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Background: Rosai-Dorfman disease (RDD) is a rare heterogeneous histiocytic disorder lacking standardized first-line treatment. Methods: This single-center, phase 2 prospective study enrolled 13 newly diagnosed and 10 recurrent RDD patients from June 2021 to March 2023 at Peking Union Medical College Hospital (Beijing, China). Lenalidomide 25 mg days 1-21 plus dexamethasone 40 mg days 1, 8, 15, 22 was administered in 28-day cycles, totaling 12 cycles. The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall response rate (ORR) to lenalidomide and dexamethasone (RD) regimen, toxicity, and overall survival (OS) measured from RD start to death or last follow-up. OS and PFS were estimated according to Kaplan-Meier survival analysis and compared with the log-rank test. For OS and OR rate, 95% confidence limits were obtained using the Clopper-Pearson method, with standard methods used for PFS. p < 0.05 was considered statistically significant. The trial was registered with ClinicalTrials.gov (NCT04924647). Findings: The median age was 44 years (IQR 35-54). All patients had extranodal RDD. MAPK pathway alterations occurred in 6/18 (33%). Elevated IL-6 and TNF-α were found in 39% (n = 9) and 70% (n = 16), respectively. All patients received ≥6 cycles (median 12, range 6-12, IQR 10-12). The ORR was 87% (20/23, 95% CI 66%-97%), 30% (n = 7) complete remission, 57% (n = 13) partial remission). Treatment with RD significantly decreased median serum levels of both IL-6 (from 5.9 (IQR 4.2-8.7) to 2.9 (IQR 2.1-5.9) pg/mL, p = 0.031) and TNF-α (from 12.2 (IQR 8.6-17.9) to 8.3 (IQR 6.1-10.5) pg/mL, p = 0.0012). With a median 26 months follow-up (range 6-28, IQR 16-28), 4 patients relapsed and none died. Two-year OS and PFS were 100.0% (95% CI 85%-100%) and 69.0% (95% CI 51%-94%), respectively. No grade 3-4 adverse events or discontinuations due to adverse events occurred. Twelve patients (n = 12, 52%) had grade 1-2 hematological toxicity. Other toxicities included constipation (n = 2, 9%), glucose intolerance (n = 2, 9%), edema (n = 2, 9%), insomnia (n = 1, 4%), and tremor (n = 1, 4%). Interpretation: Lenalidomide and dexamethasone regimen is an effective and safe regimen for newly diagnosed and recurrent RDD. Funding: National Natural Science Foundation of China, Beijing Natural Science Haidian frontier Foundation Funding, and the National High Level Hospital Clinical Research Funding.
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BACKGROUND AND AIMS: Liver involvement portends poor prognosis in adults. We aimed to characterize the clinical features, liver function tests, radiologic findings, molecular profiles, therapeutic approaches and outcomes of adults patients with Langerhans cell histiocytosis (LCH) with liver involvement. METHODS: We conducted a retrospective analysis of all adults with LCH (≥â 18 years) seen at Peking Union Medical College Hospital (Beijing, China) between January 2001 and December 2022. RESULTS: Among the 445 newly diagnosed adults with LCH, 90 patients had liver involvement at diagnosis and 22 patients at relapse. The median age was 32 years (range, 18-66 years). Of 112 evaluable patients, 108 had full liver function testing, including alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase (ALP), γ-glutamyl transpeptidase (GGT), and total bilirubin and albumin. Elevated ALP was seen in 63.0% and GGT in 86.1%; 14.8% had elevated bilirubin. Next-generation sequencing of 54 patients revealed frequent BRAFN486_P490 (29.6%), BRAFV600E (18.5%), and MAP2K1 (14.8%). OUTCOMES: After a median 40 months' follow-up (range 1-168 months), 3-year progression-free survival (PFS) and overall survival were 49.7% and 86.6% respectively. In multivariable analyses, ≥3 abnormal liver function tests (HR 3.384, 95% CI 1.550-7.388, Pâ =â .002) associated with inferior PFS; immunomodulatory drug therapy (HR 0.073, 95% CI, 0.010-0.541, Pâ =â .010) correlated with superior PFS versus chemotherapy. CONCLUSIONS: In summary, elevated GGT and ALP were common in adults with LCH liver involvement. Greater than equal to 3 abnormal liver function tests predicted poor outcomes. Immunomodulatory drug therapy was associated with favorable progression-free survival compared to chemotherapy.
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In this prospective, multicenter, Phase 2 clinical trial (NCT02987244), patients with peripheral T-cell lymphomas (PTCLs) who had responded to first-line chemotherapy with cyclophosphamide, doxorubicin or epirubicin, vincristine or vindesine, etoposide, and prednisone (Chi-CHOEP) were treated by autologous stem cell transplantation (ASCT) or with chidamide maintenance or observation. A total of 85 patients received one of the following interventions: ASCT (n = 15), chidamide maintenance (n = 44), and observation (n = 26). estimated 3 PFS and OS rates were 85.6%, 80.8%, and 49.4% (P = 0.001). The two-year OS rates were 85.6%, 80.8%, and 69.0% (P = 0.075).The ASCT and chidamide maintenance groups had significantly better progression-free survival (PFS) than the observation group (P = 0.001, and P = 0.01, respectively). The overall survival (OS) differed significantly between the chidamide maintenance group and the observation group ( P = 0.041). The multivariate and propensity score matching analyses for PFS revealed better outcomes in the subjects in the chidamide maintenance than observation groups (P = 0.02). The ASCT and chidamide maintenance groups had significant survival advantages over the observation group. In the post-remission stage of the untreated PTCL patients, single-agent chidamide maintenance demonstrated superior PFS and better OS than observation. Our findings highlight the potential benefit of chidamide in this patient subset, warranting further investigation through larger prospective trials. Clinical trial registration: clinicaltrial.gov, NCT02987244. Registered 8 December 2016, http://www.clinicaltrials.gov/ct2/show/NCT02987244 .
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Aminopiridinas , Protocolos de Quimioterapia Combinada Antineoplásica , Benzamidas , Trasplante de Células Madre Hematopoyéticas , Linfoma de Células T Periférico , Humanos , Linfoma de Células T Periférico/terapia , Linfoma de Células T Periférico/mortalidad , Linfoma de Células T Periférico/tratamiento farmacológico , Masculino , Femenino , Adulto , Persona de Mediana Edad , Aminopiridinas/uso terapéutico , Benzamidas/uso terapéutico , Estudios Prospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , China/epidemiología , Trasplante Autólogo , Anciano , Tasa de Supervivencia , Adulto Joven , Quimioterapia de Mantención , Autoinjertos , Inducción de Remisión , AdolescenteRESUMEN
BACKGROUND: Cryoglobulinemia with pulmonary involvement is rare, and its characteristics, radiological findings, and outcomes are still poorly understood. METHODS: Ten patients with pulmonary involvement of 491 cryoglobulinemia patients at Peking Union Medical College Hospital were enrolled in this retrospective study. We analyzed the characteristics, radiological features and management of pulmonary involvement patients, and compared with those of non-pulmonary involvement with cryoglobulinemia. RESULTS: The 10 patients with pulmonary involvement (2 males; median age, 53 years) included three patients with type I cryoglobulinemia and seven patients with mixed cryoglobulinemia. All of 10 patients were IgM isotype cryoglobulinemia. All type I patients were secondary to B-cell non-Hodgkin lymphoma. Four mixed patients were essential, and the remaining patients were secondary to infections (n = 2) and systemic lupus erythematosus (n = 1), respectively. Six patients had additional affected organs, including skin (60%), kidney (50%), peripheral nerves (30%), joints (20%), and heart (20%). The pulmonary symptoms included dyspnea (50%), dry cough (30%), chest tightness (30%), and hemoptysis (10%). Chest computed tomography (CT) showed diffuse ground-glass opacity (80%), nodules (40%), pleural effusions (30%), and reticulation (20%). Two patients experienced life-threatening diffuse alveolar hemorrhage. Five patients received corticosteroid-based regimens, and four received rituximab-based regimens. All patients on rituximab-based regimens achieved clinical remission. The estimated two-year overall survival (OS) was 40%. Patients with pulmonary involvement had significantly worse OS and progression-free survival than non-pulmonary involvement patients of cryoglobulinemia (P < 0.0001). CONCLUSIONS: A diagnosis of pulmonary involvement should be highly suspected for patients with cryoglobulinemia and chest CT-indicated infiltrates without other explanations. Patients with pulmonary involvement had a poor prognosis. Rituximab-based treatment may improve the outcome.
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Crioglobulinemia , Humanos , Crioglobulinemia/patología , Crioglobulinemia/diagnóstico por imagen , Crioglobulinemia/complicaciones , Masculino , Persona de Mediana Edad , Femenino , Estudios Retrospectivos , Anciano , Adulto , Tomografía Computarizada por Rayos X , Enfermedades Pulmonares/diagnóstico por imagen , Enfermedades Pulmonares/patología , Enfermedades Pulmonares/tratamiento farmacológico , Pulmón/diagnóstico por imagen , Pulmón/patologíaAsunto(s)
Anticuerpos Monoclonales , Protocolos de Quimioterapia Combinada Antineoplásica , Bortezomib , Dexametasona , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas , Humanos , Bortezomib/administración & dosificación , Bortezomib/efectos adversos , Bortezomib/uso terapéutico , Dexametasona/administración & dosificación , Dexametasona/efectos adversos , Dexametasona/uso terapéutico , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/tratamiento farmacológico , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/mortalidad , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/diagnóstico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/uso terapéutico , Masculino , Femenino , Estudios Prospectivos , Anciano , Resultado del Tratamiento , Persona de Mediana Edad , Estadificación de NeoplasiasRESUMEN
Waldenström macroglobulinemia (WM) is a type of B-cell lymphoma that produces IgM. Our study aimed to investigate the role of CXCL13, a chemokine essential for B lymphocytes, in the evaluation of treatment response and prognosis in WM. We collected serum samples and clinical data from 72 WM patients, with 69 patients receiving systemic therapy and 3 patients opting not to receive treatment. Serum CXCL13 levels at baseline and after six months of treatments were measured by enzyme-linked immunosorbent assay. The median serum level of CXCL13 was 1 539.2 pg/ml (range 10.0-21 389.9) at baseline and significantly decreased to 123.1 pg/ml (range 0.0-6 741.5) after 6 months of treatments. At baseline, higher CXCL13 levels were associated with lower hemoglobin levels (p = 0.001), higher ß2-microglobulin levels (p = 0.001), lower albumin levels (p = 0.046), and higher IPSS-WM scores (p = 0.013). After 6 months of treatment, patients who achieved PR/VGPR had significantly lower CXCL13 levels compared to those with SD (70.2 pg/ml vs 798.6 pg/ml, p = 0.002). The median follow-up period was 40 months (range 4.2-188). Eight patients died during the follow-up period. Overall survival differed based on CXCL13 levels. When grouped by baseline CXCL13 levels, the median OS was 60.0 months in patients with serum CXCL13 > 2 000 pg/ml, while it was not reached in patients with low CXCL13 levels (p < 0.001). Based on CXCL13 levels after the treatments, the median OS was 74.0 months in patients with serum CXCL13 > 200 pg/ml, while it was not reached in patients with CXCL13 ≤ 200 pg/ml. In a subgroup of 28 patients with a series of serum samples, the increase of serum CXCL13 level was associated with disease progression or the start of next-line therapy (p < 0.001). Our study concludes that serum CXCL13 levels decrease in WM patients treated with various regimens and correlate with treatment response. Detecting serum CXCL13 at baseline or after treatment help in predicting prognosis.
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Langerhans cell histiocytosis (LCH) lacks a standardized first-line therapy. This single-center, phase 2 prospective study (NCT04121819) enrolled 61 newly diagnosed adult LCH patients with multisystem or multifocal single system disease from October 2019 to June 2022. Subcutaneous cytarabine (100 mg/m2 for 5 days) was administered in 35-day cycles for 12 total cycles. The primary endpoint was event-free survival (EFS). The median age was 33 years (range 18-66). Twelve patients (19.7%) had liver involvement, of which 2 also had spleen involvement. Among 43 patients undergoing next-generation sequencing, BRAF alterations (44.2%) were most frequent, followed by TP53 (16.3%), MAP2K1 (14.0%) and IDH2 (11.6%). MAPK pathway alterations occurred in 28 patients (65.1%). The overall response rate was 93.4%, with 20 (32.7%) achieving complete response and 37 (60.7%) partial response. After a median 30 months follow-up, 21 (34.4%) relapsed without deaths. Estimated 3-year OS and EFS were 100.0% and 58.5%, respectively. Multivariate analysis identified ≥3 involved organs (P = 0.007; HR 3.937, 95% CI: 1.456-9.804) and baseline lung involvement (P = 0.028; HR 2.976, 95% CI: 1.126-7.874) as poor prognostic factors for EFS. The most common grade 3-4 toxicities were neutropenia (27.9%), thrombocytopenia (1.6%), and nausea (1.6%). In conclusion, cytarabine monotherapy is an effective and safe regimen for newly diagnosed adults, while baseline lung or ≥3 involved organs confers poor prognosis.
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Citarabina , Histiocitosis de Células de Langerhans , Adulto , Humanos , Adolescente , Adulto Joven , Persona de Mediana Edad , Anciano , Estudios Prospectivos , Histiocitosis de Células de Langerhans/tratamiento farmacológico , Histiocitosis de Células de Langerhans/diagnóstico , Supervivencia sin Enfermedad , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
BACKGROUND: Langerhans cell histiocytosis (LCH) is a rare highly heterogeneous histiocytosis, which can be divided into single system and multiple system disease according to site of involvement. There is a paucity of studies examining unifocal LCH in adults in the molecular era. RESULTS: We retrospectively analysed records from 70 patients with unifocal LCH. The median age at diagnosis was 36 years (18-69). The most common organ involved was the bone (70.0%), followed by pituitary gland (7.1%). Target gene sequencing of lesion tissues was performed on 32 of the 70 patients. MAPK/PI3K pathway alterations were observed in 78.1% of the patients; the most common mutations included BRAFV600E (28.1%), MAP2K1 (18.8%) and PIK3CA (9.4%). After a median follow-up time of 39.4 months (0.7-211.8), 10 (14.3%) patients developed disease progression, of whom 4 had local recurrence, 2 progressed to single-system multifocal and 4 progressed to multiple system LCH. The 3-year progression-free survival (PFS) was 81.9%. Univariate analysis showed that age < 30 years at diagnosis was associated with worse 3-year PFS (52.2% vs. 97.0%, p = 0.005). The 3-year overall survival was 100%. CONCLUSIONS: In our large cohort of adults with unifocal LCH, we found that prognosis of unifocal LCH in adults was very good, and age < 30 years at diagnosis was associated with increased relapse risk.
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Histiocitosis de Células de Langerhans , Fosfatidilinositol 3-Quinasas , Humanos , Adulto , Adolescente , Adulto Joven , Persona de Mediana Edad , Anciano , Estudios Retrospectivos , Histiocitosis de Células de Langerhans/genética , Progresión de la Enfermedad , GenómicaRESUMEN
Erdheim-Chester disease (ECD) is a rare and probably fatal multisystemic non-Langerhans cell histiocytosis (LCH). To comprehensively investigate the clinical features, genomic analysis, treatments, and prognostic factors of ECD, we retrospectively analyzed the clinical data of 75 ECD patients and 10 mixed LCH and ECD patients in our center. The median age at diagnosis was 46 years (range, 5-70). ECD patients were older at diagnosis (p = 0.006) and had more cardiac involvement (p = 0.011) as well as vascular (p = 0.031) involvement compared to mixed LCH and ECD patients. 64.8% of ECD patients and 87.5% of mixed LCH and ECD patients carried BRAFV600E mutation. The BRAFV600E mutation correlated with a greater number of affected organs (p = 0.030) and was associated with lung involvement (p = 0.033) as well as pleural involvement (p = 0.002). The median follow-up time was 38 months (range, 1-174). The estimated 5-year progression-free survival (PFS) and overall survival (OS) were 48.9% and 84.7%, respectively. In a multivariate analysis, right atrial pseudotumor (p = 0.013) and pancreatic involvement (p = 0.005) predicted worse OS, while pleural (p = 0.042) and central nervous system (CNS) involvement (p = 0.043) predicted worse PFS. Our study described the clinical spectrum of ECD and mixed LCH and ECD, while also revealed the prognostic value of right atrial pseudotumor and pancreatic, pleural, and CNS involvement for worse survival.
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Fibrilación Atrial , Enfermedad de Erdheim-Chester , Histiocitosis de Células de Langerhans , Humanos , Preescolar , Niño , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad , Anciano , Enfermedad de Erdheim-Chester/genética , Enfermedad de Erdheim-Chester/complicaciones , Pronóstico , Estudios Retrospectivos , Proteínas Proto-Oncogénicas B-raf/genética , Fibrilación Atrial/complicaciones , Histiocitosis de Células de Langerhans/patologíaRESUMEN
BACKGROUND: Hepatitis B virus (HBV) infection is a rare etiology of cryoglobulinemia, and its clinical characteristics, virological features and treatment are poorly understood. METHODS: This retrospective study enrolled 23 patients with HBV-related cryoglobulinemia from 497 cryoglobulinemia patients at Peking Union Medical College Hospital between January 2015 and February 2023. We analyzed the clinical characteristics, virological features and management of patients with HBV-related cryoglobulinemia. RESULTS: The 23 patients (13 males; median age 48 years) were all mixed cryoglobulinemia and serological HBsAg positive, while 15 patients exhibited HBV-DNA replication. The presence of HBsAg in cryoglobulins was evaluated in 7 patients, all of whom were positive. The most commonly involved organs were kidneys (69.6%), skin (65.2%), peripheral nerves (21.7%), joints (8.7%), gastrointestinal tract (4.3%), and cardiac (4.3%). Eight patients received antiviral therapy with nucleot (s)ide analogues (NAs) alone, 12 patients received NA- and corticosteroid-based regimens, and 3 patients received NA- and rituximab-based regimens based on the severity of clinical symptoms. After a median follow-up of 44 months, four patients died, and one patient was lost to follow-up. All remaining patients (n = 18) achieved clinical remission, and HBV-DNA replication was not detected in 16 out of 18 patients. There was no HBV reactivation in patients treated with rituximab. The three-year overall survival and progression-free survival were 87.0% and 80.3%, respectively. CONCLUSIONS: HBV-related cryoglobulinemia patients should be treated with antiviral therapy. Corticosteroids and rituximab are effective for severe cases, but patients need to be closely monitored for therapy-related infection.
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Mieloma Múltiple , Humanos , Bortezomib/uso terapéutico , Estudios Prospectivos , Ciclofosfamida/efectos adversos , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/diagnóstico , Dexametasona/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
Waldenström's macroglobulinemia (WM) is an uncommon lymphoproliferative disorder, and the precise cellular landscape and the mechanisms of progression from IgM monoclonal gammopathy of undetermined significance (MGUS) to WM remain unclear. We performed single-cell RNA sequencing of CD19 + and CD19-CD38 + cells from healthy donors, IgM MGUS and WM patients. We found that samples from IgM MGUS and WM patients were composed of fewer early B-cell subsets and more T cells and NK cells than those from healthy controls. Compared with those of IgM MGUS patients, mature B cells of WM patients showed upregulation of HES1, GADD45B, NEAT1, DUSP22, RGS1, RGS16, and PIM1. We also identified a subpopulation of CD3 + CD19 + cells in IgM MGUS and WM patients, and trajectory analysis suggested that this subpopulation might be a stem cell-like subset. Further targeted gene sequencing of CD3 + CD19 + and CD3-CD19 + cells proved that MYD88 might be the early events in tumorigenesis according to variant allele fraction analysis. Additional subclonal hits such as CXCR4 and MAP2K1 mutations could be acquired during tumor progression. CXCL signaling, CCL signaling, IL2 signaling and TGFß signaling pathways were involved in communication between CD3 + CD19 + cells and other immune cells. Our findings reveal the composition of CD38 + immune microenvironment together with B cells and plasma cells in IgM MGUS and WM patients, and provide comprehensive insights into mechanisms of progression from IgM MGUS to WM. The rare CD3 + CD19 + cells might be cells with "stemness" feature.
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OBJECTIVE: To explore the regulatory effect of chidamide on CD8+ T cells in T-cell acute lymphoblastic leukemia. METHODS: The expression levels of CXCL9 and CXCL3 mRNA in Jurkat cells, lymphocytes treated with chidamide and lymphocytes co-cultured with chidamide-treated Jurkat cells were detected by fluorescence quantitative PCR. The proportion of CD8+ T cells in lymphocytes treated with chidamide and lymphocytes co-cultured with chidamide-treated Jurkat cells was determined by flow cytometry. RESULTS: Chidamide upregulated CXCL9 mRNA expression in Jurkat cell line in a dose-dependent manner (r=0.950). The mRNA expression of CXCL9 in chidamide 5 µmol/L group was 164 times higher than that in control group. Chidamide upregulated CXCL9 mRNA expression in lymphocytes, but the up-regulated level was significantly lower than that in Jurkat cell line treated with the same concentration of chidamide. Co-culture with chidamide treated Jurkat cells upregulated the proportion of CD8+ T cells in lymphocytes. CONCLUSION: In T-cell acute lymphoblastic leukemia, chidamide may increase the concentration of CXCL9 in the tumor microenvironment by up-regulating the expression of CXCL9 in tumor cells, leading to an increase in the number of CD8+ T cells.
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Linfocitos T CD8-positivos , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Humanos , Aminopiridinas/farmacología , Células Jurkat , ARN Mensajero , Línea Celular Tumoral , Apoptosis , Microambiente TumoralRESUMEN
OBJECTIVE: To explore the role of chidamide in the regulatory mechanism of PD-1/PD-L1 immune escape signaling pathway in peripheral T-cell lymphoma. METHODS: Jurkat cell line was treated with different concentrations of chidamide. The changes of PD-L1 and JAK/STAT pathway gene mRNA expression and PD-L1 protein expression on cell surface were detected by fluorescence quantitative PCR and flow cytometry after treatment. RESULTS: Chidamide upregulated PD-L1 mRNA expression in Jurkat cell line in a dose-dependent manner (r=0.989). The mRNA expression of PD-L1 in 5.0 µmol/L group was 15.4 times higher than that in the control group. The proportion of PD-L1 positive cells in Jurkat cell line was less than 0.5%. Chidamide upregulated PD-L1 protein expression on Jurkat cell surface. Chidamide upregulated the mRNA expression of JAK2, STAT1 and STAT3 in Jurkat cell line. The level of up-regulation was obvious in high concentration group (5.0 µmol/L group). Meanwhile, the mRNA expression of SOCS1 and SOCS3, the negative regulatory genes upstream of the JAK/STA T pathway, were up-regulated. CONCLUSION: In peripheral T-cell lymphoma, chidamide may up-regulate the expression of cell surface PD-L1 and induce T-cell chemokines by upregulation of STAT1 expression, thus improving the reaction rate of PD-1 monoclonal antibody and T-cell toxicity.