IgG4-related disease (IgG4-RD) is an immune-mediated condition with diagnostic challenges in clinical practice. Sensitive biomarkers are needed for diagnosis, disease activity and disease progression assessment. This study aimed to identify and validate novel serum protein biomarkers of IgG4-RD to improve clinical management. Using Olink proteomics, we analyzed the expression of 92 serum immuno-oncology-related proteins in 11 treatment-naïve IgG4-RD patients and 11 healthy controls (HCs). Candidate biomarkers capable of distinguishing IgG4-RD patients from HC were subsequently validated by enzyme-linked immunosorbent assay in a large independent cohort (n = 220). Diagnostic performance was assessed via 5-fold cross-validation. Correlations between biomarkers and clinical characteristics were also investigated, as well as predictive value for disease relapse. Olink proteomic analysis identified 27 differentially expressed proteins between IgG4-RD and HCs. Through longitudinal follow-up, serum PD1, OX40, CCL19, and MMP12 were significantly upregulated in IgG4-RD patients and closely associated with disease progression, serum IgG4 levels and inflammatory indicators. A comprehensive diagnostic model incorporating the four biomarkers was developed and showed high discriminatory capacity. Elevated baseline PD1 level served as an independent risk factor to predict clinical relapse of IgG4-RD patients. This study identifies four novel serum biomarkers that effectively assist diagnosis, assess disease activity, and one capable for clinical relapse prediction. These findings provide a practical approach for large-scale clinical screening and monitoring of IgG4-RD patients. Furthermore, the identified proteins may offer new insights into disease pathogenesis and represent potential therapeutic targets for this challenging condition.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only curative option for chronic myelomonocytic leukemia (CMML), yet the population benefit from HSCT and the optimal timing of HSCT remain controversial. Current guidelines, largely based on older CPSS criteria and retrospective data, may not reflect recent advances in transplant techniques and molecular stratification systems. This multicenter retrospective analysis included 389 adult CMML patients from 14 Chinese centers (2015-2023), aiming to reassess the survival benefit of allo-HSCT in a large multicenter cohort within the molecular era. Among all patients, 145 (37.3%) underwent allo-HSCT, including 68.3% from haploidentical donors. Risk stratification was performed using CPSS, MDAPS, CPSS-mol, and MMM systems. Landmark analysis set at day 148 (median transplant interval) was used to assess the effect of time-dependent covariates on long-term survival. The entire cohort had 1-, 3-, and 5-year overall survival (OS) rates of 82.7%, 55.5%, and 46.1%, respectively. In patients ≤70 years, allo-HSCT was associated with significantly improved 3-year OS in CPSS intermediate-1 (63.4% vs. 45.4%, p = 0.038) and intermediate-2 (60.2% vs. 38.7%, p = 0.049), MDAPS intermediate-1 (69.5% vs. 47.4%, p = 0.004), intermediate-2 (60.6% vs. 30.4%, p = 0.029), and high-risk (51.4% vs. 45.0%, p = 0.022), CPSS-mol intermediate-2 (59.8% vs. 39.0%, p = 0.046), and MMM high-risk groups (65.5% vs. 10.5%, p < 0.001). Landmark analysis confirmed sustained benefit in these subgroups. Haploidentical HSCT yielded outcomes comparable to matched donors. Multivariable analysis identified HSCT as an independent favorable factor for survival (HR = 0.619, p = 0.031). These findings advocate expanding transplant eligibility through integration of molecular stratification and modern HSCT platforms, particularly haploidentical protocols.

Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) is a major subtype of secondary HLH and is increasingly recognized as a heterogeneous entity. However, the clinical differences between acute EBV-HLH (AEBV-HLH) and chronic active EBV infection-associated HLH (CAEBV-HLH) have not been systematically characterized. We conducted a scoping review of PubMed up to December 7, 2024, and identified 168 eligible articles involving 714 adult patients with EBV-HLH, including 584 with AEBV-HLH and 130 with CAEBV-HLH. Epidemiologic features, clinical manifestations, treatment patterns, and prognostic factors were summarized and compared between the two subgroups. Patients with AEBV-HLH showed more severe HLH-related abnormalities, including lower blood counts and higher ferritin, triglyceride, lactate dehydrogenase, and plasma EBV-DNA levels, whereas central nervous system involvement was more frequent in CAEBV-HLH. The median overall survival was significantly longer in CAEBV-HLH (8.9 months) than AEBV-HLH (2.4 months, P=0.005). In the overall cohort, ferritin >5000 μg/L, soluble CD25 >10000 U/mL, EBV-DNA >10000 copies/mL, and receiving hematopoietic stem cell transplantation (HSCT) were independently associated with better overall survival. In subgroup analyses, soluble CD25, EBV-DNA, and HSCT remained independent predictors in AEBV-HLH, whereas undergoing HSCT was the only independent prognostic factor in CAEBV-HLH. These findings support distinct clinical and prognostic characteristics between AEBV-HLH and CAEBV-HLH, especially in adults. AEBV-HLH is characterized by a more fulminant inflammatory presentation, whereas CAEBV-HLH more often follows a chronic course with greater extensive organ. HSCT appears to be central to long-term outcome in both subtypes.

This study aimed to explore risk factors for symptomatic venous thromboembolism (VTE) in newly diagnosed multiple myeloma (NDMM) patients, with particular focus on the moderating effect of age. A retrospective case-control study was conducted, and clinical and laboratory data from 309 NDMM patients were analyzed. Multivariable logistic regression and interaction analysis were employed to identify independent risk factors and assess age as an effect modifier. Age (OR = 1.060, 95

Purpose:To explore the prognostic value of inflammatory indexes and novel echocardiographic parameters in light-chain myocardial amyloidosis (AL-CA) patients. Methods:We retrospectively collected clinical, laboratory, electrocardiography and echocardiographic parameters of patients. The prognostic value of inflammation indexes and echocardiographic parameters was assessed, and the association of inflammation indexes with cardiac function and the type of light chain (AL) was analyzed. Results:In total, 83 biopsy-proven AL-CA patients were studied (age: 61.42±10.7 years; 68.7% male). The inflammation indexes [PLR (Platelet-to-Lymphocyte ratio), NLR (Neutrophil-to-Lymphocyte ratio), NMLR ((Neutrophil+Monocyte)-to-Lymphocyte ratio), SIRI ((Monocyte × Neutrophil)-to-Lymphocyte ratio), SII ((Platelet × Neutrophil)-to-Lymphocyte ratio), (all P<0.001)] and echocardiographic parameter TRV (Tricuspid Regurgitation Velocity), (P=0.005) were significantly higher in deceased patients compared with survivors. Multivariate COX regression analysis indicated that PLR, TRV, Lymphocyte (LYM) and Left Ventricular Ejection Fraction (LVEF) were independent outcome predictors. The PLR, TRV, and the combined indicator (PLR+TRV) showed great value in predicting short-term prognosis. The likelihood ratio χ2 test showed that PLR and TRV added predictive values to the Mayo04, Mayo12, and Euro15 models. The Spearman correlation analysis demonstrated a positive correlation between the inflammation indexes and New York Heart Association (NYHA) class, Mayo04 stage, Mayo12 stage, and Euro15 stage. Additionally, the NLR (P<0.001), NMLR (P=0.002), SIRI (P=0.029), and SII (P<0.001) were higher in Lambda than in Kappa light-chain patients. Conclusion:Our study revealed that PLR and TRV were valid predictors of short-term survival in AL-CA, and the levels of several inflammation indexes correlated with the severity of cardiac involvement and AL subtype.

Chimeric antigen receptor (CAR) T cell therapy is used to treat hematological malignancy. However, it carries the risk of life‑threatening inflammatory toxicity, including cytokine release syndrome (CRS) and CAR T cell‑associated hemophagocytic lymphohistiocytosis (CARHLH). CRS is a common side effect of CAR T cell therapy, with fever and multiorgan functional impairment as the primary clinical manifestation. CARHLH and CRS have similar clinical manifestations. However, CARHLH is associated with a high mortality rate. CARHLH was previously considered a specific type of CRS, however, it must be promptly differentiated from CRS for treatment initiation, with management differing from that of CRS. The pathogenesis of CARHLH differs from that of CRS. The present review aimed to summarize the pathogenesis, diagnosis and treatment of CARHLH to assist in its early identification and management.

BACKGROUND:Five fulfilled hemophagocytic lymphohistiocytosis (HLH)-2004 criteria, and the HScore are widely used and recommended by international expert consensus to diagnose secondary HLH. Both diagnostic scores have never been validated in heterogeneous patient cohorts of secondary HLH patients. We aimed to systematically optimize and validate diagnostic criteria of secondary HLH using a multicenter approach. METHODS:We developed optimized criteria in our cohort of critically ill patients as a first step. We next validated these new criteria together with the original and modified HLH-2004 criteria as well as the HScore using original data of 13 published cohorts, which were identified by a systematic literature search. RESULTS:The best performing HLH diagnostic criteria sets over all 13 validation cohorts were the original HLH-2004 criteria with a decreased cut-off (cut-off 4, mean sensitivity 86.5%, mean specificity 86.1%), followed by the revised HLH-2004 criteria (natural killer cell activity removed; cut-off 4, mean sensitivity 83.8%, mean specificity 87.8%) and the HScore (cut-off 169, mean sensitivity 82.4%, mean specificity 87.6%). Our newly developed HLH diagnostic criteria showed inferior performance. Ferritin ≥500 µg/L had 94.0% mean sensitivity over all cohorts. CONCLUSIONS:In this first multicenter validation study, four fulfilled HLH-2004 criteria and an HScore of 169 were suitable to diagnose secondary HLH, which will lead to rapid diagnosis and improved patient outcomes. Ferritin proved as a reliable HLH screening marker. Our results should be taken into account in clinical recommendations and in designing new studies.

Haemophagocytic lymphohistiocytosis (HLH) is a serious condition characterised by uncontrolled hyperinflammation. Etoposide has been used as a treatment option in paediatric HLH; however, its effectiveness and the necessity for adult induction therapy remain unclear. This systematic review and meta-analysis aimed to assess the effectiveness of etoposide-based induction therapy in adult HLH, focusing on overall response (OR). A systematic literature search was conducted to identify relevant studies on 11 December 2023, resulting in the inclusion of seven studies in the analysis. The pooled data demonstrated a significant improvement in OR with etoposide-based therapy in adult patients with HLH (1.95, 95% CI 1.51-2.53), compared with non-etoposide-treated patients. Furthermore, overall survival improved with etoposide treatment (1.25, 95% CI 1.03-1.52). Our analysis revealed the potential benefit of etoposide-based therapy in adult patients with HLH. Therefore, etoposide should be considered as a timely and early therapeutic option for the management of adult HLH.

Philadelphia chromosome-negative myeloproliferative neoplasms (Ph-MPNs) are a group of malignant clonal disorders originating from bone marrow hematopoietic stem cells, and pulmonary hypertension (PH) is a serious progressive disease often coexisting with Ph-MPNs, with a prevalence ranging from 5 to 50%. The aim of this study was to analyze the prevalence, clinical characteristics, and associated risk factors of PH in 130 patients with Ph-MPNs, to investigate the impact of PH on patients' prognosis, and to provide a reference for the clinical identification of adverse prognostic factors and early prevention and treatment of PH. One hundred and thirty patients with Ph-MPNs treated at Beijing Anzhen Hospital from January 1, 2020 to December 31, 2024 were included in the study. PH risk was assessed by echocardiography (ECHO), and tricuspid regurgitation velocity (TRV) > 2.8 m/s was used as the criterion for high risk of PH. General information, hematological indices, biochemical indices, gene mutations and echocardiographic data of the patients were collected and statistically analyzed. The overall prevalence of PH among the 130 patients with Ph-MPNs was 15.4%. patients with PMF had the highest prevalence of PH (72.3%), which was significantly higher than that of patients with PV (9.9%) and ET (10.4%) (P < 0.05). patients in the PH high-risk group were older, had lower hemoglobin levels, and had a higher prevalence of splenomegaly and secondary myelofibrosis. the PH high-risk group Patients had a significantly higher mortality rate than the normal risk group (20% vs. 1.81%, P = 0.0004). Multifactorial Cox regression analysis showed that advanced age (HR = 1.029, P = 0.0332) and high risk of PH (HR = 1.034, P = 0.0432) were independent risk factors for patient survival.Logistic regression analysis showed that decreased hemoglobin (OR = 0.9657, P = 0.0062), splenomegaly (OR = 5.105, P = 0.0413) and secondary myelofibrosis (OR = 7.959, P = 0.0321) were independent risk factors for high risk of PH. This study revealed the prevalence of PH, risk factors, and their prognostic implications in patients with Ph-MPNs. It is suggested that regular monitoring of changes in relevant risk factors and vigilance and prevention of PH during the treatment of patients with Ph-MPNs are clinically important to improve the prognosis of patients.

嵌合抗原受体T细胞（CAR-T）疗法为恶性肿瘤的治疗带来了巨大的突破，但也伴随着不容忽视的相关风险。细胞因子释放综合征（CRS）是CAR-T常见的不良反应之一，以发热、多器官功能损害为主要临床表现。CAR-T相关噬血细胞综合征（CAR-HLH）在越来越多的研究中被提及，其临床表现与CRS相似，具有更高的致死性。既往认为CAR-HLH是CRS的一种特殊类型，然而新近研究提示二者发病机制并不相同。本文综述了CAR-HLH发病机制、诊断及治疗进展，为临床CAR-HLH的早期识别与治疗提供参考。

Introduction The treatment of AL amyloidosis primarily relies on anti-plasma cell therapy and supportive care. Daratumumab, bortezomib, cyclophosphamide, and dexamethasone (Dara-CyborD) are the standard first-line treatment and have been shown to achieve a complete hematologic response (CHR) in nearly 60% of patients. An early achievement of a CHR is particularly crucial in patients with advanced organ involvement. International Society of Amyloidosis recommended that treatment change should be considered if less than partial hematological response after two cycles or very good partial response after three cycles. Our retrospective study has shown that the earlier differences between free light chain (dFLC) response can predict CHR. To validate this hypothesis, we are conducting a multi-center prospective observational study in China. Methods This ongoing prospective and observational study enrolled patients who all received Dara-CyborD or daratumumab, bortezomib, dexamethasone and had an evaluable dFLC value of more than 50 mg/L. Active myeloma was excluded. All patients received dFLC examination after one week and once a month until CHR. Results As of April 30, 2025, 43 patients were enrolled. This ensures that all patients have at least three months of follow-up. The median age was 66 years (range, 40-90). The cases in Mayo 2004 stage 1/2/3a/3b were 11/10/18/4, respectively, and the cases in Mayo 2012 stage 1/2/3/4 were 8/11/10/14. 32 (74.4%) patients had cardiac involvement. The median dFLC level at baseline was 219.5 mg/L (range, 53.04-1850.30), and 25 of 43 patients had dFLC levels greater than 180 mg/L. Receiver operating characteristic (ROC) curve analysis was performed to determine the optimal threshold for the dFLC reduction after one week and after cycle one treatment, which best predicts the hematological complete response within six cycles of treatment. ROC curve analyses revealed that an optimum cut-off point of dFLC reduction ≥ 73% after one week is an effective biomarker for CHR (AUC 0.809, sensitivity 0.759, specificity 0.833, p = 0.002). In addition, dFLC reduction after one cycle of ≥ 90.1% also demonstrated excellent predictive performance to predict CHR (AUC 0.876, sensitivity 0.862, specificity 0.833, p < 0.001). Conclusions In conclusion, our study demonstrates that profound dFLC reduction after one week and after one cycle indicates a high likelihood of CHR, potentially allowing for early modifications of therapy in selected patients, i.e., BCMA bispecific antibody and Bcl-2 inhibitor.

Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory syndrome with high mortality rate. The response to induction therapy is an important factor affecting survival. The purpose is to investigate laboratory predictors for induction response in adult patients with HLH, which are convenient, practical, and timeliness. Clinical data from January 2017 to December 2020 was retrospectively analyzed, and 269 patients were included. Patients were divided into remission and non-remission groups according to their induction response, 177 in the remission group, and 92 in the non-remission group. We reviewed general characteristics and analyzed the predictive value of serum ferritin, triglycerides, alanine aminotransferase (ALT), and blood cells before and 1-4 weeks after induction therapy for induction response by univariate analysis, ROC curves, etc. There was a correlation between serum ferritin, ALT, leukocytes, neutrophils, hemoglobin, platelets, and induction response (P < 0.05). Serum ferritin and platelets 1-4 weeks after induction therapy, respectively, might be a good predictor for induction response in adults with HLH, with AUC values close to or greater than 0.7. We established a new clinical model of the ferritin/platelet ratio. The results showed that the ferritin/platelet ratio at 1-4 weeks after induction therapy might be a practical index for predicting induction response, which significantly improved the area under the ROC curve (AUC > 0.75). Patients with a ferritin/platelet ratio > 16.08 at 2 weeks after induction therapy may have a relatively poor induction response. Ferritin/platelet ratio after induction therapy can be a good predictor for induction response in adult patients with HLH.

Lymphoid proliferations and lymphomas arising in post-transplantation are potentially life-threatening complications after solid organ transplant (SOT) and hematopoietic stem cell transplant (HSCT). The lymphoid proliferations and lymphomas arising in post-transplantation originating from different cell lineages in the same patient are highly unusual. Herein, we delineate a case of isolated spinal cord involvement with B cell lymphoid proliferations and lymphomas arising in post-transplantation at 11 months post-transplantation, which was successfully treated with chemotherapy and intrathecal injection. Six months later, the patient again developed lymphoma arising in post-transplantation, presenting with predominant subcutaneous tissue involvement deriving from EBV-positive NK/T cells, and received four courses of chemotherapy. Ultimately, she achieved complete remission (CR). The report further contributes to our new insights into the unusual clinical presentations of lymphoid proliferations and lymphomas arising in post-transplantation.

Objective: This study investigates the effect of signal-to-noise ratio (SNR), frequency, and bandwidth on horizontal sound localization accuracy in normal-hearing young adults. Methods: From August 2022 to December 2022, a total of 20 normal-hearing young adults, including 7 males and 13 females, with an age range of 20 to 35 years and a mean age of 25.4 years, were selected to participate in horizontal azimuth recognition tests under both quiet and noisy conditions. Six narrowband filtered noise stimuli were used with central frequencies (CF) of 250, 2 000, and 4 000 Hz and bandwidths of 1/6 and 1 octave. Continuous broadband white noise was used as the background masker, and the signal-to-noise ratio (SNR) was 0, -3, and -12 dB. The root-mean-square error (RMS error) was used to measure sound localization accuracy, with smaller values indicating higher accuracy. Friedman test was used to compare the effects of SNR and CF on sound localization accuracy, and Wilcoxon signed-rank test was used to compare the impact of the two bandwidths on sound localization accuracy in noise. Results: In a quiet environment, the RMS error in horizontal azimuth in normal-hearing young adults ranged from 4.3 to 8.1 degrees. Sound localization accuracy decreased with decreasing SNR: at 0 dB SNR (range: 5.3-12.9 degrees), the difference from the quiet condition was not significant (P>0.05); however, at -3 dB (range: 7.3-16.8 degrees) and -12 dB SNR (range: 9.4-41.2 degrees), sound localization accuracy significantly decreased compared to the quiet condition (all P<0.01). Under noisy conditions, there were differences in sound localization accuracy among stimuli with different frequencies and bandwidths, with higher frequencies performing the worst, followed by middle frequencies, and lower frequencies performing the best, with significant differences (all P<0.01). Sound localization accuracy for 1/6 octave stimuli was more susceptible to noise interference than 1 octave stimuli (all P<0.01). Conclusions: The ability of normal-hearing young adults to localize sound in the horizontal plane in the presence of noise is influenced by SNR, CF, and bandwidth. Noise with SNRs of ≥-3 dB can lead to decreased accuracy in narrowband sound localization. Higher CF signals and narrower bandwidths are more susceptible to noise interference.

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome characterized by aberrant immunological activity with a dismal prognosis. Epstein-Barr virus-associated HLH (EBV-HLH) is the most common type among adults. Patients with EBV infection to B cells could benefit from rituximab, whereas lethal outcomes may occur in patients with EBV infection to T cells, nature killer (NK) cells, or multilineages. The necessity of allogeneic hematopoietic stem cell transplantation (HSCT) in adult EBV-HLH patients remains controversial. A total of 356 adult EBV-HLH patients entered this study. Eighty-eight received HSCT under medical recommendation. Four received salvage HSCT. The 5-year overall survival (OS) rate of HSCT group was 48.7% (vs 16.2% in non-transplanted patients, p<0.001). There was no difference in OS between patients who received transplantation at first complete remission (CR1) and those at first partial remission (PR1) nor between patients at CR1 and CR2. Patients who received transplantation at PR2 had inferior survival. The rate of reaching CR2 was significantly higher in patients with CR1 than PR1 (p=0.014). Higher sCD25 levels, higher EBV-DNA loads in plasma after HSCT, poorer remission status, more advanced acute graft-versus-host disease (aGVHD), and the absence of localized chronic GVHD (cGVHD) were associated with an inferior prognosis (p<0.05). HSCT improved the survival of adult EBV-HLH significantly. For patients who achieved PR after initial treatment, HSCT was recommended. A wait-and-see strategy could be adopted for patients who achieved CR after initial treatment, but with the risk of failing to achieve a second CR.

BACKGROUND:Epstein-Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis (EBV-HLH) is a common subtype of HLH with heterogeneous clinical presentations from self-limited to death, of which adults are worse than children. OBJECTIVE:To establish predictors of mortality risk in adult EBV-HLH patients for timely and appropriate treatment. METHODS:Patients with confirmed EBV-HLH admitted to Beijing Friendship Hospital from January 2015 to December 2019 were enrolled and statistical analysis of their laboratory test results was performed. RESULTS:Among 246 adult patients with EBV-HLH, the deceased were older (p < 0.05), with fewer blood cells (p < 0.05), poorer renal function (p < 0.01), higher levels of procalcitonin (PCT) (p < 0.01), as well as soluble interleukin-2 receptor (sCD25) (p < 0.01). The overall median survival time of patients was 135 days, 87 days for patients without transplantation and 294 days with transplantation (p < 0.001). A combined index of sCD25, PCT, and estimated glomerular filtration rate (eGFR) was obtained to predict prognosis, named the Improved HLH index (IH index), and patients were divided into three groups meeting IH- (i.e. sCD25 ≤ 18,000 pg/mL, PCT ≤ 1.8 ng/mL, eGFR ≥ 90 mL/min/1.73m2), IH1+ (i.e. only sCD25 > 18,000 pg/mL or only eGFR < 90 mL/min/1.73m2), and IH2+ (i.e. the rest), respectively. In patients with the HScore ≥ 169 or meeting HLH-04, those meeting IH2+ had significantly worse prognoses than those who met IH1+ or IH- (p < 0.001). In the group meeting IH + or IH2+, patients who received allo-HSCT had better prognoses than those who did not (p < 0.05), but there was still a significant difference in prognosis among the three groups in transplanted patients (p < 0.001). CONCLUSION:The IH index can early identify adult patients with a poor prognosis of EBV-HLH, initiating timely and appropriate treatment.KEY MESSAGESA combined index of sCD25, PCT, and eGFR was obtained to predict prognosis, named the Improved Hemophagocytic Lymphohistiocytosis index (IH index).IH index can early identify adult patients with a poor prognosis of EBV-HLH, initiating timely and appropriate treatment.

Lymphoma-associated haemophagocytic syndrome (LAHS) is a group of malignant diseases with rapid progression and a high mortality rate. Our study aimed to discover the significance of serum sCD25/ferritin ratio as well as cytokines in assisting the diagnosis of LAHS. We retrospectively analyzed the clinical data of 82 patients with LAHS with hemophagocytic lymphohistiocytosis (HLH) as the first manifestation and divided them into B-LAHS group and T/NK-LAHS group according to lymphoma pathological diagnosis for comparison. And patients with LAHS were divided into responding group, non-responding group according to the assessment of efficacy after receiving DEP/L-DEP induction therapy for 2 weeks to compare possible valuable indicators. Serum sCD25/ferritin ratio and MCP-1 levels were significantly different between B-LAHS and T/NK-LAHS groups (P = 0.001, P = 0.022). An sCD25/ferritin ratio > 7.8 tended to suggest a diagnosis of B-LAHS (AUC = 0.71, 95

Objectives: Chronic active Epstein-Barr virus infection (CAEBV) is a prototype of EBV-associated T-or NKcell lymphoproliferative diseases. It is a disease with poor outcome. Almost all current therapies are ineffective except of allogeneic hematopoietic stem cell transplantation. Methods: We investigated the efficacy and safety of programmed death 1 (PD-1) blockade (Sintilimab), combined with lenalidomide, which is an immunomodulatory drug, in an open-label, single-center, prospective study involving CAEBV patients. PD1 blockade 2mg/kg was given every two weeks by intravenous infusion on day 1, and lenalidomide 5mg (age<18 years)/10mg (age >= 18 years) was given orally once a day on day 1-14. Results: As of Nov 15, 2020, 34 patients were enrolled. As of the Feb 1, 2021 analysis cut-off date, 24 cases completed at least 3 courses and were assessed for efficacy. The overall response rate is 54.2% (13/24, 45.8% complete response; 8.3% partial response). EBV-DNA copies in PBMC decreased significantly (p = 0.002). The proportion of CD8+T cells in lymphocytes increased (p = 0.007). The comparative analysis between response group and non-response group showed the proportion of Effector Memory CD8thorn T cells and cytokines of CTLs activation (IFN-gamma, CD27, CD30, MIG, IP-10) increased significantly in Response-group after treatment. Whole-exome sequencing generated from peripheral blood and saliva samples reveal that Non-Response group had a higher somatic mutational load of copy number variation in background. With a median follow-up time of 17.8 months, 22 of 24 patients were alive with an estimated survival probability of 91.3% at 1 year. All 34 patients were assessed for safety evaluation. The possible drug-related adverse events were reported in 17 (50%) patients. Conclusions: PD-1 blockade combined with lenalidomide was an effective and safe therapy for CAEBV patients. The significant therapeutic effect and the different characteristics between response and nonresponse group, provides a possible predictive value for CAEBV treatment option.