Risk factors for high-dose methotrexate-induced nephrotoxicity.

High-dose methotrexate (MTX) is widely used for the treatment of hematological malignancies. Despite the application of routine supportive care measures, such as intensive fluid hydration and urine alkalinization, nephrotoxicity is still a problem. The present study aimed to evaluate the risk factors for MTX-induced nephrotoxicity. We retrospectively reviewed 88 patients who received a regimen consisting of high-dose MTX (1000 mg/m2) and cytosine arabinoside between 2006 and 2018. Nephrotoxicity (≥ grade 2) was observed in 11 patients. Nephrotoxicity was observed only in patients with a high MTX concentration. Other than the MTX concentration, the serum uric acid level and urine pH at day 1 were associated with nephrotoxicity. A multivariate analysis revealed that urine pH was an independent risk factor for MTX-induced nephrotoxicity. Urine pH < 7.0 at day 1 was a significant risk factor for nephrotoxicity (odds ratio, 8.05; 95% confidence interval 1.95-33.3) and was also a predictor of delayed MTX elimination at 72 h after injection. Among pre-treatment factors, a low serum calcium level predicted urine pH < 7.0 at day 1. In conclusion, the present study suggests that low urine pH at day 1 is an independent risk factor for MTX-induced nephrotoxicity.

Impacts of thymoglobulin in patients with acute leukemia in remission undergoing allogeneic HSCT from different donors.

Antithymocyte globulin (ATG) is widely used to reduce acute graft-versus-host disease (aGVHD) and chronic GVHD (cGVHD). To clarify the different impacts of ATG for conditioning across different donor types, we retrospectively analyzed patients with acute leukemia (n = 6617) who underwent hematopoietic stem cell transplantation between 2008 and 2015 with ATG (n = 279) or without ATG (n = 6338). Because thymoglobulin is the only ATG drug approved for GVHD prophylaxis in Japan since September 2008, we included thymoglobulin alone in the present analysis. The survivors' median follow-up time was 1081 days. Patients were categorized into 5 groups: cord blood (CB; n = 1915), matched related donor (n = 1772), 1-antigen mismatched related donor (1-MMRD; n = 225), matched unrelated donor (MUD; n = 1742), and 1-allele mismatched unrelated donor (1-MMUD; n = 963). In multivariate analysis, ATG decreased overall survival (hazard ratio [HR], 1.403; P = .054) and GVHD-free/relapse-free survival (GRFS) (HR, 1.458; P = .053) in association with increased nonrelapse mortality (NRM) (HR, 1.608; P =03) with CB, whereas it improved GRFS (HR, 0.515; P < .01) and decreased grades II to IV aGVHD (HR, 0.576; P < .01), extensive cGVHD (HR, 0.460; P = .02), and NRM (HR, 0.545; P = .03) with 1-MMUD. ATG did not impact survival with 1-MMRD and MUD. The use of ATG in conditioning is beneficial due to the reduction in acute/chronic GVHD without increasing NRM or disease relapse only in 1-MMUD transplantation. On the other hand, ATG is not recommended for CB transplantation.

Coffee and green tea consumption and subsequent risk of acute myeloid leukemia and myelodysplastic syndromes in Japan.

Although coffee and green tea are suggested to reduce the risk of some types of cancers, only a few epidemiological studies have investigated their effect on the risk of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Here, we investigated the association of coffee and green tea consumption and the risk of AML and MDS in a large-scale population-based cohort study in Japan. A total of 95,807 Japanese subjects (45,937 men and 49,870 women; age 40-69 years at baseline) were followed to the end of 2012, for an average of 18 years. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) for the association between coffee and green tea consumption at baseline and the risk of AML and MDS were assessed using a Cox proportional hazards model with adjustment for potential confounders. During 1,751.956 person-years, we identified 85 AML cases and 70 MDS cases. Our findings showed no significant association between coffee consumption and the risk of AML, or between green tea consumption and the risk of AML or MDS. In contrast, we observed a decreasing dose-response relationship between coffee consumption and the risk of MDS among men (almost none: reference, 1-4 times/week: HR = 0.83, 95% CI: 0.43-1.62; ≥1cups/day: HR = 0.47, 0.22-0.99, p for trend = 0.049). Stratified analysis by smoking status suggested that the observed relative risk for AML and MDS of coffee drinkers relative to non-coffee drinkers might be due to residual confounding by smoking. These findings deserve further investigation in future studies.

Coffee and Green Tea Consumption and Subsequent Risk of Malignant Lymphoma and Multiple Myeloma in Japan: The Japan Public Health Center-based Prospective Study.

Background: The aim of this study was to investigate the association of coffee and green tea consumption and the risk of malignant lymphoma and multiple myeloma in a large-scale population-based cohort study in Japan.Methods: In this analysis, a total of 95,807 Japanese subjects (45,937 men and 49,870 women; ages 40-69 years at baseline) of the Japan Public Health Center-based Prospective Study who completed a questionnaire about their coffee and green tea consumption were followed up until December 31, 2012, for an average of 18 years. HRs and 95% confidence intervals were estimated using a Cox regression model adjusted for potential confounders as a measure of association between the risk of malignant lymphoma and multiple myeloma associated with coffee and green tea consumption at baseline.Results: During the follow-up period, a total of 411 malignant lymphoma cases and 138 multiple myeloma cases were identified. Overall, our findings showed no significant association between coffee or green tea consumption and the risk of malignant lymphoma or multiple myeloma for both sexes.Conclusions: In this study, we observed no significant association between coffee or green tea consumption and the risk of malignant lymphoma or multiple myeloma.Impact: Our results do not support an association between coffee or green tea consumption and the risk of malignant lymphoma or multiple myeloma. Cancer Epidemiol Biomarkers Prev; 26(8); 1352-6. ©2017 AACR.

Unrelated bone marrow transplantation or immediate umbilical cord blood transplantation for patients with acute myeloid leukemia in first complete remission.

BACKGROUND: While unrelated bone marrow transplantation (UBMT) has been widely used as alternative donor transplantation, the use of umbilical cord blood transplantation (UCBT) is increasing recently. METHODS: We conducted a decision analysis to address which transplantation procedure should be prioritized for younger patients with acute myeloid leukemia (AML) harboring high- or intermediate-risk cytogenetics in first complete remission (CR1), when they lack a matched related donor but have immediate access to a suitable umbilical cord blood unit. Main sources for our analysis comprised the data from three phase III trials for a chemotherapy cohort (n = 907) and the registry data for a transplantation cohort (n = 752). RESULTS: The baseline analysis showed that when the 8/8 match was considered for UBMT, the expected 5-year survival rate was higher for UBMT than for UCBT (58.1% vs. 51.8%). This ranking did not change even when the 7/8 match was considered for UBMT. Sensitivity analysis showed consistent superiority of UBMT over UCBT when the time elapsed between CR1 and UBMT was varied within a plausible range of 3-9 months. CONCLUSIONS: These results suggest that 8/8 or 7/8 UBMT is a better transplantation option than UCBT even after allowing time required for donor coordination.

Human herpesvirus 6 meningoencephalitis in allogeneic hematopoietic stem cell transplant recipients.

We retrospectively investigated the clinical characteristics of human herpesvirus 6 (HHV-6) meningoencephalitis within 100 days after allogeneic hematopoietic stem cell transplantation (HSCT). Of 1148 patients who received transplants between January 1999 and December 2003, 11 patients (0.96%) with HHV-6 meningoencephalitis were identified. Ten of 11 recipients received hematopoietic stem cells from donors other than HLA-identical siblings. Confusion was the most frequent central nervous system (CNS) symptom, and a skin rash with high-grade fever preceded the CNS symptoms in 9 patients. Magnetic resonance imaging of the brain showed an abnormal increased T2 signal in the hypothalamus of 5 patients. Eight patients were treated with ganciclovir, and an improvement of CNS symptoms was obtained in 3 patients; 3 patients treated with acyclovir showed no improvement. Improvement in the meningoencephalitis seemed less frequent in patients with abnormal findings in the hypothalamus than in those without such findings. Because the symptoms of HHV-6 meningoencephalitis mimicked those of cyclosporine- or tacrolimus-induced encephalopathy, the drugs were withdrawn at the onset of CNS symptoms in 10 patients, resulting in the development of grade IV graft-versus-host disease (GVHD) in 5 patients. Three patients died of HHV-6 meningoencephalitis, and 6 died of other causes, including GVHD. In conclusion, HHV-6 meningoencephalitis is a rare but potentially life-threatening complication in patients who undergo allogeneic HSCT. Careful assessment of the clinical findings and the brain may allow early and precise diagnosis of HHV-6 meningoencephalitis and contribute to improving its prognosis.