Haploidentical Stem Cell Transplantation Using Post-Transplant Cyclophosphamide for T-Cell Prolymphocytic Leukemia after Alemtuzumab Induction Therapy: A Case Report

T-cell prolymphocytic leukemia (T-PLL) is a rare aggressive disease with a poor prognosis. Allogeneic stem cell transplantation (allo-SCT) followed by alemtuzumab administration is the most promising treatment for T-PLL but is associated with a high risk of infections as alemtuzumab strongly suppresses cellular immunity, leading to high transplant-related mortality and unsatisfactory survival rates. In addition, for patients without human leukocyte antigen-matched donors, haploidentical stem cell transplantation (haplo-SCT) using post-transplant cyclophosphamide (PTCy) has been used because of the ready availability of donors and achievement of results comparable to those of transplantation with human leukocyte antigen-matched donors. However, there are no reports on the efficacy and safety, including infectious complications, of haplo-SCT with PTCy after alemtuzumab therapy in patients with. Here, we describe a 66-year-old Japanese male patient with T-PLL treated successfully with haplo-SCT after induction therapy of alemtuzumab for T-PLL. Approximately 3 months after the achievement of complete remission with alemtuzumab for T-PLL, haplo-SCT with reduced-intensity conditioning and PTCy was performed. Infectious complications were improved by early therapeutic interventions, and peripheral T cell counts gradually recovered. The patient was alive for more than 16 months after allo-SCT with no signs of relapse. Thus, haplo-SCT using PTCy should be considered as an option after alemtuzumab treatment for T-PLL

Dietary supplementation with alkylresorcinols prevents muscle atrophy through a shift of energy supply

It has been reported that phytoextracts that contain alkylresorcinols (ARs) protect against severe myofibrillar degeneration found in isoproterenol-induced myocardial infarction. In this study, we examined the effect of dietary ARs derived from wheat bran extracts on muscle atrophy in denervated mice. The mice were divided into the following four groups: (1) sham-operated (control) mice fed with normal diet (S-ND), (2) denervated mice fed with normal diet (D-ND), (3) control mice fed with ARs-supplemented diet (S-AR) and (4) denervated mice fed with ARs-supplemented diet (D-AR). The intake of ARs prevented the denervation-induced reduction of the weight of the hind limb muscles and the myofiber size. However, the expression of ubiquitin ligases and autophagy-related genes, which is associated with muscle proteolysis, was slightly higher in D-AR than in D-ND. Moreover, the abundance of the autophagy marker p62 was significantly higher in D-AR than in D-ND. Muscle atrophy has been known to be associated with a disturbed energy metabolism. The expression of pyruvate dehydrogenase kinase 4 (PDK4), which is related to fatty acid metabolism, was decreased in D-ND as compared with that in S-ND. In contrast, dietary supplementation with ARs inhibited the decrease of PDK4 expression caused by denervation. Furthermore, the abnormal expression pattern of genes related to the abundance of lipid droplets-coated proteins that was induced by denervation was improved by ARs. These results raise the possibility that dietary supplementation with ARs modifies the disruption of fatty acid metabolism induced by lipid autophagy, resulting in the prevention of muscle atrophy

Clonal evolution and clinical implications of genetic abnormalities in blastic transformation of chronic myeloid leukaemia

Blast crisis (BC) predicts dismal outcomes in patients with chronic myeloid leukaemia (CML). Although additional genetic alterations play a central role in BC, the landscape and prognostic impact of these alterations remain elusive. Here, we comprehensively investigate genetic abnormalities in 136 BC and 148 chronic phase (CP) samples obtained from 216 CML patients using exome and targeted sequencing. One or more genetic abnormalities are found in 126 (92.6%) out of the 136 BC patients, including the RUNX1-ETS2 fusion and NBEAL2 mutations. The number of genetic alterations increase during the transition from CP to BC, which is markedly suppressed by tyrosine kinase inhibitors (TKIs). The lineage of the BC and prior use of TKIs correlate with distinct molecular profiles. Notably, genetic alterations, rather than clinical variables, contribute to a better prediction of BC prognosis. In conclusion, genetic abnormalities can help predict clinical outcomes and can guide clinical decisions in CML

Postazacitidine clone size predicts long-term outcome of patients with myelodysplastic syndromes and related myeloid neoplasms

Azacitidine is a mainstay of therapy for MDS-related diseases. The purpose of our study is to elucidate the effect of gene mutations on hematological response and overall survival (OS), particularly focusing on their post-treatment clone size. We enrolled a total of 449 patients with MDS or related myeloid neoplasms. They were analyzed for gene mutations in pre- (n=449) and post- (n=289) treatment bone marrow samples using targeted-capture sequencing to assess the impact of gene mutations and their post-treatment clone size on treatment outcomes. In Cox proportional hazard modeling, multi-hit TP53 mutation (HR, 2.03; 95% CI, 1.42-2.91; P<.001), EZH2 mutation (HR, 1.71; 95% CI, 1.14-2.54; P=.009), and DDX41 mutations (HR, 0.33; 95% CI, 0.17-0.62; P<.001), together with age, high-risk karyotypes, low platelet, and high blast counts, independently predicted OS. Post-treatment clone size accounting for all drivers significantly correlated with International Working Group (IWG)-response (P<.001, trend test), except for that of DDX41-mutated clones, which did not predict IWG-response. Combined, IWG-response and post-treatment clone size further improved the prediction of the original model and even that of a recently proposed molecular prediction model, IPSS-M (c-index, 0.653 vs 0.688; P<.001, likelihood ratio test). In conclusion, evaluation of post-treatment clone size, together with pre-treatment mutational profile as well as IWG-response have a role in better prognostication of azacitidine-treated myelodysplasia patients

Amplified EPOR/JAK2 Genes Define a Unique Subtype of Acute Erythroid Leukemia

ゲノム解析から急性赤白血病の変異プロファイルと治療標的を解明 --特定の遺伝子変異群の組み合わせと、特徴となる遺伝子の増幅が鍵--. 京都大学プレスリリース. 2022-08-05.Acute erythroid leukemia (AEL) is a unique subtype of acute myeloid leukemia characterized by prominent erythroid proliferation whose molecular basis is poorly understood. To elucidate the underlying mechanism of erythroid proliferation, we analyzed 121 AEL using whole-genome/exome and/or targeted-capture sequencing, together with transcriptome analysis of 21 AEL samples. Combining publicly available sequencing data, we found a high frequency of gains/amplifications involving EPOR/JAK2 in TP53-mutated cases, particularly those having >80% erythroblasts designated as pure erythroid leukemia (10/13). These cases were frequently accompanied by gains/amplifications of ERG/ETS2 and associated with a very poor prognosis, even compared with other TP53-mutated AEL. In addition to activation of the STAT5 pathway, a common feature across all AEL cases, these AEL cases exhibited enhanced cell proliferation and heme metabolism and often showed high sensitivity to ruxolitinib in vitro and in xenograft models, highlighting a potential role of JAK2 inhibition in therapeutics of AEL

Direct infiltration of clonal plasma cells causes renal insufficiency in patients with monoclonal gammopathy of undetermined significance

Abstract Monoclonal gammopathy of undetermined significance (MGUS) is a benign but precancerous condition that can progress to multiple myeloma. Patients with MGUS are typically monitored closely for signs of disease progression, but in some cases, they may also develop renal insufficiency, a condition known as monoclonal gammopathy of renal significance (MGRS). In MGRS, M‐protein secreted by a nonmalignant or premalignant cell clone triggers renal damage by definition. Herein, we report a case of a 66‐year‐old Asian male with MGUS complicated by renal insufficiency. A kidney biopsy showed no evidence of renal injury mediated by M‐protein; instead, the direct infiltration of clonal cells into renal tissues was observed. Although five similar cases have been previously reported, our case is unique in that the involvement of clonal cells was directly confirmed by fluorescence in situ hybridization. Our findings suggest the need to consider a novel disease concept, as this phenomenon appears to be reproduced