences in EFS among the 3 transplant modalities in either of these 2 risk groups. In multivariate analysis, cytogenetics was found to be an independent predictor of relapse as well as of treatment failure.

Impact of age on outcomes of allogeneic hematopoietic stem cell transplantation with reduced intensity conditioning in elderly patients with acute myeloid leukemia.

Previous studies have repeatedly reported that increasing age is a significant risk factor for worse outcomes after allogeneic hematopoietic stem cell transplantation (allo‐HSCT) among patients with acute myeloid leukemia (AML). However, more recent studies reported conflicting results regarding the association between age and outcomes in elderly patients. Therefore, we conducted a large‐scale, nationwide retrospective study to examine the impact of age on outcomes of allo‐HSCT with reduced intensity conditioning (RIC) for AML patients who were older than 50 years. Of the 757 patients, 89 patients (11.8%) were 50–54, 249 patients (32.9%) were 55–59, 301 patients (39.8%) were 60–64 and 118 patients (15.6%) were ≥65 years old. The 3‐year overall survival (OS) (47.8, 45.2, 37.9, and 36.6% for patients aged 50–54, 55–59, 60–64, and ≥65 years, respectively, P = 0.24) and nonrelapse mortality (NRM) (24.0, 22.8, 29.2, and 27.6% for patients aged 50–54, 55–59, 60–64, and ≥65 years, respectively, P = 0.49) were not significantly different among the four age groups. Multivariate analysis revealed that increased age had no significant effect on OS or NRM after adjusting for covariates. These results suggested that advanced patient age is not a contraindication for RIC allo‐HSCT in elderly AML patients. Am. J. Hematol. 91:302–307, 2016.