Lymphoma-associated Hemophagocytic Syndrome Research Articles

Clinical Features of Non-Hodgkin Lymphoma-Associated Hemophagocytic Syndrome: a Retrospective Study.

This study aims to improve the understanding of lymphoma-associated hemophagocytic syndrome, and find effective methods to identify and manage this fatal disease. Patients diagnosed with non-Hodgkin lymphoma-associated hemophagocytic syndrome from January 2008 to December 2022 in our center were included. Univariate and multivariate analyses were also conducted using the Cox proportional hazards model. Among 26 patients, 22 patients were diagnosed with T/NK cell lymphoma, while 4 patients were diagnosed with diffuse large B cell lymphoma. A total of 16 patients died with a median follow-up of 71 (26, 236) days. Compared with B cell lymphoma-associated hemophagocytic syndrome patients, T/NK cell lymphoma patients are younger, have lower platelet count, fibrinogen concentration, and serum albumin, have higher blood β2-mi-croglobulin levels and ferritin, are more likely to be infected with Epstein-Barr virus, are more inclined have a simultaneously occurrence of lymphoma and hemophagocytic syndrome. In multivariate analysis, fibrinogen, albumin, cholinesterase, uric acid, triglyceride, and ferritin are significantly associated with overall mortality. LAHS is a rare disease with poor prognosis. Early anti-inflammatory treatment combined with anti-lymphoma therapy can improve the overall survival time of patients. Prospective multi-center studies with larger sample sizes and longer follow-up periods are needed to further investigate optimal treatment and prognosis.

Progress in Diagnosis and Treatment of Lymphoma-Associated Hemophagocytic Syndrome

Progress in Diagnosis and Treatment of Lymphoma-Associated Hemophagocytic Syndrome

A novel prognosis-prediction model based on coagulation indicators in secondary hemophagocytic lymphohistiocytosis

Secondary hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disease. In the present retrospective study, we aimed to investigate coagulation disorders and their outcome implications in patients with secondary HLH. We evaluated clinical characteristics and the relationship between coagulation indices and prognosis in HLH patients (n = 141). The information, including clinical symptoms, laboratory indicators, and coagulation indices, was evaluated. Coagulation disorders and bleeding events occurred in 95 (67.4%) and 60 (42.6%) patients, respectively. A coagulation index analysis primarily showed elevated levels of D-Dimer, the international standardized ratio (INR), prothrombin time (PT), activated partial thromboplastin time (APTT), and thrombin time (TT), while the prothrombin activity, fibrinogen levels, and platelet levels were significantly decreased. Dominant disseminated intravascular coagulation (DIC) occurred in 76 patients (53.9%). Patients with lymphoma-associated hemophagocytic syndrome (LAHS) frequently exhibited apparent coagulation disorders. Multivariate analysis revealed that age ≥ 29.5 years, bleeding events, APTT ≥ 47.3 s, fibrinogen ≤ 1.68 g/L, and absolute neutrophil counts (ANC) of ≤ 1.21 × 109/L were independent prognostic factors. We thereby devised a prognostic scoring system and stratified patients into low-risk (0–2 points), intermediate-risk (3–4 points), and high-risk (5–7 points) groups, and the 1-year overall survival rates in the above-mentioned groups were 66.40%, 40.00%, and 2.30%, respectively (P < 0.0001). In conclusion, coagulation dysfunctions and bleeding tendencies were common characteristics in HLH patients. We constructed a novel prognostic score model based on APTT, fibrinogen level, ANC, age, and bleeding events, which had superior prognostic value compared with these markers alone.

Gene Polymorphisms of Patients with Lymphoma-Associated Hemophagocytic Syndrome in Longyan area, Fujian Province

To analyze the gene polymorphisms of patients with lymphoma-associated hemophagocytic syndrome in Longyan area, Fujian province. A total of 125 patients with lymphoma-associated hemophagocytic syndrome in Longyan, Fujian province, admitted to Longyan First Hospital from May 2017 to November 2020 were selected. Peripheral venous blood was collected from all the patients, and the genotypes of perforin 1 (PRF1) and interleukin-10 (IL-10) gene loci were detected by PCR-fluorescence probe method, and the correlation between PRF1 and IL-10 gene polymorphisms and lymphoma-associated hemophagocytic syndrome was analyzed. The mutation frequencies of PRF1 gene loci rs885821 (C>T), rs885822 (C>T), rs1889490 (G>A) in patients with lymphoma-associated hemophagocytic syndrome were 10.40%, 78.8% and 64.4%, respectively. The mutation frequencies of rs1800872 (A>C), rs1800871 (C>T) and rs1800896 (G>A) of IL-10 loci were 56.0%, 45.2% and 77.6%, respectively. PRF1 and IL-10 gene loci were polymorphic in patients with lymphoma-associated hemophagocytic syndrome in Longyan area, Fujian province. Alleles C and G of PRF1 and IL-10 were risk factors, and alleles T and A were protective factors.

Lymphoma-associated Hemophagocytic Syndrome: Case Report of a Natural Killer

Hemophagocytic lymphohistiocytosis (HLH) is a rare and life-threatening clinical syndrome, caused by an unregulated activation of cytotoxic T cells and macrophages. In adult patients, it is generally triggered by an underlying disease, with a significant proportion of cases being associated with malignancies (mainly lymphoma). The triad of fever, cytopenias, and hepatosplenomegaly is usually present, but, in severe cases, most patients will have a syndrome resembling sepsis and multiple organ failure, requiring admission into a critical care unit. We present a case of a 33-year-old healthy male patient, who presented with fever, malaise, and lower gastrointestinal bleeding. Upon admission, he was hypotensive and had elevated inflammatory markers, pancytopenia, and liver damage. Due to worsening shock of presumed septic and hemorrhagic origin, he was admitted to our ICU. An extensive diagnostic work-up was performed, including a bone marrow aspirate that revealed active hemophagocytosis and pleural effusion analysis that revealed abundant NK-Cells, phenotypically compatible with aggressive NK-Cell lymphoma. Anti-inflammatory and neoplastic treatments were immediately initiated, with a partial and transient response. Nonetheless, he developed refractory shock and medullary aplasia and died twenty days after being admitted. Although it is uncommon in adults, HLH is an important sepsis differential diagnosis to be aware of because it necessitates specific and timely treatment. Further investigation to determine and treat the possible underlying causes, including occult malignancies, is of paramount importance.

Clinical features and prognostic analysis of lymphoma-associated hemophagocytic syndrome: A report of 139 cases.

Lymphoma-associated hemophagocytic syndrome (LAHS) is characterized by rapid onset, rapid progression and a poor prognosis, and is easy to misdiagnose. In order to improve the clinical understanding, diagnosis and treatment of LAHS, the clinical characteristics and risk factors of LAHS were discussed by retrospective data analysis in the present study. The clinical characteristics of 324 patients with newly diagnosed hemophagocytic syndrome (HPS) were retrospectively investigated. The patients were divided into two groups: The LAHS group comprising 139 patients with LAHS and the non-LAHS group comprising 185 patients with HPS that was not associated with lymphoma. The clinical features and prognosis of the two groups were compared. Patients in the LAHS group had higher levels of total bilirubin (P=0.005) and indirect bilirubin (P=0.006). In addition, patients in the LAHS group had a higher early mortality rate (50.4 vs. 34.6%; P=0.004), higher recurrence rate (30.2 vs. 15.1%; P=0.001), reduced 5-year overall survival rate (OS; 21.5 vs. 52.4%; P<0.001) and reduced relapse-free survival rate (RFS; 7.7 vs. 48.3%; P<0.001) compared with those in the non-LAHS group. If patients with early mortality in the two groups were excluded, the 5-year OS rates were improved and also significantly different (43.3 vs. 80.2%; P=0.041). The 5-year OS and RFS of patients in the LAHS group who had received chemotherapy were significantly superior compared with those who had not received chemotherapy (P<0.001). Multivariate analysis showed that an activated partial thromboplastin time of >36.0 sec (P=0.020) and serum lactate dehydrogenase level of >1,000 U/l (P=0.045) were independent risk factors for a poor LAHS prognosis. The outcomes of the patients with LAHS were worse than those of those with other types of HPS due to the higher early mortality rate. Therefore, it may be concluded that the reduction of the early mortality rate of patients with LAHS is of great importance.

Lymphoma-associated hemophagocytic syndrome: a retrospective study from a single center

ABSTRACT Lymphoma-associated hemophagocytic syndrome (LAHS) is a rare and life-threatening clinical syndrome with rapidly deteriorating health and high mortality. We retrospectively analyzed clinical features and prognostic factors from 117 patients diagnosed with LAHS. The cumulative incidence rate of LAHS was 4.0% (117/2906). Patients were classified into B-cell LAHS (B-LAHS, n = 22) and T/natural killer (NK)-cell LAHS (T/NK-LAHS, n = 95) groups. Patients with T/NK-LAHS were younger and had lower neutrophil counts and fibrinogen values, higher LDH and transaminase levels, and were more likely to develop hemophagocytic syndrome (HPS) during the clinical course than those with B-LAHS. The median survival time for the entire cohort was 57 days, and for the T/NK-LAHS and B-LAHS groups, it was 52 and 154 days, respectively, after the diagnosis of LAHS. Patients with B-LAHS had superior 1-year OS (p = 0.003, 36.4% versus 14.5%) compared with those with T/NK-LAHS. Prognostic factor analysis revealed that elevated LDH levels (LDH > 1000 IU/L) (p = 0.004), T/NK-cell lineage (p < 0.001) and HPS onset at relapse (p = 0.001) were strongly associated with early death. For patients diagnosed with T/NK-LAHS, in addition to LDH levels and HPS onset status, high EBV-DNA copies (≥4,450 copies/mL) (p = 0.016) were also related to poor prognosis of T/NK-LAHS.

Clinical characteristics and prognosis of lymphoma-associated hemophagocytic syndrome

Subjective To investigate clinical characteristics, treatment, and prognosis of lymphoma-associated hemophagocytic syndrome (LAHS) patients. Methods: The clinical data of patients diagnosed with LAHS from January 2010 to October 2021 in West China Hospital were retrospectively analyzed. Clinical characteristics, treatment, overall response rate (ORR), and overall survival (OS) were investigated. Univariate and multivariate analysis of potential factors were conducted. Results: Of all 94 patients included, 59 were male and 35 were female. The age at hemophagocytic lymphohistiocytosis (HLH) diagnosis was (40.5±17.3) years. Seventy-four cases were T/NK cell lymphoma; 15 were B cell lymphoma; 5 were Hodgkin lymphoma. The age at HLH diagnosis of T/NK cell LAHS patients was (37.9±16.2) years, while that of B cell LAHS patients was (55.9±14.0) years. T/NK cell LAHS patients were significantly younger than B cell LAHS patients (P<0.001). Baseline fibrinogen of T/NK cell LAHS patients was 1.34 (0.86, 2.44) g/L, while that of B cell LAHS patients was 2.20 (1.75, 4.25) g/L. T/NK cell LAHS patients showed significantly lower fibrinogen levels than B cell LAHS patients (P=0.008). Combined treatment of anti-HLH and anti-lymphoma treatment was conducted in 35 patients; anti-HLH treatment was conducted in 31 patients; anti-lymphoma treatment was conducted in 8 patients; glucocorticoid treatment was conducted in 7 patients. ORR was 49.4%, and the median OS was 61 days for overall patients. Patients who received anti-HLH treatment and turned to anti-lymphoma treatment early displayed the best ORR and OS, significantly higher than those of anti-HLH patients (69.0 vs 38.7%, P=0.019, and 192.0 vs 24.5 days, P=0.028, respectively), which were also insignificantly higher than those of anti-lymphoma patients. Extranodal NK/T-cell lymphoma or aggressive natural killer cell leukemia was the risk factor of LAHS prognosis (HR=0.113, 95%CI: 0.018-0.728, P=0.022). Conclusions: Prognosis of LAHS patients is poor. Anti-lymphoma treatment should be initiated as soon as HLH is rapidly controlled.

Epstein-Barr Virus-Positive Lymphoma-Associated Hemophagocytic Syndrome: A Retrospective, Single-Center Study of 51 Patients.

PurposeTo investigate clinical characteristics, management, and prognosis of Epstein-Barr virus (EBV)-positive lymphoma-associated hemophagocytic syndrome (LAHS) patients in real-world practice.MethodsThis was a retrospective, single-center cohort study. EBV-positive LAHS patients diagnosed from January 2010 to December 2021 in our center were enrolled. Clinical characteristics, treatment, overall response rate (ORR), and overall survival (OS) were investigated. Univariate and multivariate analysis of potential factors were conducted.ResultsOf the 51 patients, 44 were T/NK cell lymphoma; five were B cell lymphoma; two were Hodgkin lymphoma. EBV-positive T/NK cell LAHS patients were significantly younger and showed lower fibrinogen levels and C-reactive protein levels than EBV-positive B cell LAHS patients (P=0.033, P=0.000, and P=0.004, respectively). Combined treatment of anti-hemophagocytic lymphohistiocytosis (HLH) and anti-lymphoma treatment was conducted in 24 patients; anti-HLH treatment was conducted in 18 patients; anti-lymphoma treatment was conducted in three patients; glucocorticoid treatment was conducted in one patient. ORR was 47.8%, and the median OS was 61 (95% confidence interval 47.9-74.1) days for overall patients. Patients who received anti-HLH treatment and turned to anti-lymphoma treatment early displayed higher ORR and OS than those of anti-HLH patients (P=0.103, and P=0.003, respectively). Elevated alanine aminotransferase level was the independent risk factor of EBV-positive LAHS prognosis.ConclusionsPrognosis of EBV-positive LAHS patients was poor. Anti-lymphoma treatment should be initiated as soon as HLH was rapidly controlled.

Clinical Features and Prognostic Risk Prediction of Non-Hodgkin Lymphoma-Associated Hemophagocytic Syndrome.

BackgroundMalignancies, especially lymphoma, are a common cause of adult secondary HLH and an independent risk factor for the prognosis of HLH patients.MethodsPatients with lymphoma alone or concurrent lymphoma-associated phagocytic syndrome (LAHS) admitted to Beijing Friendship Hospital from January 2016 to December 2020 were enrolled in this study.FindingsThere were 348 lymphoma patients, 104 concurrent with LAHS. The pathological type of lymphoma without LAHS was dominated by B-cell lymphoma, while those with LAHS were T/NK-cell lymphoma predominantly (p < 0.001). Superficial lymph node enlargement was more significant in patients with B-LAHS (p = 0.006), while patients with T/NK-LAHS had lower neutrophil counts (p = 0.005), lower fibrinogen levels (p < 0.001), higher transaminase levels, and more co-infection with EBV (p < 0.001). B-LAHS had significantly higher IL-10 levels than with T/NK-LAHS (p = 0.006), and NK/T-LAHS had significantly higher IP-10 levels than other T-LAHS (p = 0.008). Age, platelet count, IPI, history of NK/T lymphoma, and no remission of HLH were independent risk factors for prognosis in patients with non-Hodgkin lymphoma-associated phagocytic syndrome (NHL-LAHS), and a prognostic risk score model for NHL-LAHS was developed.ConclusionLAHS is a life-threatening disease with a poor prognosis. The prognostic risk score model for NHL-LAHS with a good fit and validation for the test has value for clinical application.

Clinical Features and Prognosis of B-cell Lymphoma-associated Hemophagocytic Syndrome: A Retrospective Single Center Study

PurposeCurrent knowledge of Lymphoma Associated Hemophagocytic Syndrome (LAHS) mainly relies on T/NK-cell LAHS cases, while B-cell lymphoma associated hemophagocytic syndrome (B-LAHS) variant are rare. We aimed at identifying a single-center cohort of patients with B-LAHS to shed light on relevant clinical and laboratory features, diagnosis, treatment and prognosis.MethodsThe clinical data of 36 patients with B-LAHS, admitted to the First Affiliated Hospital of Zhengzhou University in the time period ranging from January 2011 to May 2021 were analyzed retrospectively. Survival analysis was performed using the Kaplan–Meier method and groups were compared using the log-rank test.ResultsThe 36 patients included 17 males and 19 females with a median age of 53.5 years (range: 28–74 years). Among these, the most common histopathological type diagnosed was diffuse large B-cell lymphoma (69%). The initial symptoms included fever (100%), splenomegaly (97%), multicavity effusion (83%), abnormal liver function (58%), and jaundice (44%). Patients treated with dexamethasone only seemed to have an inferior prognosis compared to those treated with etoposide-involving regimens (χ2 = 20.037, p < 0.001). Patients received based on the Hemophagocytic Lymphohistocytosis (HLH)-2004 protocol combined with multidrug chemotherapy had a significantly improved Overall Survival (OS) compared to patients who only underwent treatment according to the HLH-2004 regimen (χ2 = 30.744, p < 0.001). The 2-week mortality rate was 13.9% and the 1-year OS rate was 19.4%. Compared with the median survival time of 34 patients without Epstein-Barr virus (EBV) infection, 97 days (range: 24–322 days), two patients with EBV infection died within 8 days.ConclusionB-LAHS is relatively rare and has a high early mortality rate, mostly in middle-aged and elderly patients. The HLH-2004 regimen combined with multidrug chemotherapy is a reasonable choice for the treatment of B-LAHS, and EBV infection may be used as a reference indicator of a poor prognosis.

T-cell lymphoma-associated hemophagocytic syndrome in an American Pit Bull Terrier.

A 3-y-old, intact female, American Pit Bull Terrier was presented because of acute onset of anorexia and a large subcutaneous submandibular mass that had been present for 3 wk. The submandibular mass, 2 engorged black-legged ticks on the dorsum of the neck, pyrexia, and icterus were seen on physical examination. Abnormal laboratory test results included a positive Anaplasma antibody test, severe thrombocytopenia, mild nonregenerative anemia, hyperbilirubinemia, and elevated liver enzyme activities. Cytology of the mass was interpreted as marked septic purulent inflammation with acute hemorrhage. Treatment with doxycycline for anaplasmosis was unsuccessful, and the patient died at an emergency follow-up visit 2 d after the initial presentation. Autopsy and histopathology revealed widespread metastasis of a presumptive histiocytic neoplasm with associated hemophagocytosis seen in lymph nodes (LNs), liver, and spleen. Immunohistochemistry yielded a definitive diagnosis of a CD3+/CD18+ T-cell lymphoma. In this case of canine lymphoma-associated hemophagocytic syndrome, hemophagocytes were observed as >2% of neoplastic cells in the liver, spleen, and LN histologically, a scarce or unreported finding, to our knowledge. The prognosis was grave, with a short survival time after the onset of clinical signs.

Ruxolitinib Combined with Dexamethasone in Adult Patients with Secondary HLH：a Single-Centre Pilot Trial

▪BackgroundHemophagocytic lymphohistiocytosis (HLH) is a cytokine-driven inflammatory syndrome associated with hereditary or acquired immune-dysregulation. The frontline therapy for secondary HLH in adult patients is HLH-1994 regimen, however overall survival of these patients remains suboptimal. Janus family kinases JAK1 and JAK2 are hallmarks of the final common pathway in HLH, and ruxolitinib (an oral JAK inhibitor) has shown favorable efficacy and safety in murine models and clinical trials. Recently, Lauren K. Meyer et al demonstrate that hypercytokinemia of HLH reduces the apoptotic potential of CD8 T cells leading to relative dexamethasone resistance, and this apoptotic potential is restored both in vitro and vivo when exposure to ruxolitinib. This finding provide rationale for combining dexamethasone and ruxolitinib to enhance the lymphotoxic effects of dexamethasone and thus improve the outcomes for patients with HLH. We were very interested in this finding and conducted this pilot trial in adult patients with secondary HLH.MethodsWe managed 8 newly diagnosed HLH patients with ruxolitinib combined with dexamethasone or methylprednisolone from April 1, 2021 to May 31, 2021 in the First Affiliated Hospital of Medical School of Zhejiang University. All patients fulfilled at least five of the eight HLH-2004 diagnostic criteria and the etiology was not identified at the time. The regimen in detail was ruxolitinib 15mg po. bid d1-56, dexamethasone 10mg/m 2 d1-14, 5mg/ m 2 d15-28, 2.5 mg/m 2 d29-42, 1.25mg/m 2 d43-49, reduce the dosage until withdrawal d50-56 (For patients with liver insufficiency, dexamethasone is replaced with the same equivalent of methylprednisolone). Once the patient's primary cause had been identified, we wound begin primary disease treatment immediately.ResultsEight newly diagnosed HLH patients without previous treatment were enrolled in this study with a median follow-up of 102 (2-122) days, including 5 cases of lymphoma-associated HLH, one case of bacterial infections-associated HLH, and 2 cases of unknown etiology. The overall response rate at the end of HLH treatment was 87.5% (7/8), with 50% (4/8) in complete response (CR), 37.5% (3/8) in partial response (PR), and 12.5% (1/8) in no response. Among the patients achieving CR, 100% (4/4) maintained CR condition for＞2 months. 2-month overall survival was 75% (6/8), one patient was dead because of lymphoma associated HLH progression, another patient was dead because of bronchiectasis with massive hemoptysis after the HLH was under control. For the lymphoma-associated HLH subgroup, 4 of 5 patients responded to ruxolitinib combined with dexamethasone, three patients successfully bridged to chemotherapy after diagnosis of lymphoma; One patient defused to chemotherapy because she was 77 years old and had severe bronchiectasis; the patient with NR was dead in 2 days due to the rapid progression of disease. No treatment-related deaths were observed.ConclusionsIn our trial, ruxolitinib combined with dexamethasone regimen initially demonstrated favorable efficacy in newly diagnosed adult patients with secondary HLH. Especially for patients with lymphoma-associated hemophagocytic syndrome, it is an efficient and safe bridging therapy while waiting for pathological diagnosis. This novel treaiment is promising, and should be evaluated in larger sample size studies. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

How to Identify Patients at High Risk of Developing Nasal-Type, Extranodal Nature Killer/T-Cell Lymphoma-Associated Hemophagocytic Syndrome.

Nasal-type, extranodal nature killer (NK)/T-cell lymphoma-associated hemophagocytic syndrome (NK/T-LAHS) is a rare and life-threatening disease, requiring investigation of risk stratification. We conducted a retrospective study and proposed nomograms to predict NK/T-LAHS. The discriminative ability and calibration of the nomograms for prediction were tested using C statistics and calibration plots. We analyzed 533 patients with extranodal NK/T-cell lymphoma (ENKTL), out of which 71 were diagnosed with hemophagocytic syndrome (HPS), with a cumulative incidence of 13.3%. Significant difference for 2-year survival was found between patients with and without HPS (14.7% vs. 77.5%). Analyses showed that Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥2, B symptoms, and bone marrow (BM) invasion were significantly associated with NK/T-LAHS. We used these data as the basis to establish a nomogram of risk index for ENKTL (RINK). In 335 patients with available data for Epstein-Barr virus DNA (EBV-DNA), we found high viral copies (≥4,450 copies/ml) were correlated with NK/T-LAHS. When these data were added to RINK, we developed another nomogram that included EBV-DNA data (RINK-E). The nomograms displayed good accuracy in predicting NK/T-LAHS with a C-statistics of 0.919 for RINK and a C-statistics of 0.946 for RINK-E, respectively. The calibration chart also showed an excellent consistency between the predicted and observed probabilities. The proposed nomograms provided individualized risk estimate of HPS in patients with ENKTL.

Clinical Features and Prognostic Risk Prediction of Non-Hodgkin Lymphoma-Associated Hemophagocytic Syndrome

Background: Malignancies, especially lymphoma, are a common cause of adult secondary HLH and an independent risk factor for the prognosis of HLH patients. Methods: Patients with lymphoma or lymphoma-associated phagocytic syndrome (LAHS) admitted to Beijing Friendship Hospital from January 2016 to December 2020 were enrolled in this study. Findings: In total, there were 348 lymphoma patients, 104 with LAHS and 244 without LAHS. The pathological type of non-LAHS was dominated by B-cell lymphoma, while LAHS was T/NK-cell lymphoma predominantly (p <0.001). Superficial lymph node enlargement was more significant in patients with B-LAHS compared with T/NK-LAHS (p=0.006), while patients with T/NK-LAHS had lower neutrophil counts (p=0.005), lower fibrinogen levels (p <0.001), higher transaminase levels (p <0.001), and were more likely to have co-infection with EBV (p <0.001). B-LAHS had significantly higher IL-10 levels than with T/NK-LAHS (p=0.006), and NK/T-LAHS had significantly higher IP-10 levels than other T-LAHS (p=0.008). Age, platelets count, IPI, history of NK/T lymphoma and no remission of HLH were independent risk factors for poor prognosis in patients with non-Hodgkin lymphoma associated phagocytic syndrome (NHL-LAHS), and a prognostic risk score model for NHL-LAHS was developed. Interpretation: LAHS is a life-threatening disease with poor prognosis. The prognostic risk score model for NHL-LAHS developed with a good fit and good validation for test has value for clinical application. Funding: Beijing Municipal Administration of Hospital Clinical Medicine Development of Special Funding Support (XMLX201823); National Natural Science Foundation of China (81871633); Beijing Natural Science Foundation (7181003); Beijing Municipal Administration of Hospitals’ Ascent Plan (DFL20180101). Declaration of Interest: None to declare. Ethical Approval: It was approved by the Ethics Committee at Beijing Friendship Hospital

The diagnostic value of flow cytometry in patients with lymphoma associated hemophagocytic syndrome

Objective: To evaluate the reliability of flow cytometry (FCM) for diagnosing lymphoma associated hemophagocytic syndrome (LAHS). Method: The clinical data in 57 patients with hemophagocytic lymphohistiocytosis (HLH)were retrospective analyzed at Peking University Shenzhen Hospital from July 2010 to July 2019. All patients were performed bone marrow FCM and bone marrow pathological examination before final diagnoses were made. The golden diagnosis criterion was based on clinical, biochemical and histopathological evidence, which was regarded as the standard to evaluate the sensitivity and specificity of FCM analysis in diagnosing LAHS. Results: Among 57 cases, 36 cases were eventually diagnosed with LAHS, including 15 B-cell lymphoma(14 diffuse large B-cell lymphoma, 1 B-cell lymphoma with reactive T-cell hyperplasia), 13 aggressive NK/T cell lymphoma/leukemia, 2 cases of gamma-delta T-cell lymphoma, 4 angioimmunoblastic T-cell lymphoma, 1 enteropathy-associated peripheral T-cell lymphoma and 1 anaplastic T-cell lymphoma. Lymphoma cells in bone marrow were detected in all patients by FCM except one ENTCL patient. The sensitivity and the specificity of FCM in LASH compared to bone marrow biopsy were 97.2%(P=0.014)and 90.5%(P=0.488) respectively. In the other 21 non-LAHS patients, T cell receptor Vβ (TCRVβ) rearrangement was detected in 2 patients with Epstein-Barr virus (EBV) associated primary HLH. Conclusions: FCM effectively detects lymphoma cells in bone marrow of lymphoma patients with LHL, suggesting that FCM could be an important indicator for the diagnosis of LAHS. FCM also has the advantage in differentiating LAHS from other HLH.

Profiling and bioinformatics analyses reveal differential circular RNA expression in NK/T-cell lymphoma-associated hemophagocytic syndrome.

Circular RNAs (circRNAs) may be potential biomarkers or therapeutic targets of hemophagocytic syndrome (HPS) due to their high stability, covalently closed structure and implicated roles in gene regulation. The aim of the present study was to determine and characterize the circRNAs from natural killer (NK)/T-cell lymphoma-associated hemophagocytic syndrome (NK/T-LAHS). CircRNA in NK/T-LAHS and healthy control patient serum were assessed using next-generation sequencing (NGS). One hundred and forty-three differentially expressed circRNAs of which 114 were up-regulated and 29 were down-regulated in NK/T-LAHS patients were identified. Next, Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses to explore the roles of these circRNAs were utilized, and a microRNA (miRNA) target gene prediction software to predict the interaction of circRNAs and miRNAs was used. Moreover, five circRNAs were then selected as NK/T-LAHS candidate circRNAs which were related to tumors and contained NK/T-LAHS-related miRNA-binding sites. Using real-time PCR, the significant up-regulation of these five circRNAs in NK/T-LAHS patient serum were verified. Together these results show that circRNAs may serve as valuable diagnostic biomarkers of early NK/T-LAHS, with potential therapeutic targets in disease progression.

Ruxolitinib combined with doxorubicin, etoposide, and dexamethasone for the treatment of the lymphoma-associated hemophagocytic syndrome.

Case reports suggest that ruxolitinib-containing treatment could increase the clinical response rate of patients with hemophagocytic syndrome (HPS). This study aimed to explore the effect of ruxolitinib-containing treatment for patients with lymphoma-associated hemophagocytic syndrome (LAHS). This was a retrospective study of patients with LAHS hospitalized at the First Affiliated Hospital of Guangdong Pharmaceutical University between October 2017 and September 2019. Patients were treated with HLH-94 (etoposide and dexamethasone) or R-DED regimen (ruxolitinib, doxorubicin, etoposide, and dexamethasone). The clinical characteristics, treatment responses, and overall survival (OS) were compared. The patients were divided into the HLH-94 group (n = 34) and the R-DED group (n = 36). Compared with HLH-94, R-DED might effectively improve the clinical manifestations, including fever and splenomegaly in patients with LAHS, and control the systemic cytokine storm. The response rate at 2weeks was 54.8% in the HLH-94 group, which was lower than in the R-DED group (83.3%) (p = 0.011). The OS was significantly prolonged in the R-DED group compared with the HLH-94 group (median, 5 vs. 1.5months, p = 0.003). The multivariable analysis showed that lower IL-10 levels [hazard ratio (HR)] = 1.000, [95% confidence interval (CI)] 1.000-1.000, p = 0.012), R-DED regimen (HR = 0.196, 95% CI 0.084-0.457, p < 0.001), and non-NK/T-cell lymphoma (HR = 0.254, 95% CI 0.102-0.628, p = 0.003) were associated with better OS. The prognosis of patients with LAHS was generally poor. Ruxolitinib can be combined with chemotherapy in HPS. It is feasible, with no early signals of increased toxicity.

Platelet-derived alpha-granules are associated with inflammation in patients with NK/T-cell lymphoma-associated hemophagocytic syndrome

Due to the variable overlap of multiple symptoms, accurate early diagnosis of NK/T-cell lymphoma-associated hemophagocytic syndrome (NK/T-LAHS) is difficult, making the prognosis extremely poor. Hemophagocytic syndrome (HPS) is now diagnosed primarily based on the hemophagocytic lymphohistiocytosis (HLH)-2004 diagnostic criteria, and platelet count is one of the baseline evaluations. However, in our study, the data showed that decreased platelets were not only a clinical feature of HPS but also the key cells that regulate inflammation by releasing α-granules containing upregulated platelet factor 4 (PF4) and downregulated platelet-derived growth factors (PDGFs). Furthermore, we found that angiopoietin-4 (ANG-4), which has significant differential expression, has been less reported, that may affect hematopoiesis and proinflammatory responses and can be used as diagnostic biomarkers together with PF4 and PDGFs.

Evaluation of lymphocyte function by IFN-γ secretion capability assay in the diagnosis of lymphoma-associated hemophagocytic syndrome

Lymphoma-associated hemophagocytic syndrome (LAHS) is a highly life-threatening disease characterized by an uncontrolled immune disorder. Both under-recognition and delayed diagnosis may contribute to aggressive diseases, and a poorer prognosis. Identification of laboratory features specific for LAHS patients may allow for early detection and intervention with improved outcomes. In the present study, 120 lymphoma patients at first diagnosis were recruited and the function of lymphocytes was evaluated by IFN-γ secretion assay at first diagnosis and follow up. During the surveillance period, 20 patients who complicated with hemophagocytic lymphohistiocytosis (HLH) were classified as LAHS group, and 30 patients without infectious diseases during the course of treatment were classified as lymphoma control group. In addition, 20 non-malignant associated HLH patients recruited as HLH control group and 50 healthy control (HC) subjects were also included. The IFN-γ secretion capability of lymphocytes was compared between first diagnosis of lymphoma patients who was complicate with HLH or not in the disease progression. Our results showed that only NK cell activity was decreased in lymphoma control group, but the activities of NK, CD4+ and CD8+ T cells were all significantly decreased at the time of lymphoma diagnosis in those who would progress with HLH. During the course of treatment, lymphocyte function was relatively stable in lymphoma patients but became further decreased when suffering from complication of LAHS. The IFN-γ secretion capability of lymphocytes in LAHS and non-malignant associated HLH patients were all significantly decreased compared with HCs. So the occurrence of HLH was the key factor leading to the impaired activity of lymphocytes. These data suggest that decreased lymphocyte function might be used as a predictor of LAHS, which has critical clinical significance in diagnosis and further understanding the pathogenesis of the disease.