RESUMEN
Clinical trials of biologics have frequently excluded elderly patients, resulting in inadequate data on their safety and efficacy. Additionally, evidence of their safety and efficacy remains limited, despite some real-world studies. To assess the safety and efficacy of biologics in elderly patients with psoriasis, we compared these outcomes in younger patients using data from the West Japan Psoriasis Registry (WJPR). The WJPR consists of approximately 30 facilities in Western Japan, including various healthcare settings. This study enrolled 1395 patients who participated in the 2022 follow-up survey of the WJPR and were either using or had used biologics during the survey. These included 456 patients in the elderly group (≥65 years) and 939 patients in the younger group (<65 years). Treatment-ending adverse events (TEAEs) occurred in 15.8% and 11.3% of elderly and younger patients, respectively. The incidence rate per 1000 patient-years (PY) for TEAEs was significantly higher in elderly patients than in younger patients (32.9 vs 23.2, p = 0.0234). Infectious diseases were more prevalent in the elderly group than the younger group; however, no significant difference in the frequency of infectious diseases was found between the two groups (p = 0.0807). Malignant neoplasms occurred significantly more frequently in the elderly group than in the younger group (p = 0.0169). Our results indicate a few concerns about infection when prescribing biologics to elderly patients. Biologics were effective for both elderly and younger patients. We found no significant differences in the proportion of patients with a body surface area score ≤3%, Physician's Global Assessment score 0/1, or Patient's Global Assessment score 0/1, as well as in the mean Dermatology Life Quality Index and the Itch Numerical Rating Scale between the younger and the elderly groups. Overall, our results confirm the appropriateness of using biologics in elderly patients with regard to safety and efficacy.
RESUMEN
Central hypothyroidism and dyslipidemia are well-known adverse events (AEs) of bexarotene therapy. Although hypothyroidism is known to cause dyslipidemia, no study has examined the association between hypothyroidism and dyslipidemia in patients undergoing bexarotene therapy. The aim of this study is to examine this association. A retrospective observational study was performed among 294 patients who initiated bexarotene therapy in Japan (nation-wide postmarketing complete surveillance). Jonckheere-Terpstra (one sided) test was performed to evaluate the effect of the bexarotene dose on lipid metabolisms, and regression analyses were performed to evaluate associations of bexarotene dose, free thyroxine (FT4), body mass index (BMI), and lipid metabolisms. Most patients developed hypothyroidism. Two-third of patients showed FT4 values below the lower limit at 1 week. Triglycerides (TG) increased in a bexarotene dose-dependent manner, and grade ≥3 AEs on hypertriglyceridemia was observed in 39% of the patients. Additionally, one-third of grade ≥3 AEs on hypertriglyceridemia occurred within 1 week. The delta_FT4 (difference in FT4 from baseline) negatively correlated with TG increase at 1 week (p = 0.012) but not with low density lipoprotein cholesterol (LDL-C) increase at any week. Bexarotene-induced hypothyroidism is almost inevitable and occurred quickly. Bexarotene-induced hypertriglyceridemia showed positive bexarotene dose dependency and negative delta_FT4 dependency. Prophylactic and appropriate thyroid hormone compensation therapy and starting bexarotene at low doses with subsequent titration while managing dyslipidemia may have a beneficial effect for the successful continuation of bexarotene therapy without severe endocrine and metabolic AEs.
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Bexaroteno , Dislipidemias , Hipotiroidismo , Humanos , Bexaroteno/efectos adversos , Hipotiroidismo/inducido químicamente , Hipotiroidismo/epidemiología , Masculino , Femenino , Persona de Mediana Edad , Estudios Retrospectivos , Anciano , Dislipidemias/inducido químicamente , Japón/epidemiología , Tiroxina/sangre , Triglicéridos/sangre , Adulto , Tetrahidronaftalenos/efectos adversos , Tetrahidronaftalenos/uso terapéutico , Anciano de 80 o más Años , Anticarcinógenos/uso terapéutico , Anticarcinógenos/efectos adversos , Hipertrigliceridemia/inducido químicamenteRESUMEN
BACKGROUND: Whether human T-lymphotropic virus type 1 (HTLV-1) carriers can develop sufficient humoral immunity after coronavirus disease 2019 (COVID-19) vaccination is unknown. METHODS: To investigate humoral immunity after COVID-19 vaccination in HTLV-1 carriers, a multicenter, prospective observational cohort study was conducted at five institutions in southwestern Japan, an endemic area for HTLV-1. HTLV-1 carriers and HTLV-1-negative controls were enrolled for this study from January to December 2022. During this period, the third dose of the COVID-19 vaccine was actively administered. HTLV-1 carriers were enrolled during outpatient visits, while HTLV-1-negative controls included health care workers and patients treated by participating institutions for diabetes, hypertension, or dyslipidemia. The main outcome was the effect of HTLV-1 infection on the plasma anti-COVID-19 spike IgG (IgG-S) titers after the third dose, assessed by multivariate linear regression with other clinical factors. RESULTS: We analyzed 181 cases (90 HTLV-1 carriers, 91 HTLV-1-negative controls) after receiving the third dose. HTLV-1 carriers were older (median age 67.0 vs. 45.0 years, p < 0.001) and more frequently had diabetes, hypertension, or dyslipidemia than did HTLV-1-negative controls (60.0% vs. 27.5%, p < 0.001). After the third dose, the IgG-S titers decreased over time in both carriers and controls. Multivariate linear regression in the entire cohort showed that time since the third dose, age, and HTLV-1 infection negatively influenced IgG-S titers. After adjusting for confounders such as age, or presence of diabetes, hypertension, or dyslipidemia between carriers and controls using the overlap weighting propensity score method, and performing weighted regression analysis in the entire cohort, both time since the third dose and HTLV-1 infection negatively influenced IgG-S titers. CONCLUSIONS: The humoral immunity after the third vaccination dose is impaired in HTLV-1 carriers; thus, customized vaccination schedules may be necessary for them.
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COVID-19 , Diabetes Mellitus , Dislipidemias , Infecciones por HTLV-I , Virus Linfotrópico T Tipo 1 Humano , Hipertensión , Humanos , Anciano , COVID-19/prevención & control , Vacunas contra la COVID-19 , Inmunidad Humoral , Estudios Prospectivos , Vacunación , Inmunoglobulina G , Anticuerpos AntiviralesRESUMEN
BACKGROUND: The clinical implications of DUSP22 rearrangement and the association between DUSP22 rearrangement and lymphoid enhancer-binding factor 1 (LEF1) expression pattern in CD30+ cutaneous T-cell lymphomas (CTCLs) are unknown. OBJECTIVES: This study assessed the incidence of DUSP22 rearrangement and its clinical and immunohistochemical implications in primary cutaneous anaplastic large-cell lymphoma (pcALCL), lymphomatoid papulosis (LyP) and CD30+ mycosis fungoides with large-cell transformation (MF-LCT), focusing especially on the association with the prognosis and LEF1 expression pattern. Prognostic factors of pcALCL were also examined. METHODS: We conducted a multicentre retrospective study including patients with pcALCL, LyP and MF-LCT diagnosed between 1 January 2000 and 31 December 2018 in Japan. Baseline data at diagnosis, treatment course, overall survival (OS) and disease-specific survival (DSS) were collected. Immunohistochemical analysis and fluorescence in situ hybridization to detect DUSP22 and TP63 rearrangement were performed using skin samples at diagnosis. We investigated the association between staining pattern and these gene rearrangements. We also assessed the prognostic implications of clinical status, immunohistochemical results and the presence of gene rearrangements. RESULTS: DUSP22 rearrangement was detected in 50% (11 of 22) of cases of pcALCL, but not in any cases with LyP (0 of 14) or MF-LCT (0 of 11). TP63 rearrangement was not detected in any case. Clinically, patients with pcALCL with DUSP22 rearrangement did not tend to develop ulcers (P = 0.081). There was no significant association between DUSP22 rearrangement status and immunohistochemical results, including LEF1 expression pattern. T3 stage and the presence of lower limb lesions were significantly associated with shorter OS (P = 0.012 and 0.021, respectively, by log-rank test). Similarly, they were significantly correlated with shorter DSS (P = 0.016 and 0.0001, respectively). CONCLUSIONS: DUSP22 rearrangement is relatively specific to pcALCL among CD30+ CTCLs in Japan. Although the LEF1 expression pattern was not related to DUSP22 rearrangement in pcALCL, there was no rearrangement if LEF1 was not expressed. We confirmed that T3 stage and the lower limb involvement were significantly associated with decreased OS and DSS. The presence or absence of lower limb lesions should be included in T-stage subcategorization in the future.
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Linfoma Anaplásico de Células Grandes , Papulosis Linfomatoide , Micosis Fungoide , Neoplasias Cutáneas , Humanos , Linfoma Anaplásico de Células Grandes/diagnóstico , Linfoma Anaplásico de Células Grandes/genética , Linfoma Anaplásico de Células Grandes/patología , Estudios Retrospectivos , Neoplasias Cutáneas/patología , Antígeno Ki-1 , Pronóstico , Hibridación Fluorescente in Situ , Japón/epidemiología , Micosis Fungoide/patologíaRESUMEN
Psoriasis affects approximately 0.3% of the Japanese population. Recently, various effective systemic drugs have become available, and the continuation of a given treatment has become critical because of the chronic nature of psoriasis. Factors affecting drug survival (the time until treatment discontinuation) in psoriasis treatment include efficacy, safety, ease of use, and patient preference. In the present study, the authors retrospectively surveyed a multifacility patient registry to determine the real-world evidence of the survival rate of systemic interventions for psoriasis treatment. Patients with psoriasis who visited 20 facilities in the Western Japan area between January 2019 and May 2020 and gave written consent were registered as study participants, and their medical history of systemic interventions for psoriasis (starting from 2010) was retrospectively collected and analyzed. The drugs investigated were adalimumab, infliximab, ustekinumab, secukinumab, ixekizumab, brodalumab, guselkumab, risankizumab, cyclosporine, and apremilast. When drugs were discontinued, the reasons were also recorded. A total of 1003 patients with psoriasis including 268 with psoriatic arthritis (PsA) were enrolled. In biologics, more recently released drugs such as interleukin 17 inhibitors showed a numerically higher survival rate in the overall (post-2010) analysis. However, in the subset of patients who began treatment after 2017, the difference in the survival rate among the drugs was smaller. The reasons for discontinuing drugs varied, but a loss of efficacy against dermatological or joint symptoms were relatively frequently seen with some biologics and cyclosporine. The stratification of drug survival rates based on patient characteristics such as bio-naive or experienced, normal weight or obese, and with or without PsA, revealed that bio-experienced, obese, and PsA groups had poorer survival rates for most drugs. No notable safety issues were identified in this study. Overall, the present study revealed that the biologics show differences in their tendency to develop a loss of efficacy, and the factors that negatively impact the survival rate of biologics include the previous use of biologics, obesity, and PsA.
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Artritis Psoriásica , Productos Biológicos , Psoriasis , Humanos , Artritis Psoriásica/tratamiento farmacológico , Estudios Retrospectivos , Tasa de Supervivencia , Japón/epidemiología , Psoriasis/tratamiento farmacológico , Psoriasis/diagnóstico , Productos Biológicos/uso terapéutico , Ciclosporina/uso terapéutico , Sistema de RegistrosRESUMEN
Previous studies on family history of psoriasis showed that patients with a family history have an earlier onset of the disease, but such studies in Japan are still limited. To elucidate the characteristics of patients with familial psoriasis, we studied the family history of patients with psoriasis using the West Japan Psoriasis Registry, a multi-institutional registry operated by 26 facilities in the western part of Japan, including university hospitals, community hospitals, and clinics. This study enrolled 1847 patients registered between September 2019 and December 2021, with 199 (10.8%) having a family history of psoriasis. Patients with a family history of psoriasis had significantly earlier onset of the disease than those without a family history. Furthermore, patients with a family history of psoriasis had significantly longer disease duration. Psoriatic arthritis (PsA) was significantly more common in patients with a family history (69/199, 34.7%) than in those without a family history (439/1648, 26.6%) (adjusted P = 0.023). A subanalysis of patients with PsA revealed a significant difference in the patient global assessment (PaGA) score in Fisher's exact test and adjusted test. The numbers of patients with PaGA 0/1 were 29 (43.3%) and 172 (39.9%) in patients with PsA with and without family history of psoriasis, respectively, whereas the numbers of patients with PaGA 3/4 were 13 (19.4%) and 145 (33.6%) in patients with PsA with and without family history of psoriasis, respectively. Other disease severity variables did not show a difference between the two groups. Our findings suggest that genetics play a larger role in the development of PsA than in the development of psoriasis vulgaris. Most cases of PsA occur in patients who already have psoriasis, therefore dermatologists should pay attention to joint symptoms, especially in patients with psoriasis who have a family history of psoriasis.
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Artritis Psoriásica , Psoriasis , Humanos , Artritis Psoriásica/diagnóstico , Artritis Psoriásica/epidemiología , Artritis Psoriásica/genética , Psoriasis/diagnóstico , Psoriasis/epidemiología , Psoriasis/genética , Anamnesis , Japón/epidemiologíaRESUMEN
Adult T-cell leukemia/lymphoma (ATL) is an aggressive non-Hodgkin lymphoma with poor prognosis and few treatment options for patients with relapsed, recurrent, or refractory disease. We evaluated the efficacy and safety of valemetostat, a potent enhancer of zeste homolog 2 (EZH2) and EZH1 inhibitor, in treating relapsed or refractory (R/R) ATL. This multicenter phase 2 trial enrolled patients with R/R aggressive ATL (acute, lymphoma, unfavorable chronic type). Patients received valemetostat 200 mg/day orally until progressive disease or unacceptable toxicity. The primary end point was overall response rate (ORR) centrally assessed by an independent efficacy assessment committee (IEAC). Secondary end points included best response in disease compartments, duration of response (DOR), pharmacokinetics, and safety. Twenty-five patients (median age, 69.0 years) with a median of 3 prior lines of therapy were enrolled; 24 had prior mogamulizumab treatment. The primary end point was met with a centrally reviewed ORR of 48.0% (90% confidence interval [CI], 30.5-65.9), including 5 complete and 7 partial remissions. Patients pretreated with mogamulizumab had an ORR of 45.8% (4 complete and 7 partial remissions). IEAC-assessed median DOR was not reached (NR) (95% CI, 1.87 to NR; months). Treatment-emergent adverse events (TEAEs) were manageable. TEAEs that occurred in ≥20% of patients included thrombocytopenia, anemia, alopecia, dysgeusia, neutropenia, lymphopenia, leukopenia, decreased appetite, and pyrexia. Grade ≥3 TEAEs included thrombocytopenia, anemia, lymphopenia, leukopenia, and neutropenia. Valemetostat demonstrated promising efficacy and tolerability in heavily pretreated patients, warranting further investigation in treating R/R ATL. This trial was registered at www.clinicaltrials.gov as #NCT04102150.
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Leucemia-Linfoma de Células T del Adulto , Linfoma , Linfopenia , Neutropenia , Trombocitopenia , Adulto , Humanos , Anciano , Leucemia-Linfoma de Células T del Adulto/tratamiento farmacológico , Recurrencia , Inhibidores Enzimáticos , Enfermedad CrónicaAsunto(s)
Leucemia-Linfoma de Células T del Adulto , Humanos , Leucemia-Linfoma de Células T del Adulto/genética , Cambio de Clase de Inmunoglobulina/genética , Cadenas Pesadas de Inmunoglobulina/genética , Cadenas gamma de Inmunoglobulina/genética , Reordenamiento Génico de Cadena Pesada de Linfocito BRESUMEN
Adult T-cell leukemia/lymphoma (ATL) patients have a very poor prognosis. The humanized anti-CCR4 therapeutic monoclonal antibody, mogamulizumab, is a key agent for ATL treatment. Our previous integrated molecular analysis demonstrated that among all the driver genes in ATL, CCR7 gene alterations were significantly associated with clinical response to mogamulizumab. Accordingly, here we investigated the detailed clinical impact of CCR7 alterations in a larger cohort of ATL patients. These CCR7 alterations, most of which lead to C-terminus truncations, were observed in 27 of 223 patients (12%). For patients receiving mogamulizumab but not allogeneic hematopoietic stem cell transplantation (HSCT), CCR7 alterations were significantly associated with worse survival (median survival from the first dose of mogamulizumab of 0.7 years for 12 patients with CCR7 alterations vs. 1.6 years for 72 patients without, p = 0.020). On the other hand, the presence or absence of CCR7 alterations had no significant impact on survival in the entire cohort (median overall survival of 1.4 and 1.8 years, respectively, p = 0.901), or on the survival of patients receiving allogeneic HSCT (median survival from the day of transplantation of 0.9 years for 6 patients with CCR7 alterations and 1.4 years for 48 without, p = 0.543). Multivariate analysis indicated that patients with CCR4 alterations but lacking CCR7 alterations (n = 20) had significantly better survival after receiving mogamulizumab-containing treatments (hazard ratio for survival, 0.437, 95% confidence interval, 0.192-0.994). This study contributes to the establishment of precision medicine for ATL.
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Anticuerpos Monoclonales Humanizados , Leucemia-Linfoma de Células T del Adulto , Receptores CCR7 , Humanos , Leucemia-Linfoma de Células T del Adulto/tratamiento farmacológico , Leucemia-Linfoma de Células T del Adulto/genética , Receptores CCR7/genética , Anticuerpos Monoclonales Humanizados/uso terapéuticoRESUMEN
This multicenter, prospective phase IIb trial evaluating the efficacy and safety of tucidinostat (HBI-8000) in patients with relapsed or refractory (R/R) adult T-cell leukemia/lymphoma (ATLL) was undertaken in Japan. Eligible patients had R/R ATLL and had failed standard of care treatment with chemotherapy and with mogamulizumab. Twenty-three patients received tucidinostat 40 mg orally twice per week and were included in efficacy and safety analyses. The primary end-point was objective response rate (ORR) assessed by an independent committee. The ORR was 30.4% (95% confidence interval [CI], 13.2, 52.9]. Median progression-free survival was 1.7 months (95% CI, 0.8, 7.4), median duration of response was 9.2 months (95% CI, 2.6, not reached), and median overall survival was 7.9 months (95% CI, 2.3, 18.0). All patients experienced adverse events (AEs), which were predominantly hematologic and gastrointestinal. Incidence of grade 3 or higher AEs was 78.3%; most were laboratory abnormalities (decreases in platelets, neutrophils, white blood cells, and hemoglobin). Tucidinostat was well tolerated with AEs that could be mostly managed with supportive care and dose modifications. Tucidinostat is a meaningful treatment option for R/R ATLL patients; further investigation is warranted.
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Leucemia-Linfoma de Células T del Adulto , Linfoma Folicular , Adulto , Benzamidas , Inhibidores de Histona Desacetilasas/efectos adversos , Humanos , Leucemia-Linfoma de Células T del Adulto/tratamiento farmacológico , Linfoma Folicular/tratamiento farmacológico , Estudios Prospectivos , Piridinas , Recurrencia , Resultado del TratamientoRESUMEN
Cutaneous lymphoma is generally treated with skin-directed therapies (SDT) during the early and localized stages. For the refractory or advanced stages, systemic therapies are used. Previously, retinoids and interferons were used for SDT-resistant cases. Only a few chemotherapy options were available for more advanced disease. In recent years, many novel agents have been introduced and the strategy for systemic therapy has changed, especially for cutaneous T-cell lymphoma (CTCL). For SDT, helical tomotherapy, a new radiation modality, has been drawing attention as an option for radiotherapy. Targeted therapies such as histone deacetylase inhibitors, mogamulizumab, brentuximab vedotin, and denileukin diftitox are new treatment options. Chemotherapy agents such as gemcitabine and pralatrexate have been introduced; they are expected to have meaningful efficacy as monotherapy. Allogeneic hematopoietic stem cell transplantation is still considered for young patients with advanced CTCL as the only potentially curative treatment.
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Antineoplásicos , Trasplante de Células Madre Hematopoyéticas , Linfoma Cutáneo de Células T , Neoplasias Cutáneas , Antineoplásicos/uso terapéutico , Humanos , Linfoma Cutáneo de Células T/tratamiento farmacológico , Retinoides/uso terapéutico , Neoplasias Cutáneas/tratamiento farmacológicoRESUMEN
Total skin electron beam therapy (TSEBT) is a treatment option for mycosis fungoides (MF). In Japan, it has been rarely performed because of the time required for each treatment, physical burden on patients, and difficulties in providing uniform dosimetry. In recent years, helical tomotherapy, an intensity-modulated radiation therapy that applies helical computed tomography technology, has been used to treat cancer. Total skin helical tomotherapy (TSHT) has been suggested as a promising alternative to TSEBT for patients with MF, but there are few reports from Japan. We used TSHT to treat a 28-year-old Japanese woman with tumor stage MF. She achieved complete remission with TSHT (12 Gy in six fractions over 6 days) and remained in remission for 32 months without additional treatment. Treatment-related grade 4 myelosuppression was observed, but resolved with blood transfusions and subcutaneous injection of granulocyte colony stimulating factor. Other adverse events were tolerable. Although careful attention should be paid to myelosuppression, TSHT might be a useful treatment option for MF.
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Micosis Fungoide , Radioterapia de Intensidad Modulada , Neoplasias Cutáneas , Adulto , Femenino , Humanos , Micosis Fungoide/radioterapia , Inducción de Remisión , Piel , Neoplasias Cutáneas/radioterapiaRESUMEN
'Monitoring of immune responses following mogamulizumab-containing treatment in patients with adult T-cell leukaemia-lymphoma (ATL)' (MIMOGA) is a multicentre prospective clinical study (UMIN000008696). In the MIMOGA study, we found that a lower percentage of CD2- CD19+ B cells in peripheral blood mononuclear cells (PBMC) was a significant unfavourable prognostic factor for overall survival (OS). Accordingly, we then analysed the immunoglobulin G (IgG) heavy-chain repertoire in PBMC by high-throughput sequencing. Of the 101 patients enrolled in the MIMOGA study, for 81 a sufficient amount of PBMC RNA was available for repertoire sequencing analysis. Peripheral IgG B cells in patients with ATL had a restricted repertoire relative to those in healthy individuals. There was a significant positive correlation between the Shannon-Weaver diversity index (SWDI) for the IgG repertoire and proportions of B cells in the PBMC of the patients. Multivariate analysis identified two variables significantly affecting OS: a higher serum soluble interleukin-2 receptor level, and a lower SWDI for the IgG repertoire [hazard ratio, 2·124; 95% confidence interval, 1·114-4·049; n = 44]. The present study documents the importance of humoral immune responses in patients receiving mogamulizumab-containing treatment. Further investigation of strategies to enhance humoral immune responses in patients with ATL is warranted.
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Biomarcadores de Tumor , ADN Tumoral Circulante , Inmunoglobulina G/genética , Cadenas Pesadas de Inmunoglobulina/genética , Leucemia-Linfoma de Células T del Adulto/genética , Leucocitos Mononucleares/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Femenino , Variación Genética , Humanos , Leucemia-Linfoma de Células T del Adulto/sangre , Leucemia-Linfoma de Células T del Adulto/tratamiento farmacológico , Leucemia-Linfoma de Células T del Adulto/mortalidad , Masculino , Persona de Mediana Edad , Pronóstico , Modelos de Riesgos Proporcionales , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
CD28, one of the costimulatory molecules, has a pivotal role in T-cell activation, and its expression is strictly regulated in normal T cells. Gain-of-function genetic alterations involving CD28 have been frequently observed in adult T-cell leukemia/lymphoma (ATLL). These abnormalities, such as CD28 fusions and copy number variations, may not only confer continuous, prolonged, and enhanced CD28 signaling to downstream pathways but also induce overexpression of the CD28 protein. In this study, 120 ATLL cases were examined by immunohistochemistry for CD28 and its ligands CD80 and CD86, and their expression on tumor cells was semiquantitatively evaluated. CD28 was overexpressed in 55 (46%) cases, and CD80 or CD86 (CD80/CD86) was infrequently overexpressed in 12 (11%). Compared with non-overexpressers, CD28 overexpressers showed a higher frequency of CD28 genetic alterations and had an increased number of CD80/CD86-positive non-neoplastic cells infiltrating tumor microenvironment. In the entire ATLL patient cohort, CD28 overexpressers showed a significantly poorer overall survival (OS) compared with non-overexpressers (P = .001). The same was true for a subgroup who were treated with multidrug regimens with or without mogamulizumab. CD28 overexpression had no prognostic impact in the group who received allogeneic hematopoietic stem cell transplantation. In the multivariate analysis for OS, CD28 overexpression was selected as an independent risk factor. These results suggest ATLL patients with CD28 overexpression have more aggressive clinical course and are more refractory to treatment with multidrug chemotherapy. CD28 overexpression appears to be a novel unfavorable prognostic marker in ATLL patients, and further prospective studies are warranted to establish its prognostic significance.
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Antígeno B7-1/metabolismo , Antígeno B7-2/metabolismo , Antígenos CD28/genética , Antígenos CD28/metabolismo , Leucemia-Linfoma de Células T del Adulto/mortalidad , Regulación hacia Arriba , Adulto , Anciano , Anciano de 80 o más Años , Variaciones en el Número de Copia de ADN , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Leucemia-Linfoma de Células T del Adulto/genética , Leucemia-Linfoma de Células T del Adulto/metabolismo , Masculino , Persona de Mediana Edad , Pronóstico , Análisis de Supervivencia , Microambiente TumoralRESUMEN
To establish real-world evidence about the safety and efficacy of bexarotene for Japanese patients with cutaneous T-cell lymphoma, we conducted a nationwide cohort study using data from post-marketing surveillance for bexarotene treatment. In total, 294 patients with cutaneous T-cell lymphoma were identified between June 2016 and June 2018. Of these, 267 patients were included as the safety analysis set. Of the 267 patients, 175 were included in the efficacy analysis set. Of these, 139 patients had mycosis fungoides, including 46 with early stage disease and 93 with advanced stage disease. Among the 139 patients with mycosis fungoides, the objective response rate was 46.8%. A significant difference in objective response rate was detected between patients who started with bexarotene at 300 mg/m2 (61.6%) and patients who started with bexarotene at less than 300 mg/m2 (22.6%, p < 0.001). Of the 139 patients with mycosis fungoides, 92 were treated with a combination of bexarotene plus photo(chemo)therapy. A significant difference in objective response rate was seen between bexarotene with a combination of photo(chemo)therapy (57.6%) and bexarotene without a combination of photo(chemo)therapy (25.5%, p < 0.001). Starting bexarotene at 300 mg/m2 and combination with photo(chemo)therapy were detected as independent factors influencing response. Common treatment-related adverse events included hypothyroidism (85.8%), hypertriglyceridemia (68.5%), hypercholesterolemia (43.8%), and neutropenia (21.3%). Hypertriglyceridemia, hypercholesterolemia, and neutropenia occurred more frequently in patients who started with bexarotene at 300 mg/m2 than patients who started with bexarotene at less than 300 mg/m2 (hypertriglyceridemia, 76.4% vs. 57.0%, p = 0.001; hypercholesterolemia, 49.0% vs. 36.4%, p = 0.045; neutropenia, 28.0% vs. 12.1%, p = 0.002; respectively). The present study indicates that starting bexarotene at 300 mg/m2 and combination of photo(chemo)therapy offer a promising efficacy for the treatment of patients with mycosis fungoides. Efficacy of low-dose bexarotene plus photo(chemo)therapy should be evaluated in future.
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Linfoma Cutáneo de Células T , Micosis Fungoide , Neutropenia , Neoplasias Cutáneas , Bexaroteno , Estudios de Cohortes , Humanos , Japón/epidemiología , Linfoma Cutáneo de Células T/tratamiento farmacológico , Micosis Fungoide/tratamiento farmacológico , Vigilancia de Productos Comercializados , Resultado del TratamientoRESUMEN
Generalized pustular psoriasis (GPP) is a rare and severe subtype of psoriasis. Because of its rarity, GPP studies with a large sample size have been scarce. We studied the characteristics of GPP and pustular psoriasis using data from the West Japan Psoriasis Registry that had been registered until the end of December 2020. The dataset included 104 patients with pustular psoriasis and 1290 patients with other subtypes of psoriasis. Multivariate analysis revealed a significantly greater number of female patients, a significantly lower mean body mass index, and a significantly lower ratio of habitual drinkers in pustular psoriasis, compared to other subtypes of psoriasis. Of the 104 patients, 102 had GPP, including 88 von Zumbusch, 10 juvenile-onset, and four annular pustular psoriasis. Although the male : female ratio of GPP with psoriasis vulgaris (GPP+PsV) (47/20) was similar to that of psoriasis in Japan, the GPP without PsV (GPP-PsV) group highlighted a female predominance (13/22). The mean age at GPP onset was 45.3 years, and the mean interval from PsV onset to GPP onset was 12.5 years. Four of nine patients with GPP had an IL36RN gene mutation. Infection, medicine, and pregnancy were the precipitating factors for GPP. A family history of psoriasis was present in eight (7.8%) patients with GPP. Twenty-four patients with GPP had psoriatic arthritis. Biologics were used in 76.5% of patients with GPP, followed by etretinate (37.3%), cyclosporine (24.5%), methotrexate (13.7%), apremilast (8.8%), and granulocyte and monocyte adsorption apheresis (6.9%). Etretinate was used in 17 (51.5%) of 33 patients with GPP with less than 10-year history. Thus, etretinate remains a good treatment option for GPP even in the era of biologics. Hypertension was the most commonly identified comorbidity, followed by diabetes. We believe that the characteristics revealed in this study can further contribute to effective GPP management.
Asunto(s)
Psoriasis , Enfermedades Cutáneas Vesiculoampollosas , Femenino , Humanos , Interleucinas , Japón/epidemiología , Masculino , Metotrexato , Persona de Mediana Edad , Embarazo , Psoriasis/epidemiologíaRESUMEN
Adult T-cell leukaemia/lymphoma (ATL) patients have a poor prognosis. Here, we investigated the impact of TP53 gene mutations on prognosis of ATL treated in different ways. Among 177 patients, we identified 47 single nucleotide variants or insertion-deletions (SNVs/indels) of the TP53 gene in 37 individuals. TP53 copy number variations (CNVs) were observed in 38 patients. Altogether, 67 of 177 patients harboured TP53 SNVs/indels or TP53 CNVs, and were categorized as having TP53 mutations. In the entire cohort, median survival of patients with and without TP53 mutations was 1·0 and 6·7 years respectively (P < 0·001). After allogeneic haematopoietic stem cell transplantation (HSCT), median survival of patients with (n = 16) and without (n = 29) TP53 mutations was 0·4 years and not reached respectively (P = 0·001). For patients receiving mogamulizumab without allogeneic HSCT, the median survival from the first dose of antibody in patients with TP53 mutations (n = 27) was only 0·9 years, but 5·1 years in those without (n = 42; P < 0·001). Thus, TP53 mutations are associated with unfavourable prognosis of ATL, regardless of treatment strategy. The establishment of alternative modalities to overcome the adverse impact of TP53 mutations in patients with ATL is required.
Asunto(s)
Genes p53 , Leucemia-Linfoma de Células T del Adulto/genética , Mutación , Adulto , Anciano , Anciano de 80 o más Años , Aloinjertos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Antígenos CD28/genética , Carboplatino/administración & dosificación , Ciclofosfamida/administración & dosificación , Variaciones en el Número de Copia de ADN , Doxorrubicina/administración & dosificación , Etopósido/administración & dosificación , Femenino , Trasplante de Células Madre Hematopoyéticas , Humanos , Mutación INDEL , Estimación de Kaplan-Meier , Lenalidomida/administración & dosificación , Leucemia-Linfoma de Células T del Adulto/tratamiento farmacológico , Leucemia-Linfoma de Células T del Adulto/mortalidad , Leucemia-Linfoma de Células T del Adulto/terapia , Masculino , Persona de Mediana Edad , Compuestos de Nitrosourea/administración & dosificación , Polimorfismo de Nucleótido Simple , Prednisolona/administración & dosificación , Prednisona/administración & dosificación , Pronóstico , Receptores CCR4/genética , Vincristina/administración & dosificación , Vindesina/administración & dosificaciónRESUMEN
E7777 is a recombinant cytotoxic fusion protein composed of the diphtheria toxin fragments A and B and human interleukin-2. It shares an amino acid sequence with denileukin diftitox, but has improved purity and an increased percentage of active monomer. We undertook a multicenter, single-arm phase II study of E7777 in patients with relapsed or refractory peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL) to evaluate its efficacy, safety, pharmacokinetics, and immunogenicity. A total of 37 patients were enrolled, of which 17 and 19 patients had PTCL and CTCL, respectively, and one patient with another type of lymphoma (extranodal natural killer/T-cell lymphoma, nasal type), diagnosed by the Central Pathological Diagnosis Committee. Among the 36 patients with PTCL and CTCL, objective response rate based on the independent review was 36% (41% and 31%, respectively). The median progression-free survival was 3.1 months (2.1 months in PTCL and 4.2 months in CTCL). The common adverse events (AEs) observed were increased aspartate aminotransferase (AST) / alanine aminotransferase (ALT), hypoalbuminemia, lymphopenia, and pyrexia. Our results indicated that a 9 µg/kg/d dose of E7777 shows efficacy and a manageable safety profile in Japanese patients with relapsed or refractory PTCL and CTCL, with clinical activity observed across the range of CD25 expression. The common AEs were manageable, but increase in ALT / AST, hypoalbuminemia, and capillary leak syndrome should be carefully managed during the treatment.
Asunto(s)
Interleucina-2/administración & dosificación , Linfoma Cutáneo de Células T/tratamiento farmacológico , Linfoma de Células T Periférico/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Proteínas Recombinantes de Fusión/administración & dosificación , Administración Intravenosa , Sitios de Unión , Toxina Diftérica/administración & dosificación , Toxina Diftérica/efectos adversos , Toxina Diftérica/química , Toxina Diftérica/genética , Toxina Diftérica/farmacocinética , Esquema de Medicación , Femenino , Humanos , Interleucina-2/efectos adversos , Interleucina-2/química , Interleucina-2/genética , Interleucina-2/farmacocinética , Japón , Linfoma Cutáneo de Células T/sangre , Linfoma de Células T Periférico/sangre , Masculino , Recurrencia Local de Neoplasia/sangre , Proteínas Recombinantes de Fusión/efectos adversos , Proteínas Recombinantes de Fusión/farmacocinética , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
Mogamulizumab targets extracellular N-terminal domain of CCR4, which is expressed in most adult T-cell leukemia/lymphoma (ATL) cases. Recently, we reported that CCR4 C-terminal gain-of-function mutations were frequent in ATL cases, and a subgroup with these mutations who were treated without allogenic hematopoietic stem cell transplantation (HSCT) and with mogamulizumab-containing [HSCT (-) and mogamulizumab (+)] regimens had a superior survival rate. Although these mutations are most likely a biomarker for predicting a strong response to mogamulizumab, their detection is time-consuming and costly. A more convenient screening tool may be necessary in the clinical setting. In this study, the clinicopathological importance of immunohistochemistry for the CCR4 N-terminus (CCR4-N-IHC) and C-terminus (CCR4-C-IHC) was examined in a large ATL cohort (n = 92). We found that CCR4-C-IHC, but not CCR4-N-IHC, was inversely correlated with the CCR4 mutation status. In ATL patients negative for CCR4-C-IHC, a subgroup treated with HSCT (-) and mogamulizumab (+) regimens showed a significantly better prognosis. In addition, CCR4-C-IHC was found to be a useful marker for high-sensitivity screening of the CCR4 mutational status (87%). The present study suggests that CCR4-C-IHC may be useful for identifying ATL patients harboring mutated CCR4 who may benefit from the superior efficacy of mogamulizumab-containing regimens and that CCR4-C-IHC may be a rapid and cost-efficient tool for screening for CCR4 mutation status.