Loss-of-function mutations in ten-eleven translocation-2 (TET2) are recurrent events in acute myeloid leukemia (AML) as well as in preleukemic hematopoietic stem cells (HSCs) of age-related clonal hematopoiesis. TET3 mutations are infrequent in AML, but the level of TET3 expression in HSCs has been found to decline with age. We examined the impact of gradual decrease of TET function in AML development by generating mice with Tet deficiency at various degrees. Tet2f/f and Tet3f/f mice were crossed with mice expressing Mx1-Cre to generate Tet2f/wtTet3f/fMx-Cre+ (T2ΔT3), Tet2f/fTet3f/wtMx-Cre+ (ΔT2T3), and Tet2f/fTet3f/fMx-Cre+ (ΔT2ΔT3) mice. All ΔT2ΔT3 mice died of aggressive AML at a median survival of 10.7 weeks. By comparison, T2ΔT3 and ΔT2T3 mice developed AML at longer latencies, with a median survival of ∼27 weeks. Remarkably, all 9 T2ΔT3 and 8 ΔT2T3 mice with AML showed inactivation of the remaining nontargeted Tet2 or Tet3 allele, respectively, owing to exonic loss in either gene or stop-gain mutations in Tet3. Recurrent mutations other than Tet3 were not noted in any mice by whole-exome sequencing. Spontaneous inactivation of residual Tet2 or Tet3 alleles is a recurrent genetic event during the development of AML with Tet insufficiency.

Background: Nearly half of all patients with primary central nervous system lymphoma (PCNSL) are known to be aged over 60 years. However, clinical factors affecting treatment outcomes in elderly patients are understudied. Methods: We analyzed 38 patients with PCNSL older than 60 years. All patients were treated with a nonradiation, intermediate-dose methotrexate-containing regimen between March 2005 and May 2013 at the University of Tsukuba Hospital. Results: The 3-year overall survival and progression-free survival rates were 56.2% (95% confidence interval (CI) 36.2-76.2%) and 29.8% (95% CI 9-50.6%), respectively, with a median follow-up of 36.5 months. We found that an age > 75 years, a Karnofsky performance score < 70, altered mentation, and a creatinine clearance (CrCl) > 90 ml/min were significant (p < 0.05) factors associated with a worse survival, by univariate analysis. Multivariate analysis revealed that CrCl (p < 0.05; hazard ratio (HR) = 3.39; 95% CI 1.08-10.68) and altered mentation (p < 0.05; HR = 6.27; 95%CI 1.37-28.83) were independent significant association factors. The most frequent adverse event was myelosuppression, with grade 3-4 hematologic toxicities in 28 patients. No delayed neurotoxicities were observed. Conclusion: More intensive therapy may be introduced in selected patients with poor prognosis factors to improve outcomes.

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PurposeWe evaluated the efficacy and safety of febuxostat, a non-purine xanthine oxidase inhibitor, used for prevention of hyperuricemia associated with tumor lysis syndrome (TLS).MethodsRecords of adult patients with newly diagnosed or relapsed hematologic malignancies who received febuxostat within 7 days before initiation of chemotherapy were retrieved retrospectively at a single institute. The changes in serum uric acid levels from before and 7 days after initiation of febuxostat were evaluated and compared with the historical control group of patients who received allopurinol. We also evaluated non-hematological adverse events during the study period.ResultsA total of 78 patients’ records were analyzed, 38 in the febuxostat group and 39 in the allopurinol group. There were no significant differences in the incidence of treatment failure, defined as development of clinical TLS or receiving rasburicase, between the febuxostat and allopurinol group (5.2% vs 5.1%, P>0.99). The mean serum uric acid levels were significantly decreased, compared to the baseline (5.6 ± 2.1 mg/dL), at 7 days after initiation of febuxostat (3.1 ± 1.5 mg/dL, last observation carried forward, P<0.001). There were no statistically significant differences in the percent change in the serum uric acid levels between the 40 mg/day febuxostat and the 300 mg/day allopurinol groups (P = 0.57). Grade 3–4 liver dysfunctions were observed in both the febuxostat and allopurinol groups, without significant differences in incidence between the two groups (2.6% vs 5.1%, P>0.99). Neither gout flare nor skin rash occurred in any patients.ConclusionsFebuxostat is feasible for prevention of hyperuricemia associated with TLS.