Kimikazu Yakushijin

Changes in incidence and causes of non-relapse mortality after allogeneic hematopoietic cell transplantation in patients with acute leukemia/myelodysplastic syndrome: an analysis of the Japan Transplant Outcome Registry

The outcomes for allogeneic hematopoietic cell transplantation (allo-HCT) are heavily influenced by non-relapse mortality (NRM). We retrospectively assessed the changes in the incidence and causes of NRM after allo-HCT over the past 12 years. NRM, relapse rate and OS were analyzed using the Japan transplant outcome database of 6501 adult patients with acute leukemia or myelodysplastic syndrome who received their first allo-HCT in remission from 1997 through 2008. In multivariate analysis in patients aged 16–49 years, the adjusted hazard ratios (HRs) for NRM for 2001–2004 and 2005–2008 were 0.78 (95% confidence interval, 0.65–0.93) and 0.64 (0.54–0.78), respectively, compared with 1997–2000. The HR for overall mortality in 2005–2008 was 0.81 (0.70–0.93) compared with 1997–2000. In patients aged 50–70 years, the HRs for NRM and overall mortality in 2005–2008 were 0.56 (0.46–0.68) and 0.66 (0.47–0.93), respectively, compared with those in 2001–2004. We found that causes of death that contributed to the changes in NRM varied among subgroups. In conclusion, our study indicated that the incidence of NRM after allo-HCT has significantly decreased over the past 12 years, which has led to an improvement of OS, and also showed reductions in NRM in subgroups consisting of older patients and those who received unrelated cord blood transplantation.

Methotrexate-associated lymphoproliferative disorders: management by watchful waiting and observation of early lymphocyte recovery after methotrexate withdrawal

No optimum treatment of iatrogenic immunodeficiency-associated lymphoproliferative disorders due to methotrexate in patients with rheumatoid arthritis (MTX-LPD) has yet been established, although MTX withdrawal is known to have a substantial effect on tumor regression. Here, we retrospectively analyzed 20 cases of MTX-LPD. Tumor shrinkage occurred in 18 of 20 cases, but only following MTX withdrawal. This tumor regression ratio was considerably better than in previous reports, and appeared due to longer “watchful waiting.” Lymphocyte recovery at 2 weeks after MTX withdrawal was significantly higher in cases with tumor regression in 1 month than in those without tumor regression (p = 0.001). Median time to maximal efficacy after MTX cessation in cases without chemotherapy was 12 weeks (range 2–76). In conclusion, watchful waiting for a longer period after MTX cessation with observation of early lymphocyte recovery and uninterrupted continuation of other anti-rheumatoid drugs may be an acceptable management plan for MTX-LPD.

The role of transcriptional coactivator TRAP220 in myelomonocytic differentiation

The TRAP220 subunit of the thyroid hormone receptor‐associated polypeptide transcription coactivator complex (TRAP/Mediator complex), mammalian counterpart of the yeast Mediator complex, is proposed to act on a variety of major and specific biological events through physical interactions with nuclear receptors. The vitamin D receptor (VDR) and retinoic acid receptor (RAR), coupled with retinoid X receptor (RXR), are nuclear receptors which have important roles for monopoiesis and granulopoiesis, respectively. In this study, we present the functional role of TRAP220 in nuclear receptor‐mediated monopoiesis and granulopoiesis. The mouse Trap220−/– yolk sac hematopoietic progenitor cells were resistant to 1,25‐dihydroxyvitamin D3‐stimulated differentiation into monocytes/macrophages. Furthermore, flow cytometric analyses showed that HL‐60 cells, human promyelocytic leukemia cell line, wherein TRAP220 was down‐regulated, did not differentiate efficiently into monocytes and granulocytes by stimulation with 1,25‐dihydroxyvitamin D3 and all‐trans retinoic acid, correspondingly. The expression of direct target genes of VDR or RAR, as well as the differentiation marker genes, was low in the knockdown cells. These results indicated a crucial role of TRAP220 in the optimal VDR‐ and RAR‐mediated myelomonocytic differentiation processes in mammalian hematopoiesis.

Feasibility of Reduced-Intensity Cord Blood Transplantation as Salvage Therapy for Graft Failure: Results of a Nationwide Survey of Adult Patients

To evaluate whether rescue with cord blood transplantation (CBT) could improve the poor survival after graft failure (GF), we surveyed the data of 80 adult patients (median age, 51 years) who received CBT within 3 months of GF (primary 64, secondary 16), with fludarabine-based reduced-intensity regimens with or without melphalan, busulfan, cyclophosphamide, and/or 2-4 Gy total-body irradiation (TBI). A median number of 2.4 × 10(7)/kg total nucleated cells (TNC) were infused, and among the 61 evaluable patients who survived for more than 28 days, 45 (74%) engrafted. The median follow-up of surviving patients was 325 days, and the 1-year overall survival rate was 33% despite poor performance status (2-4, 60%), carryover organ toxicities (grade 3/4, 14%), and infections (82%) prior to CBT. Day 100 transplantation-related mortality was 45%, with 60% related to infectious complications. Multivariate analysis showed that the infusion of TNC ≥2.5 × 10(7)/kg and an alkylating agent-containing regimen were associated with a higher probability of engraftment, and that high risk-status at the preceding transplantation and grade 3/4 organ toxicities before CBT were associated with an increased risk of mortality. In conclusion, in an older population of patients, our data support the feasibility of CBT with a reduced-intensity conditioning regimen for GF.

A biphenotypic transformation of 8p11 myeloproliferative syndrome with CEP1/FGFR1 fusion gene

Abstract:  We describe here the first case of 8p11 myeloproliferative syndrome (EMS) with t(8;9)(p11;q33), who unusually demonstrated B‐lymphoblastic/monoblastic biphenotypic transformation. A 57‐year‐old woman was admitted because of leukocytosis and diagnosed as EMS. Bone marrow was infiltrated with myeloperoxidase (MPO)‐, CD10+, CD19+, CD20+, CD34+, HLA‐DR+ small lymphoblasts and MPO+, CD2+, CD4+, CD13+, CD14+, CD33+, HLA‐DR+ large monoblasts. The karyotype was 46,XX,t(8;9)(p11;q33)[20] and the CEP1/FGFR1 fusion transcript between CEP1 exon 38 and FGFR1 exon 9 was detected. This case clearly indicates that the blastic transformation in EMS with t(8;9) could arise in the stem cells, which differentiate into not only myelomonocytic but also B‐lymphocytic lineages.

Sinusoidal obstruction syndrome after allogeneic hematopoietic stem cell transplantation: Incidence, risk factors and outcomes

This retrospective study was conducted in Japan to determine the incidence, risk factors and outcomes of sinusoidal obstruction syndrome (SOS) after allogeneic hematopoietic stem cell transplantation (HSCT). Among 4290 patients undergoing allogeneic HSCT between 1999 and 2010, 462 were diagnosed with SOS according to the Seattle criteria (cumulative incidence, 10.8%). The cumulative incidence of SOS diagnosed by the modified Seattle criteria was 9.3%. Of 462 patients, 107 met the Baltimore criteria and 168 had severe SOS with renal and/or respiratory failure. The median onset for SOS was 12 days after HSCT (range, −2–30). Overall survival at day 100 was 32% for SOS and 15% for severe SOS. Multivariate analyses showed that significant independent risk factors for SOS were the number of HSCTs, age, performance status, hepatitis C virus-seropositivity, advanced disease status and myeloablative regimen. SOS was highly associated with overall mortality (hazard ratio, 2.09; P<0.001). Our retrospective survey showed that the cumulative incidence of SOS in Japan was 10.8%, similar to that previously reported in Western countries, and that the overall survival of patients who developed SOS was low. Furthermore, several risk factors were identified. Preventive and therapeutic strategies for high-risk SOS patients must be established to improve overall survival.

Impact of hepatitis C virus infection on clinical outcome in recipients after allogeneic hematopoietic cell transplantation

The impact of hepatitis C virus (HCV) infection on outcomes following allogeneic hematopoietic cell transplantation (HCT) remains a matter of debate. We have retrospectively examined the significance of HCV infection among recipients who received allogeneic HCT, using a Japan transplant outcome registry database between 2006 and 2009. Among 7,831 recipients, 136 were HCV‐positive. The rate of hematopoietic recovery was lower in the HCV‐positive group (neutrophil recovery of 500 × 106/L or higher: 79% vs. 87% at Day 30, P = 0.087; platelet recovery of 50 × 109/L or higher: 57% vs. 65% at Day 60, P = 0.012). The HCV‐positive group had a significantly higher incidence of nonrelapse mortality 38% vs. 25% at 2 years, P < 0.01) and inferior overall survival (41% vs. 51% at 2 years, P < 0.01). A multivariate analysis revealed that HCV seropositivity was associated with an independent risk for higher nonrelapse mortality (hazard ratio: 1.65, P < 0.01) and inferior overall survival (hazard ratio: 1.39, P < 0.01). The incidences of death due to hepatic problems (8% vs. 2%, P < 0.01), bacterial infection (10% vs. 4%, P < 0.01), or graft failure (5% vs. 2%, P = 0.084) tended to be higher in the HCV‐positive group. HCV infection had an adverse impact on the clinical outcome following HCT, especially in the setting of unrelated transplantation. Careful evaluation before embarking on HCT and intensive assessment against complications are warranted in HCV‐infected recipients. Am. J. Hematol. 88:477–484, 2013.

A novel RDH5 gene mutation in a patient with fundus albipunctatus presenting with macular atrophy and fading white dots

PURPOSE To report a novel homozygous RDH5 gene mutation in a 76-year-old fundus albipunctatus who developed macular atrophy with the disappearance of white dots. DESIGN Observational case report. METHODS Direct genomic sequencing for RDH5 mutations was done after complete ophthalmic examination. RESULTS Fundoscopy revealed only macular atrophy with notable absence of white dots. A homozygous G490T (Val164Phe) missense RDH5 gene mutation was detected. CONCLUSIONS This is the first reported long-term case of fundus albipunctatus demonstrating macular atrophy with fading of the typical white dots. Gene studies may be the only method for distinguishing fundus albipunctatus from other types of macular atrophy in the elderly.

Severe weight loss in 3 months after allogeneic hematopoietic SCT was associated with an increased risk of subsequent non-relapse mortality

Patients after allogeneic hematopoietic SCT (HSCT) are at risk of malnutrition. To assess the impact of malnutrition after allogeneic HSCT on transplant outcomes, we conducted a retrospective study. Adult patients who received allogeneic HSCT from 2000 to 2009 for standard-risk leukemia and achieved disease-free survival up to 3 months after allogeneic HSCT were included. From participating centers, 145 patients were enrolled. Median age was 46 years (19–68). Patients were classified based on weight loss during 3 months after allogeneic HSCT as follows: normal group (weight loss <5%, n=53), mild malnutrition group (5%⩽weight loss<10%, n=47), severe malnutrition group (10% ⩽weight loss, n=45). The cumulative incidences of 2-year nonrelapse mortality (NRM) were 3.8% in the normal group, 8.5% in the mild malnutrition group and 27.3% in the severe malnutrition group. The probabilities of a 2-year OS were 73.2% in the normal group, 74.5% in the mild malnutrition group and 55.3% in the severe malnutrition group. In multivariate analysis, severe malnutrition was associated with an increased risk of NRM and a worse OS. In conclusion, weight loss ⩾10% was associated with a worse clinical outcome. Prospective studies that identify patients at risk of malnutrition and intervention by a nutritional support team are warranted.

Recent decrease in non-relapse mortality due to GVHD and infection after allogeneic hematopoietic cell transplantation in non-remission acute leukemia

Although recent improvements have been indicated in the outcome after allogeneic hematopoietic cell transplantation (allo-HCT), little information is available on how changes in transplant modalities have affected the outcomes after allo-HCT in non-remission, based on patient age, donor source and disease type. We compared the incidence and causes of non-relapse mortality (NRM) after allo-HCT in non-remission among three consecutive four-year periods using a nationwide transplant outcome registry database. A total of 3308 patients with acute leukemia in non-remission were analyzed. The risk of NRM decreased over the three periods, and the hazard ratios (HRs) in 2001–2004 and 2005–2008 compared with 1997–2000 were 0.86 (95% CI, 0.70–1.06; P=0.16) and 0.65 (95% CI, 0.53–0.80; P<0.01), respectively. A significant decrease in the HR for overall mortality was also observed in 2005–2008 (HR 0.85; 95% CI, 0.75–0.97; P=0.02). We found that a decrease in the incidences of death due to GVHD and infection contributed to the reduction in NRM, to which high-resolution donor-recipient HLA matching and other improvements may have contributed. As none of the subgroups showed improved survival without a reduction in NRM, the effective prevention of transplant-related complications appears to be necessary for improving outcomes after allo-HCT in non-remission.