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Alemtuzumab is recommended as first-line and second-line therapies for T-cell prolymphocytic leukemia (T-PLL). This study retrospectively evaluated the efficacy and safety of alemtuzumab in nine Japanese patients with T-PLL at five participating institutions who were treated between January 2015 and August 2023. The median age at first administration of alemtuzumab was 72 years (range, 39 to 78). Two patients were treatment naïve, and seven had been treated with a median of one (range, 1 to 3) prior systemic therapy. Six patients were refractory to their most recent therapy. Three patients completed 12 weeks of treatment. The overall response rate and the complete response (CR) rate were 78% and 11%, respectively. Among the six patients who achieved a partial response, two achieved clinical CR but did not undergo bone marrow examination. One patient also achieved clinical CR but did not undergo CT or bone marrow examination for response evaluation. The median progression-free survival time was 8.1 months (95% confidence interval, 0.9 to 18.6). Three patients received readministration of alemtuzumab monotherapy after disease progression. There were no treatment-related deaths. The grade 3 or 4 nonhematologic adverse events included infusion reaction (grade 3, n = 2), cytomegalovirus reactivation (grade 3, n = 2), and pulmonary edema (grade 3, n = 1). One patient experienced EpsteinâBarr virus-positive diffuse large B-cell lymphoma 15 months after the last dose of alemtuzumab. These results confirm that the efficacy and safety of alemtuzumab monotherapy in Japanese patients are comparable to those previously reported.
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Mogamulizumab is a humanized antibody targeting CC chemokine receptor 4 (CCR4). This post-marketing surveillance was conducted in Japan as a regulatory requirement from 2014 to 2020 to ensure the safety and effectiveness of mogamulizumab in patients with relapsed or refractory (r/r) CCR4-positive peripheral T-cell lymphoma (PTCL) or r/r cutaneous T-cell lymphoma (CTCL). Safety and effectiveness data were collected for up to 31 weeks after treatment initiation. A total of 142 patients were registered; safety was evaluated in 136 patients. The median number of doses was 8.0 (range, 1-18). The main reasons for treatment termination were insufficient response (22.1%) and adverse events (13.2%). The frequency of any grade adverse drug reaction was 57.4%, including skin disorders (26.5%), infections and immune system disorders (16.2%), and infusion-related reactions (13.2%). Graft-versus-host disease, grade 2, developed in one of two patients who underwent allogeneic-hematopoietic stem cell transplantation after receiving mogamulizumab. Effectiveness was evaluated in 131 patients (103 with PTCL; 28 with CTCL). The best overall response rate was 45.8% (PTCL, 47.6%; CTCL, 39.3%). At week 31, the survival rate was 69.0% (95% confidence interval, 59.8%-76.5%) [PTCL, 64.4% (54.0%-73.0%); CTCL, 90.5% (67.0%-97.5%)]. Safety and effectiveness were comparable between patients <70 and ≥ 70 years old and between those with relapsed and refractory disease. The safety and effectiveness of mogamulizumab for PTCL and CTCL in the real world were comparable with the data reported in previous clinical trials. Clinical Trial Registration.
Assuntos
Anticorpos Monoclonais Humanizados , Linfoma Cutâneo de Células T , Linfoma de Células T Periférico , Receptores CCR4 , Humanos , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/administração & dosagem , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Receptores CCR4/antagonistas & inibidores , Adulto , Japão , Linfoma Cutâneo de Células T/tratamento farmacológico , Linfoma Cutâneo de Células T/patologia , Linfoma de Células T Periférico/tratamento farmacológico , Idoso de 80 Anos ou mais , Vigilância de Produtos Comercializados , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Adulto Jovem , Resistencia a Medicamentos AntineoplásicosRESUMO
A 24-year-old man was found to have an ileocecal ulcer by colonoscopy. A pathological diagnosis of diffuse large B-cell lymphoma (DLBCL) with diffuse positive reaction of Epstein-Barr encoding region (EBER) by in situ hybridization was made based on analysis of the specimen. Acquired immunodeficiency syndrome (AIDS) complicated by pneumocystis jirovecii pneumonia was also diagnosed. As no other significant lymphomatous lesions were identified by further examination, a clinical diagnosis of EBV-positive mucocutaneous ulcer (EBVMCU) was made. Rather than performing systemic chemotherapy, the lesion was closely monitored and antiretroviral therapy (ART) for AIDS was started with the hope of treating the lesion through immune reconstitution. The lesion had completely disappeared by day 79 after starting ART, and has not recurred for over 3 years. EBVMCU is known to develop secondary to various immunosuppressive states including AIDS. Here we report a rare case of EBVMCU detected at diagnosis of AIDS that entered complete remission after immune reconstitution by ART.
Assuntos
Síndrome da Imunodeficiência Adquirida , Infecções por Vírus Epstein-Barr , Infecções por HIV , Linfoma Difuso de Grandes Células B , Masculino , Humanos , Adulto Jovem , Adulto , Úlcera/etiologia , Herpesvirus Humano 4 , Remissão Espontânea , Síndrome da Imunodeficiência Adquirida/complicações , Recidiva Local de Neoplasia , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/diagnóstico , Linfoma Difuso de Grandes Células B/complicações , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/patologia , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológicoRESUMO
Epcoritamab is a subcutaneously administered CD3xCD20 bispecific Ab that showed deep, durable responses with a manageable safety profile in patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) in the global multicenter pivotal phase II trial EPCORE NHL-1. Here, we present results from the similar EPCORE NHL-3 phase I/II trial evaluating epcoritamab monotherapy in Japanese patients with R/R CD20+ B-cell non-Hodgkin's lymphoma previously treated with two or more lines of therapy. Epcoritamab was dosed subcutaneously in 28-day cycles; once weekly during cycles 1-3, every 2 weeks during cycles 4-9, and every 4 weeks from cycle 10 until disease progression or unacceptable toxicity. Step-up dosing and cytokine release syndrome (CRS) prophylaxis were used during treatment cycle 1. As of January 31, 2022, 36 patients received treatment with 48 mg epcoritamab monotherapy. At a median follow-up of 8.4 months, overall response and complete response rates by independent review committee were 55.6% and 44.4%, respectively. The median duration of response, duration of complete response, and overall survival were not reached at the time of data cut-off. The most common treatment-emergent adverse events of any grade were CRS (83.3%), injection-site reactions (69.4%), infections (44.4%), neutropenia (38.9%), hypokalemia (27.8%), and decreased lymphocyte count (25.0%). Cytokine release syndrome occurrence was predictable; events were primarily low grade (grade 1-2), all resolved, and none led to treatment discontinuation. These encouraging results are consistent with previous findings and support the ongoing clinical evaluation of epcoritamab for the treatment of R/R DLBCL, including in earlier treatment lines.
Assuntos
Antineoplásicos , Linfoma Difuso de Grandes Células B , Linfoma não Hodgkin , Adulto , Humanos , Antineoplásicos/uso terapêutico , Síndrome da Liberação de Citocina/tratamento farmacológico , Japão , Linfoma Difuso de Grandes Células B/patologia , Linfoma não Hodgkin/tratamento farmacológico , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Estudos Multicêntricos como AssuntoRESUMO
IMPORTANCE: The World Health Organization estimated that 5-10 million people are infected with human T-cell leukemia virus type 1 (HTLV-1). This number is likely to be underestimated because reliable endemic data are available for only approximately 1.5 billion people worldwide. The point-of-care test is a powerful tool for the easy and quick detection of infections without the requirement for expensive instruments and laboratory equipment. Espline HTLV-I/II, a newly developed rapid immunochromatographic antibody test that was evaluated in this study, might significantly advance our understanding of the global epidemiology of HTLV-1 infection.
Assuntos
Infecções por HTLV-I , Vírus Linfotrópico T Tipo 1 Humano , Humanos , Infecções por HTLV-I/diagnóstico , Infecções por HTLV-I/epidemiologiaRESUMO
This prospective observational study aimed to assess the serological response and safety after the third booster shot of SARS-CoV-2 mRNA vaccines in 292 hematopoietic cell transplant (HCT) recipients. In our patients, mild systemic reactions were present in 10-40% and GVHD aggravation in 1.1%. Overall, clinically relevant response (>250 U/mL) was observed in 93.1% of allogeneic (allo)-HCT recipients and 70.6% of autologous (auto)-HCT recipients, respectively. Of note, detectable antibody response with any titer following the first two doses was a powerful predictor for adequate response after booster shot in both cohorts. For such patients, 98.8% of allo- and 92.3% of auto-HCT recipients obtained clinically relevant response after dose 3. In addition, continued systemic steroid and/or calcineurin inhibitors at the booster shot significantly correlated with serological response. These findings highlighted that booster vaccination efficiently improved serological response without safety concerns and thus recommended for the majority of HCT recipients.
Assuntos
Vacinas contra COVID-19 , COVID-19 , Transplante de Células-Tronco Hematopoéticas , Humanos , Anticorpos Antivirais , COVID-19/prevenção & controle , População do Leste Asiático , Transplantados , Vacinas contra COVID-19/administração & dosagemRESUMO
Adult T-cell leukemia/lymphoma (ATL) is a hematopoietic malignancy with a poor prognosis that develops in approximately 5% of human T-cell leukemia virus type 1 (HTLV-1) carriers. Cyclin-dependent kinase 9 (CDK9), together with Cyclin T, forms a transcription elongation factor, positive transcription elongation factor b (P-TEFb). P-TEFb promotes transcriptional elongation by phosphorylating the second serine (Ser2) of the seven amino acid repeat sequence in the C-terminal domain of RNA polymerase II (RNAP II). CDK9 inhibitors suppress cell proliferation by inducing apoptosis in chronic lymphocytic leukemia and breast cancer but there are no reports on autophagy of CDK9 inhibitors. Here, we investigated the effect of LY2857785, a novel CDK9 selective inhibitor, on cell death in ATL-related cell lines in vitro, freshly isolated cells from ATL patients ex vivo, and on ATL tumor xenografts in NOD/SCID mice in vivo. LY2857785 significantly reduced cell viability and induced apoptosis, as shown by annexin V-positive cells, cleaved poly(ADP-ribose) polymerase (PARP), and cleaved caspase-3, and suppressed the levels of anti-apoptotic protein myeloid cell leukemia-1 (MCL-1). LY2857785 decreased RNAP II Ser2 phosphorylation and downstream c-Myc protein levels. Interestingly, LY2857785 also increased microtubule-associated proteins 1A/1B light chain 3B (LC3)-II binding to autophagosome membranes. Furthermore, LY2857785 decreased the viability of freshly isolated ATL cells and induced apoptosis. Finally, LY2857785 significantly decreased the growth of ATL tumor xenografts. These results suggest that LY2857785 induces cell death of ATL cells by MCL-1-dependent apoptosis and autophagy and has anti-tumor activity.
Assuntos
Neoplasias da Mama , Leucemia-Linfoma de Células T do Adulto , Linfoma , Camundongos , Adulto , Animais , Humanos , Feminino , Camundongos Endogâmicos NOD , Camundongos SCID , Leucemia-Linfoma de Células T do Adulto/tratamento farmacológico , Fator B de Elongação Transcricional Positiva , Proteína de Sequência 1 de Leucemia de Células Mieloides , Inibidores de Proteínas Quinases , Apoptose , Autofagia , Quinase 9 Dependente de CiclinaRESUMO
Adult T-cell leukemia-lymphoma is defined as peripheral T-cell lymphoma caused by the human T-cell leukemia virus type I. Adult T-cell leukemia-lymphoma is classified into indolent (favorable chronic or smoldering) or aggressive (acute, lymphoma or unfavorable chronic) types. This review discusses the therapeutic developments for patients with adult T-cell leukemia-lymphoma and unmet issues in treating adult T-cell leukemia-lymphoma. For indolent adult T-cell leukemia-lymphoma, a watchful waiting strategy is recommended until the disease progresses to aggressive adult T-cell leukemia-lymphoma. For aggressive adult T-cell leukemia-lymphoma, multi-agent chemotherapy with or without allogeneic hematopoietic stem cell transplantation has been recommended. However, many patients with adult T-cell leukemia-lymphoma relapse, and their prognosis is poor. Recently, novel agents, including mogamulizumab, lenalidomide, brentuximab vedotin, tucidinostat and valemetostat, have been approved for patients with relapsed or refractory aggressive adult T-cell leukemia-lymphoma, and the combination of mogamulizumab with multi-agent chemotherapy or brentuximab vedotin with cyclophosphamide, doxorubicin and prednisone has been approved for patients with untreated aggressive adult T-cell leukemia-lymphoma in Japan. Importantly, the aging of patients with adult T-cell leukemia-lymphoma has recently been reported, and no standard of care for elderly patients with adult T-cell leukemia-lymphoma has been established. New evidence must be obtained from prospective clinical trials to improve the prognosis of patients with adult T-cell leukemia-lymphoma.
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Transplante de Células-Tronco Hematopoéticas , Leucemia-Linfoma de Células T do Adulto , Adulto , Humanos , Idoso , Leucemia-Linfoma de Células T do Adulto/tratamento farmacológico , Brentuximab Vedotin/uso terapêutico , Estudos Prospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclofosfamida/uso terapêuticoRESUMO
Enhancer of zeste homolog (EZH), a subunit of polycomb repressive complex 2 (PRC2), suppresses gene expression by methylation of H3K27. EZH is closely associated with B-cell development and pathogenesis of certain malignant lymphomas. In follicular lymphoma (FL), gain-of-function mutation and upregulation of EZH2 are observed in approximately 30% and 15% of cases, respectively. Moreover, one-third of diffuse large B-cell lymphomas carry an EZH2 mutation, mostly co-existing with translocation involving Bcl-2. Genome-wide trimethylation of H3K27 is a unique characteristic induced by upregulation of both EZH2 and EZH1, and is responsible for more than half of the gene suppression that occurs in adult T-cell leukemia/lymphoma (ATL). Inhibition of EZH can reduce H3K27 methylation and subsequently restore epigenetically suppressed genes. Currently, an EZH2 inhibitor and dual EZH1/2 inhibitor have been clinically used to treat relapsed/refractory FL and ATL, respectively. EZH-targeted treatment for lymphoma has only just begun, and further development of these drugs for various other malignancies, both alone and in combination with other therapeutics, is ongoing.
Assuntos
Leucemia-Linfoma de Células T do Adulto , Linfoma Difuso de Grandes Células B , Adulto , Humanos , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Complexo Repressor Polycomb 2/genética , Inibidores EnzimáticosRESUMO
Adult T-cell leukemia/lymphoma (ATL) is a malignancy of mature peripheral T-lymphocytes caused by human T-cell leukemia virus type I (HTLV-I). There are an estimated 5-20 million HTLV-1-infected individuals worldwide. Conventional chemotherapeutic regimens used against other malignant lymphomas have been administered to patients with ATL, but the therapeutic outcomes of acute and lymphoma-type ATL remain extremely poor. In the course of our screening program for novel chemotherapeutic candidate compounds from plants against two human T-cell leukemia virus I-infected T-cell lines (MT-1 and MT-2), we screened 16 extracts obtained from different parts of 7 Solanaceae plants. We identified that the extracts of Physalis pruinosa and P. philadelphica showed potent anti-proliferative activity in MT-1 and MT-2 cells. In our previous study, we have isolated withanolides from extract of aerial parts of P. pruinosa and examined their structure-activity relationships. In addition, we are also investigating further structure-activity relationships about other withanolides from Solanaceae plants (Withania somnifera, Withania coagulans, Physalis angulate, Nicandra physalodes, Petunia hybrida, and Solanum cilistum). In this study, we attempted to isolate their active compounds against MT-1 and MT-2 from extracts of P. philadelphica. We identified 13 withanolides, including six newly isolated compounds [24R, 25S-4ß, 16ß, 20R-trihydroxy-1-oxowitha-2-en-5ß, 6 ß -epoxy-22,26-olide (1), 4ß, 7ß,20R-trihydroxy-1-oxowitha-2-en-5ß, 6ß -epoxy-22,26-olide (2), 17ß,20 S-dihydroxywithanone (3), 2,3-dihydro-3ß-methoxy-23ß-hydroxywithaphysacarpin (4), 3-O-(4-rhamnosyl)glucosyl-physalolactone B (5), and 17R, 20R, 22S, 23S, 24R, 25R-4ß, 5α, 6ß, 20ß, 22α -tetrahydroxy-16ß, 23-diepoxy-1-oxowitha-2-en-26, 23-olide (6)], from the extract and examined the structure-activity relationships. The 50% effective concentration of withaphysacarpin (compound 7) [MT-1: 0.10 µM and MT-2: 0.04 µM] was comparable to that of etoposide [MT-1: 0.08 µM and MT-2: 0.07 µM]. Therefore, withanolides might be promising candidates for the treatment of ATL.
Assuntos
Leucemia-Linfoma de Células T do Adulto , Physalis , Solanaceae , Vitanolídeos , Humanos , Vitanolídeos/farmacologia , Leucemia-Linfoma de Células T do Adulto/tratamento farmacológico , Relação Estrutura-Atividade , Extratos Vegetais/farmacologiaRESUMO
T-cell lymphomas are rare and aggressive tumors, and not only basic research but also the establishment of standard therapies and development of novel drugs for these tumors once lagged behind those for B-cell lymphomas. Now, times have changed. Recent progress in genome-wide analysis made it possible to elucidate the molecular pathophysiology of T-cell lymphomas, and will further facilitate the development of individualized treatment. Japan has a terrible form of virally induced T-cell lymphoma known as adult T-cell leukemia/lymphoma (ATL). Japanese researchers have played significant roles in both basic and clinical research, and finally successfully introduced two brand new drugs from Japan, an anti-CCR4 antibody and an EZH1/2 inhibitor. Large phase 3 trials have now established the addition of brentuximab vedotin to conventional chemotherapy as the standard of care for CD30-positive peripheral T-cell lymphoma (PTCL), including ATL. In contrast, most novel drugs for relapsed/refractory PTCL have been approved on the basis of evidence from small phase 2 trials. Patients still have many unmet needs that we must address. This issue of Progress in Hematology focuses on progress in basic and clinical research on PTCL and ATL.
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Linfoma de Células T Periférico , Linfoma de Células T , Adulto , Humanos , Linfoma de Células T Periférico/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma de Células T/tratamento farmacológico , Brentuximab Vedotin/uso terapêutico , RecidivaRESUMO
A tyrosine kinase inhibitor (TKI) was used to treat the patient, a 35-year-old woman who was diagnosed with chronic myeloid leukemia at the age of 22 years. Since a four-year deep molecular response (DMR) was obtained, spontaneous pregnancy was planned under TKI withdrawal. Even though her disease had advanced to MR2.0 at the time of pregnancy confirmation, 2 months from TKI cessation, interferon α therapy was initiated in light of the patient's history. Later, the patient reached MR3.0, gave birth to a healthy baby, and maintained MR3.0-4.0. TKI was resumed after about 6 months of breastfeeding. Treatment-free remission (TFR) is required for natural conception despite the teratogenicity and miscarriage risks associated with BCR::ABL1 TKIs. When planning a pregnancy, it is also necessary to take the patients' backgrounds, disease states, and medical history into account.
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Leucemia Mielogênica Crônica BCR-ABL Positiva , Humanos , Gravidez , Feminino , Adulto Jovem , Adulto , Interferon-alfa/uso terapêutico , Proteínas de Fusão bcr-abl/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Inibidores de Proteínas Quinases/uso terapêutico , Recidiva , Resultado do TratamentoRESUMO
Next-generation sequencing of AML has identified specific genetic mutations in AML patients. Hematologic Malignancies (HM)-SCREEN-Japan 01 is a multicenter study to detect actionable mutations using paraffin-embedded bone marrow (BM) clot specimens rather than BM fluid in AML patients for whom standard treatment has not been established. The purpose of this study is to evaluate the presence of potentially therapeutic target gene mutations in patients with newly diagnosed unfit AML and relapsed/refractory AML (R/R-AML) using BM clot specimens. In this study, 188 patients were enrolled and targeted sequencing was undertaken on DNA from 437 genes and RNA from 265 genes. High-quality DNA and RNA were obtained using BM clot specimens, with genetic alterations successfully detected in 177 patients (97.3%), and fusion transcripts in 41 patients (23.2%). The median turnaround time was 13 days. In the detection of fusion genes, not only common fusion products such as RUNX1-RUX1T1 and KMT2A rearrangements, but also NUP98 rearrangements and rare fusion genes were observed. Among 177 patients (72 with unfit AML, 105 with R/R-AML), mutations in KIT and WT1 were independent factors for overall survival (hazard ratio = 12.6 and 8.88, respectively), and patients with high variant allele frequency (≥40%) of TP53 mutations had a poor prognosis. As for the detection of actionable mutations, 38% (n = 69) of patients had useful genetic mutation (FLT3-ITD/TKD, IDH1/2, and DNMT3AR822 ) for treatment selection. Comprehensive genomic profiling using paraffin-embedded BM clot specimens successfully identified leukemic-associated genes that can be used as therapeutic targets.
Assuntos
Neoplasias Hematológicas , Leucemia Mieloide Aguda , Humanos , Medula Óssea , Prognóstico , Nucleofosmina , Japão , Inclusão em Parafina , Mutação , Leucemia Mieloide Aguda/tratamento farmacológico , RNA , GenômicaRESUMO
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).
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Transplante de Células-Tronco Hematopoéticas , Leucemia-Linfoma de Células T do Adulto , Linfoma , Adulto , Humanos , Leucemia-Linfoma de Células T do Adulto/genética , Leucemia-Linfoma de Células T do Adulto/terapia , Prognóstico , Receptores CCR7 , Estudos RetrospectivosRESUMO
Adult T-cell leukemia/lymphoma (ATL) is a peripheral T-cell malignancy caused by human T-cell leukemia virus type-I (HTLV-1). This study investigated whether the number of newly diagnosed patients with ATL is decreasing in the background of a declining number of individuals infected by HTLV-1 in Kagoshima, Japan, one of the most endemic areas of HTLV-1 in the world. We retrospectively analyzed the number of newly diagnosed patients with ATL between January 2001 and December 2021 in three major hospitals. The number of newly diagnosed patients with B-cell non-Hodgkin lymphoma (B-NHL) in the same period was examined as an internal control. One thousand eighteen and 2,029 patients with ATL and B-NHL were registered, respectively. The age-adjusted incidence of ATL steadily increased between 2001 and 2012, whereas that between 2013 and 2021 decreased. Despite the limitation of its retrospective nature, this is the first report indicating a decrease in ATL patients in Japan.
Assuntos
Vírus Linfotrópico T Tipo 1 Humano , Leucemia-Linfoma de Células T do Adulto , Linfoma , Adulto , Humanos , Leucemia-Linfoma de Células T do Adulto/diagnóstico , Leucemia-Linfoma de Células T do Adulto/epidemiologia , Estudos Retrospectivos , Japão/epidemiologia , Linfoma/complicaçõesRESUMO
Essential thrombocythemia (ET) cases without canonical JAK2, CALR, or MPL mutations, that is, triple-negative (TN) ET, have been found in 10%-20% of ET cases. Owing to the limited number of TN ET cases, its clinical significance remains unclear. This study evaluated TN ET's clinical characteristics and identified novel driver mutations. Among 119 patients with ET, 20 (16.8%) had no canonical JAK2/CALR/MPL mutations. Patients with TN ET tended to be younger and had lower white blood cell counts and lactate dehydrogenase values. We identified putative driver mutations in 7 (35%): MPL S204P, MPL L265F, JAK2 R683G, and JAK2 T875N were previously reported as candidate driver mutations in ET. Moreover, we identified a THPO splicing site mutation, MPL*636Wext*12, and MPL E237K. Four of the seven identified driver mutations were germline. Functional studies on MPL*636Wext*12 and MPL E237K revealed that they are gain-of-function mutants that increase MPL signaling and confer thrombopoietin hypersensitivity with very low efficiency. Patients with TN ET tended to be younger, although this was thought to be due to the inclusion of germline mutations, hereditary thrombocytosis. Accumulating the genetic and clinical characteristics of noncanonical mutations may help future clinical interventions in TN ET and hereditary thrombocytosis.