Prevalence of chromosome 8p11.2 translocations and correlation with myeloid and lymphoid neoplasms associated with FGFR1 abnormalities in a consecutive cohort from nine institutions in Japan.

Myeloid and lymphoid neoplasms associated with FGFR1 abnormalities (MLN-FGFR1 abnormalities) are rare hematologic malignancies associated with chromosome 8p11.2 abnormalities. Translocations of 8p11.2 were detected in 10 of 17,039 (0.06%) unique patient cytogenetic studies performed at nine institutions in Japan. No inversions or insertions of 8p11.2 were detected. Among the 10 patients with 8p11.2 translocations, three patients were diagnosed with MLN-FGFR1 abnormalities, which were confirmed by FISH analysis. Peripheral blood eosinophilia was observed in all three patients, and all progressed to AML or T-lymphoblastic lymphoma/leukemia. The prevalence of 8p11.2 translocations in clinical practice and the proportion of MLN-FGFR1 abnormalities in patients with 8p11.2 translocations in Japan were consistent with those in previous reports from Western countries.

A novel BRD4 degrader, ARV-825, attenuates lung fibrosis through senolysis and antifibrotic effect.

BACKGROUND: Recent studies suggest that cellular senescence is related to the pathogenesis of idiopathic pulmonary fibrosis. However, cellular senescence has yet to be targeted therapeutically in clinical practice. ARV825, a recently developed BRD4 degrader, has been reported as a novel senolytic drug. Conversely, it has also been reported that BRD4 regulates the pro-fibrotic gene expression of fibroblasts. Therefore, this study focuses on the senolytic and anti-fibrotic effects of ARV825 and evaluated these effects on lung fibrosis. METHODS: Lung fibroblasts were induced to senescence through serial passage. The expression of senescence markers and pro-fibrotic markers were determined through quantitative PCR or immunoblot analysis. Lung fibrosis was induced in mice through intratracheal administration of bleomycin. Mice treated with ARV825 underwent histological analysis of lung fibrosis using the Ashcroft score. Total lung collagen was quantified through a hydroxyproline assay. Respiratory mechanics analysis was performed using the flexiVent system. RESULTS: For senescent cells, ARV825 induced the expression of an apoptosis marker while reducing the expression of BRD4 and senescence markers. On the other hand, for early passage pre-senescent cells, ARV825 reduced the expression of collagen type 1 and α-smooth muscle actin. In an experimental mouse model of lung fibrosis, ARV825 attenuated lung fibrosis and improved lung function. Immunohistochemical staining revealed a significant decrease in the number of senescent alveolar type 2 cells in lung tissue due to ARV825 treatment. CONCLUSIONS: These results suggest that ARV825 may impact the progressive and irreversible course of fibrotic lung diseases.

A polo-like kinase inhibitor identified by computational repositioning attenuates pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a fatal fibrotic lung disease with few effective therapeutic options. Recently, drug repositioning, which involves identifying novel therapeutic potentials for existing drugs, has been popularized as a new approach for the development of novel therapeutic reagents. However, this approach has not yet been fully utilized in the field of pulmonary fibrosis. METHODS: The present study identified novel therapeutic options for pulmonary fibrosis using a systematic computational approach for drug repositioning based on integration of public gene expression signatures of drug and diseases (in silico screening approach). RESULTS: Among the top compounds predicted to be therapeutic for IPF by the in silico approach, we selected BI2536, a polo-like kinase (PLK) 1/2 inhibitor, as a candidate for treating pulmonary fibrosis using an in silico analysis. However, BI2536 accelerated mortality and weight loss rate in an experimental mouse model of pulmonary fibrosis. Because immunofluorescence staining revealed that PLK1 expression was dominant in myofibroblasts while PLK2 expression was dominant in lung epithelial cells, we next focused on the anti-fibrotic effect of the selective PLK1 inhibitor GSK461364. Consequently, GSK461364 attenuated pulmonary fibrosis with acceptable mortality and weight loss in mice. CONCLUSIONS: These findings suggest that targeting PLK1 may be a novel therapeutic approach for pulmonary fibrosis by inhibiting lung fibroblast proliferation without affecting lung epithelial cells. In addition, while in silico screening is useful, it is essential to fully determine the biological activities of candidates by wet-lab validation studies.

Longitudinal trajectory of vascular age indices and cardiovascular risk factors: a repeated-measures analysis.

This study aimed to identify the modifiable cardiovascular risk factors associated with longitudinal changes, which are nine functional and structural biological vascular aging indicators (BVAIs), to propose an effective method to prevent biological vascular aging. We conducted a longitudinal study of 697 adults (a maximum of 3636 BVAI measurements) who were, at baseline, aged between 26 and 85 years and whose BVAIs were measured at least twice between 2007 and 2018. The nine BVAIs were measured using vascular testing and an ultrasound device. Covariates were assessed using validated questionnaires and devices. During the mean follow-up period of 6.7 years, the average number of BVAI measurements ranged from 4.3 to 5.3. The longitudinal analysis showed a moderate positive correlation between the common carotid intima-media thickness (IMT) and chronological age in both men (r = 0.53) and women (r = 0.54). In the multivariate analysis, BVAIs were associated with factors such as age, sex, residential area, smoking status, blood clinical chemistry test levels, number of comorbidities, physical fitness, body mass, physical activity, and dietary intake. The IMT is the most useful BVAI. Our findings suggest that modifiable cardiovascular risk factors are associated with longitudinal changes in BVAI as represented by IMT.

Integrated genetic and clinical prognostic factors for aggressive adult T-cell leukemia/lymphoma.

The prognosis of aggressive adult T-cell leukemia/lymphoma (ATL) is poor, and allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment. In order to identify favorable prognostic patients after intensive chemotherapy, and who therefore might not require upfront allo-HSCT, we aimed to improve risk stratification of aggressive ATL patients aged <70 years. The clinical risk factors and genetic mutations were incorporated into risk modeling for overall survival (OS). We generated the m7-ATLPI, a clinicogenetic risk model for OS, that included the ATL prognostic index (PI) (ATL-PI) risk category, and non-silent mutations in seven genes, namely TP53, IRF4, RHOA, PRKCB, CARD11, CCR7, and GATA3. In the training cohort of 99 patients, the m7-ATLPI identified a low-, intermediate-, and highrisk group with 2-year OS of 100%, 43%, and 19%, respectively (hazard ratio [HR] =5.46; P<0.0001). The m7-ATLPI achieved superior risk stratification compared to the current ATL-PI (C-index 0.92 vs. 0.85, respectively). In the validation cohort of 84 patients, the m7-ATLPI defined low-, intermediate-, and high-risk groups with a 2-year OS of 81%, 30%, and 0%, respectively (HR=2.33; P=0.0094), and the model again outperformed the ATL-PI (C-index 0.72 vs. 0.70, respectively). The simplified m7-ATLPI, which is easier to use in clinical practice, achieved superior risk stratification compared to the ATLPI, as did the original m7-ATLPI; the simplified version was calculated by summing the following: high-risk ATL-PI category (+10), low-risk ATL-PI category (-4), and non-silent mutations in TP53 (+4), IRF4 (+3), RHOA (+1), PRKCB (+1), CARD11 (+0.5), CCR7 (-2), and GATA3 (-3).

The lymphocyte-specific protein tyrosine kinase-specific inhibitor A-770041 attenuates lung fibrosis via the suppression of TGF-ß production in regulatory T-cells.

BACKGROUND: Lymphocyte-specific protein tyrosine kinase (Lck) is a member of the Src family of tyrosine kinases. The significance of Lck inhibition in lung fibrosis has not yet been fully elucidated, even though lung fibrosis is commonly preceded by inflammation caused by infiltration of T-cells expressing Lck. In this study, we examined the effect of Lck inhibition in an experimental mouse model of lung fibrosis. We also evaluated the effect of Lck inhibition on the expression of TGF-ß1, an inhibitory cytokine regulating the immune function, in regulatory T-cells (Tregs). METHODS: Lung fibrosis was induced in mice by intratracheal administration of bleomycin. A-770041, a Lck-specific inhibitor, was administrated daily by gavage. Tregs were isolated from the lung using a CD4+CD25+ Regulatory T-cell Isolation Kit. The expression of Tgfb on Tregs was examined by flow cytometry and quantitative polymerase chain reaction. The concentration of TGF-ß in bronchoalveolar lavage fluid (BALF) and cell culture supernatant from Tregs was quantified by an enzyme-linked immunosorbent assay. RESULTS: A-770041 inhibited the phosphorylation of Lck in murine lymphocytes to the same degree as nintedanib. A-770041 attenuated lung fibrosis in bleomycin-treated mice and reduced the concentration of TGF-ß in BALF. A flow-cytometry analysis showed that A-770041 reduced the number of Tregs producing TGF-ß1 in the lung. In isolated Tregs, Lck inhibition by A-770041 decreased the Tgfb mRNA level as well as the concentration of TGF-ß in the supernatant. CONCLUSIONS: These results suggest that Lck inhibition attenuated lung fibrosis by suppressing TGF-ß production in Tregs and support the role of Tregs in the pathogenesis of lung fibrosis.

Lysophosphatidic acid, ceramide 1-phosphate and sphingosine 1-phosphate in peripheral blood of patients with idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is the most common idiopathic interstitial pneumonias. Lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) are signaling lipids that evoke growth factor-like responses to many cells. Recent studies revealed the involvement of LPA and S1P in the pathology of IPF. In this study, we determined LPA, S1P and ceramide 1-phosphate (C1P) in peripheral blood plasma of IPF patients, and examined correlation to the vital capacity of lung (VC), an indicator of development of fibrosis. Blood plasma samples were taken from eleven patients with IPF and seven healthy volunteers. The lipids of the sample were extracted and subjected to liquid chromatography-tandem mass spectrometry for analysis. Results showed that there is a significant negative correlation between VC and plasma LPA levels, indicating that IPF patients with advanced fibrosis had higher concentration of LPA in their plasma. Average of S1P levels were significantly higher in IPF patients than those in healthy subjects. Although it is not statistically significant, a similar correlation trend that observed in LPA levels also found between VC and S1P levels. These results indicated that plasma LPA and S1P may be associated with deterioration of pulmonary function of IPF patients. J. Med. Invest. 69 : 196-203, August, 2022.

Prognosis of Indolent Adult T-Cell Leukemia/Lymphoma.

A retrospective chart survey of the clinical features of indolent adult T-cell leukemia/lymphoma (ATL) was conducted in the Miyazaki Prefecture, Japan. This study enrolled 24 smoldering-type ATLs, 10 favorable chronic-type ATLs, and 20 unfavorable chronic-type ATLs diagnosed between 2010 and 2018. Among them, 4, 3, and 10 progressed to acute-type ATLs during their clinical course. The median survival time (MST) in smoldering-type ATL and favorable chronic-type ATL was not reached, and their 4-year overall survival (OS) was 73% and 79%, respectively. Compared with this, the prognosis of unfavorable chronic-type ATL was poor. Its MST was 3.32 years, and the 4-year OS was 46% (p = 0.0095). In addition to the three features that determine the unfavorable characteristics of chronic-type ATL, namely, increased lactate dehydrogenase, increased blood urea nitrogen, and decreased albumin, the high-risk category by the indolent ATL-Prognostic Index, which was defined by an increment of soluble interleukin-2 receptor (sIL2-R) of >6000 U/mL, could explain the poor prognosis in indolent ATL patients. The level of sIL-2R might be an indicator of the initiation of therapy for indolent ATL.

Development of organ-specific autoimmunity by dysregulated Aire expression.

Deficiency for AIRE/Aire in both humans and mice results in the development of organ-specific autoimmune disease. We tested whether augmented and/or dysregulated AIRE/Aire expression might be also prone to the breakdown of self-tolerance. To define the effect of augmented Aire expression on the development of autoimmunity, antigen-specific clonal deletion and production of clonotypic regulatory T cells (Tregs) in the thymus were examined using mice expressing two additional copies of Aire in a heterozygous state (3xAire-knockin mice: 3xAire-KI). We found that both clonal deletion of autoreactive T cells and production of clonotypic Tregs in the thymus from 3xAire-KI were impaired in a T-cell receptor-transgenic system. Furthermore, 3xAire-KI females showed higher scores of experimental autoimmune encephalomyelitis induced by myelin oligodendrocyte glycoprotein than wild-type littermates, suggesting that augmented Aire expression exacerbates organ-specific autoimmunity under disease-prone conditions. In humans, we found that one patient with amyopathic dermatomyositis showed CD3- CD19- cells expressing AIRE in the peripheral blood before the treatment but not during the remission phase treated with immunosuppressive drugs. Thus, not only loss of function of AIRE/Aire but also augmented and/or dysregulated expression of AIRE/Aire should be considered for the pathogenesis of organ-specific autoimmunity. We suggest that further analyses should be pursued to establish a novel link between organ-specific autoimmune disease and dysregulated AIRE expression in clinical settings.

Lenvatinib-induced Interstitial Pneumonia in a Patient with Hepatocellular Carcinoma.

Lenvatinib is a multi-targeted tyrosine kinase inhibitor available for the treatment of unresectable hepatocellular carcinoma (HCC). We herein report an 84-year-old-man with interstitial pneumonia caused by lenvatinib. Four months after the start of lenvatinib administration for HCC, chest computed tomography revealed bilateral ground-glass opacity. However, he continued to take lenvatinib for four more months until he complained of dyspnea on exertion. This is a case of lenvatinib-induced interstitial pneumonia that progressed relatively slowly with a long asymptomatic period despite the appearance of pneumonia on image findings.

Radiation-associated Angiosarcoma Presenting as Massive Pleural Effusion.

A 67-year-old man was admitted to our hospital for massive pleural effusion. He had a history of mandibular gingival carcinoma treated with radiation therapy (RT). Based on the cytology findings of pleural effusion and a thoracoscopic pleural biopsy, we finally diagnosed him with radiation-associated angiosarcoma. Retrospective cell-block immunocytochemistry with pleural effusion also showed potential utility for the diagnosis. This case highlights the importance of considering the possibility of radiation-associated secondary cancer in patients with pleural effusion who have a history of RT.

First-line sorafenib sequential therapy and liver disease etiology for unresectable hepatocellular carcinoma using inverse probability weighting: A multicenter retrospective study.

BACKGROUND AND AIMS: Sequential therapy with molecular-targeted agents (MTAs) is considered effective for unresectable hepatocellular carcinoma (HCC) patients. This study purposed to evaluate the efficacy of sequential therapy with sorafenib (SORA) as a first-line therapy and to investigate the therapeutic impact of SORA in nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steato hepatitis (NASH)-related HCC. METHODS: We evaluated 504 HCC patients treated with SORA (Study-1). The times of administration for sorafenib from 2009 to 2015, 2016 to 2017, and 2018 and later were defined as the early-, mid-, and late-term periods, respectively. Among them, 180 HCC patients treated with SORA in addition to MTAs in the mid- and late-term periods were divided into groups based on disease etiology (NAFLD or NASH [n = 37] and viral or alcohol [n = 143]), and outcomes were compared after inverse probability weighting (IPW) (Study-2). RESULTS: Overall survival (OS) of HCC patients who received sequential MTA therapy after first-line SORA was significantly longer. The median survival times (MST) were 12.6 versus 17.6 versus 17.4 months in the early-term group, mid-term group, and the later-time group (early vs. mid, p = 0.014, early vs. later. p = 0.045), respectively. (Study-1). In Study-2, there was no significant differences in OS between the Virus/alcohol group and the NAFLD/NASH group in patients who received sequential therapy (MST was 23.4 and 27.0 months p = 0.173, respectively). The NAFLD or NASH, female sex, albumin-bilirubin (ALBI) grade 2b, and major Vp (Vp3/Vp4) were significant factors for OS treated with SORA. CONCLUSIONS: Sequential therapy with SORA as the first-line treatment improved the prognosis of unresectable HCC patients and was effective regardless of HCC etiology.

Effect of a 1-year intervention comprising brief counselling sessions and low-dose physical activity recommendations in Japanese adults, and retention of the effect at 2 years: a randomized trial.

BACKGROUND: In an effort to increase people's adherence to active lifestyles, contemporary physical activity (PA) guidelines now include low-dose PA. METHODS: PA was evaluated in 583 participants of the Nutritional and Physical Activity Intervention Study (NEXIS) cohort (30-65 years old); 349 inactive participants (MVPA, 2.7 ± 1.0 MET-h/day) were randomly assigned to the intervention or control groups, and 235 active participants participated in follow-up visits. The intervention aimed to increase MVPA and comprised five brief counseling sessions over 1 year. The 1-year target for the participant was increasing their step-count to 10,000 steps/d or +3000 steps/d, relative to the baseline score. The counseling sessions were designed to stimulate progressive changes in physical behaviors by recommendations promoting small and/or light-intensity bouts of PA. PA was measured at baseline, the end of the intervention, and 1 year after the intervention ended. Additionally, several nutrition, health, and fitness parameters were measured. RESULTS: Participants in the intervention group significantly increased their step-count from 8415 ± 1924 at baseline to 9493 ± 2575 at the end of the 1-year period. During the same period, MVPA significantly increased by 0.9 MET-h. The daily time spent in ≥ 3, ≥ 4 and ≥ 5 MET activities increased by 11, 6, and 3 min, respectively. This increase in PA remained observable 1 year after intervention concluded. The active group maintained higher physical activity levels throughout the two years. The intervention group showed smaller energy intakes at the end of the 2-year period. Significant correlations were noted between the 1-year change in MVPA and the change in resting heart rate (r = - 0.22), and between the 2-year change in MVPA and the change in waist circumference (r = - 0.08) and peak oxygen consumption capacity (r = 0.23) in the intervention group only. CONCLUSIONS: A prolonged and progressive PA intervention promoting small bouts of light-to-moderate PA may be used in healthy, not-optimally-active people to increase PA beyond the strict period of the intervention. Further studies are necessary to understand whether low-dose PA messages can be effective in initiating a progressive increase toward larger amounts of PA. TRIAL REGISTRATION: Clinical Trials.gov, NCT00926744, retrospectively registered.

Abatacept is Efficacious in the Treatment of Older Patients with csDMARD-Refractory Rheumatoid Arthritis: A Prospective, Multicenter, Observational Study.

INTRODUCTION: Abatacept efficacy in older patients with rheumatoid arthritis (RA) has been primarily demonstrated via retrospective comparisons with younger patients. The objective of this study was to compare efficacy of abatacept in older vs. younger patients with RA, and efficacy of abatacept with that of conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) in both age groups. METHODS: This prospective, multicenter, observational study (UMIN000014913) enrolled csDMARD-refractory patients without previous biological DMARD treatment. Abatacept (A) or csDMARDs (C) were administered at the treating physician's discretion to older (O, ≥ 65 years) and younger (Y, 20-64 years) patients, producing AO, AY, CO, and CY groups. Clinical efficacy after 24 weeks was evaluated using European League Against Rheumatism (EULAR) erythrocyte sedimentation rate response criteria. RESULTS: Overall, 202 patients were evaluated. Compared with the CO group, more patients in the AO group achieved a EULAR good or moderate response (p < 0.0001). Compared with the CY group, more patients in the AY group achieved a EULAR good or moderate response (p < 0.01). Similar proportions of patients in the AO and AY groups achieved a EULAR good response or a good or moderate response. Few adverse events were reported. CONCLUSIONS: This prospective study demonstrated that abatacept is efficacious and safe in older patients with RA and a history of being refractory to csDMARDs. Abatacept was shown to be more efficacious than adding or switching to a new csDMARD in both younger and older csDMARD-refractory patients with RA. TRIAL REGISTRATION: UMIN000014913.

Greater arterial wall viscosity in endurance-trained men.

PURPOSE: The age-associated increase in arterial wall viscosity (AWV) is attenuated by high cardiorespiratory fitness level. However, AWV in endurance-trained athletes have not been determined. We designed a cross sectional study to compare central AWV and compliance between endurance-trained young athletes and age-matched control men. METHODS: Twenty-one endurance-trained men (age 20.7 ± 0.3 years) and 20 age-matched healthy control men (age 21.6 ± 0.4 years) were studied. The common carotid artery was measured noninvasively by tonometry and automatic tracking of B-mode images to obtain instantaneous pressure and diameter hysteresis loops, and we calculated the dynamic carotid arterial compliance, static (effective and isobaric) compliance, and viscosity index. RESULTS: The AWV index in the endurance-trained men was larger than the control peers (2285 ± 181 vs. 1429 ± 124 mmHg·s/mm: P < 0.001). In addition, dynamic and static compliance were not statistically different between both groups. CONCLUSION: The present study indicated that the central AWV in endurance-trained athletes was greater than age-matched healthy control men. We believe that the AWV, as well as arterial compliance, is an important element for assessing vascular adaptation to endurance training.

Survival Benefit of Hepatic Arterial Infusion Chemotherapy over Sorafenib in the Treatment of Locally Progressed Hepatocellular Carcinoma.

BACKROUND: Not all patients with hepatocellular carcinoma (HCC) benefit from treatment with molecular targeted agents such as sorafenib. We investigated whether New-FP (fine-powder cisplatin and 5-fluorouracil), a hepatic arterial infusion chemotherapy regimen, is more favorable than sorafenib as an initial treatment for locally progressed HCC. METHODS: To avoid selection bias, we corrected the data from different facilities that did or did not perform New-FP therapy. In total, 1709 consecutive patients with HCC initially treated with New-FP or sorafenib; 1624 (New-FP, n = 644; sorafenib n = 980) were assessed. After propensity score matching (PSM), overall survival (OS) and prognostic factors were assessed (n = 344 each). Additionally, the patients were categorized into four groups: cohort-1 [(without macrovascular invasion (MVI) and extrahepatic spread (EHS)], cohort-2 (with MVI), cohort-3 (with EHS), and cohort-4 (with MVI and EHS) to clarify the efficacy of each treatment. RESULTS: New-FP prolonged OS than sorafenib after PSM (New-FP, 12 months; sorafenib, 7.9 months; p < 0.001). Sorafenib treatment, and severe MVI and EHS were poor prognostic factors. In the subgroup analyses, the OS was significantly longer the New-FP group in cohort-2. CONCLUSIONS: Local treatment using New-FP is a potentially superior initial treatment compared with sorafenib as a multidisciplinary treatment in locally progressed HCC without EHS.

Neuropsychiatric systemic lupus erythematosus with cerebellar vasculitis and obstructive hydrocephalus requiring decompressive craniectomy.

A 36-year-old woman who had been diagnosed with systemic lupus erythematosus (SLE) was admitted to our hospital due to increasing disease SLE activity. Despite the intensification of immunosuppressive treatment, headache newly developed and worsened. Magnetic resonance imaging (MRI) revealed spreading of a high-intensity area along the sulci of the bilateral cerebellar hemispheres. She was diagnosed with neuropsychiatric SLE and methylprednisolone (mPSL) pulse therapy was started. However, consciousness disorder due to cerebellar oedema with obstructive hydrocephalus appeared and required decompressive craniectomy. The histological findings of the biopsy specimens from cerebellar vermis were compatible with features of vasculitis. She was successfully treated adding intravenous cyclophosphamide therapy.

Development of improved method to identify and analyze lung fibrocytes with flow cytometry in a reporter mouse strain.

INTRODUCTION: Fibrocytes are emerging myeloid-derived circulating cells that can migrate into damaged tissues and usually contribute to their repair. Key features of fibrocytes include the expression myeloid markers, production of extracellular matrix proteins, and secretion of various humoral factors that activate resident fibroblasts; they also have the potential to differentiate into fibroblasts. However, no specific surface markers have been identified to identify fibrocytes in vivo. One reason could be that the method used to detect fibrocytes requires intracellular collagen staining. METHODS: In the present study, to establish an improved method for the detection of lung fibrocytes and to analyze viable fibrocytes, we used collagen I(α)2-green fluorescent protein (Col-GFP) reporter mice, which had undergone the intratracheal instillation of bleomycin (BLM). RESULTS: Using flow cytometry to gate out cells with autofluorescence, we clearly found that CD45+ GFP+  cells resided in the lungs of Col-GFP mice at a steady state and these cells increased after BLM injury, peaking at Day 14. These cells expressed not only known cell surface markers of fibrocytes, but also some novel markers, in addition to a low level of collagen I in comparison to CD45- GFP+  cells. CONCLUSION: Our findings suggest that the improved method can be a useful for the detection of pure lung fibrocytes and allows us to further analyze the characteristics of viable fibrocytes.

Higher average chemotherapy dose intensity improves prognosis in patients with aggressive adult T-cell leukemia/lymphoma.

OBJECTIVE AND METHOD: Adult T-cell leukemia/lymphoma (ATL) is an aggressive peripheral T-cell lymphoma with poor prognosis. We retrospectively reviewed the medical records of 312 patients with aggressive ATL and analyzed the effect of chemotherapy dose intensity on prognosis in clinical practice. RESULT: As first-line therapy, 62 patients underwent best supportive care (BSC) or single-agent chemotherapy, and 235 underwent intensive chemotherapy. The median survival time (MST) was 0.58 years in the 312 total patients, and 0.13 years and 0.75 years in the BSC/single-agent chemotherapy group and intensive chemotherapy group, respectively. The median average relative dose intensity (ARDI) of patients who received intensive chemotherapy was 60%. We divided patients into 3 groups according to ARDI. Those in the top tertile of ARDI (ARDI ≥ 75%, n = 82) had better overall survival compared with those in the intermediate tertile (45% ≤ ARDI < 75%, n = 79) (P < .0001), with MSTs of 4.69 and 0.75 years, respectively. The occurrence of organ dysfunction and infectious complications was comparable between the two ARDI groups. CONCLUSION: Higher ARDI improves prognosis in patients with aggressive ATL in clinical practice.